CA2573124A1 - Anti-inflammatory medicaments - Google Patents
Anti-inflammatory medicaments Download PDFInfo
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- CA2573124A1 CA2573124A1 CA002573124A CA2573124A CA2573124A1 CA 2573124 A1 CA2573124 A1 CA 2573124A1 CA 002573124 A CA002573124 A CA 002573124A CA 2573124 A CA2573124 A CA 2573124A CA 2573124 A1 CA2573124 A1 CA 2573124A1
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- kinase
- phenyl
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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Abstract
Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.
Description
ANTI-INFLAMMATORY MEDICAMENTS
BACKGROUND OF THE INVENTION
Related Applications This application is a-continuation-in-part of Application S/N 10/746,460 filed December 24, 2003. This prior application is incorporated by reference herein.
Sequence Listing The following application contains a sequence listing in computer readable format (CRF).
The content the enclosed CRF is hereby incorporated by reference.
Field of the Invention The present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases.
Description of the Prior Art Basic research has recently provided the life sciences community with an unprecedented volume of information on the human genetic code and the proteins that are produced by it. In 2001, the complete sequence of the human genome was reported (Lander, E.S. et al.
Initial sequencing and analysis of the human genome. Nature (2001) 409:860; Venter, J.C. et al. The sequence of the human genome. Science (2001) 291:1304). Increasingly, the global research community is now classifying the 50,000+ proteins that are encoded by this genetic sequence, and more importantly, it is attempting to identify those proteins that are causative of major, under-treated human diseases.
Despite the wealth of information that the human genome and its proteins are providing, particularly in the area of conformational control of protein function, the methodology and strategy by which the pharmaceutical industry sets about to develop small molecule therapeutics has not significantly advanced beyond using native protein active sites for binding to small molecule therapeutic agents. These native active sites are normally used by proteins to perform essential cellular functions by ~inding to and processing natural substrates or tranducing signals from natural ligands. Because these native pockets are used broadly by many other proteins within protein families, drugs which interact with them are often plagued by lack of selectivity and, as a consequence, insufficient therapeutic windows to achieve maximum efficacy.
Side effects and toxicities are revealed in such small molecules, either during preclinical discovery, clinical trials, or later in the marketplace. Side effects and toxicities continue to be a major reason for the high attrition rate seen within the drug development process. For the kinase protein family of proteins, interactions at these native active sites have been recently reviewed:
see J. Dumas, Protein Kinase Inhibitors: Emerging Pharmacophores 1997-2001, Expert Opinion on Therapeutic Patents (2001) 11: 405-429; J. Dumas, Editor, New challenges in Protein Kinase Inhibition, in Current Topics in Medicinal Chemistry (2002) 2: issue 9.
It is known that proteins are flexible, and this flexibility has been reported and utilized with the discovery of the small molecules which bind to alternative, flexible active sites with proteins. For review of this topic, see Teague, Nature Reviews/Drug Discovery, Vol. 2, pp. 527-541 (2003). See also, Wu et al., Structure, Vol. 11, pp. 399-410 (2003).
However these reports focus on small molecules which bind only to proteins at the protein natural active sites. Peng et al., Bio. Organic and Medicinal Chemistry Ltrs., Vol. 13, pp. 3693-3699 (2003), and Schindler, et al., Science, Vol. 289, p. 1938 (2000) describe inhibitors of abl kinase.
These inhibitors are identified in WO Publication No. 2002/034727. This class of inhibitors binds to the ATP active site while also binding in a mode that induces movement of the kinase catalytic loop. Pargellis et al., Nature Structural Biology, Vol. 9, p. 268 (2002) reported inhibitors p38 alpha-kinase also disclosed in WO Publication No. 00/43384 and Regan et al., J. Medicinal Chemistry, Vol. 45, pp. 2994-3008 (2002). This class of inhibitors also interacts with the kinase at the ATP active site involving a concomitant movement of the kinase activation loop.
More recently, it has been disclosed that kinases utilize activation loops and kinase domain regulatory pockets to control their state of catalytic activity. This has been recently reviewed (see, e.g., M. Huse and J. Kuriyan, Cell (2002) 109:275).
SUMMARY OF THE INVENTION
The present invention is broadly concerned with new compounds for use in treating anti-inflammatory conditions and methods of treating such conditions.. In more detail, the inventive compounds have the formula ( -D-~E~Y}-Q (IA
) wherein:
BACKGROUND OF THE INVENTION
Related Applications This application is a-continuation-in-part of Application S/N 10/746,460 filed December 24, 2003. This prior application is incorporated by reference herein.
Sequence Listing The following application contains a sequence listing in computer readable format (CRF).
The content the enclosed CRF is hereby incorporated by reference.
Field of the Invention The present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases.
Description of the Prior Art Basic research has recently provided the life sciences community with an unprecedented volume of information on the human genetic code and the proteins that are produced by it. In 2001, the complete sequence of the human genome was reported (Lander, E.S. et al.
Initial sequencing and analysis of the human genome. Nature (2001) 409:860; Venter, J.C. et al. The sequence of the human genome. Science (2001) 291:1304). Increasingly, the global research community is now classifying the 50,000+ proteins that are encoded by this genetic sequence, and more importantly, it is attempting to identify those proteins that are causative of major, under-treated human diseases.
Despite the wealth of information that the human genome and its proteins are providing, particularly in the area of conformational control of protein function, the methodology and strategy by which the pharmaceutical industry sets about to develop small molecule therapeutics has not significantly advanced beyond using native protein active sites for binding to small molecule therapeutic agents. These native active sites are normally used by proteins to perform essential cellular functions by ~inding to and processing natural substrates or tranducing signals from natural ligands. Because these native pockets are used broadly by many other proteins within protein families, drugs which interact with them are often plagued by lack of selectivity and, as a consequence, insufficient therapeutic windows to achieve maximum efficacy.
Side effects and toxicities are revealed in such small molecules, either during preclinical discovery, clinical trials, or later in the marketplace. Side effects and toxicities continue to be a major reason for the high attrition rate seen within the drug development process. For the kinase protein family of proteins, interactions at these native active sites have been recently reviewed:
see J. Dumas, Protein Kinase Inhibitors: Emerging Pharmacophores 1997-2001, Expert Opinion on Therapeutic Patents (2001) 11: 405-429; J. Dumas, Editor, New challenges in Protein Kinase Inhibition, in Current Topics in Medicinal Chemistry (2002) 2: issue 9.
It is known that proteins are flexible, and this flexibility has been reported and utilized with the discovery of the small molecules which bind to alternative, flexible active sites with proteins. For review of this topic, see Teague, Nature Reviews/Drug Discovery, Vol. 2, pp. 527-541 (2003). See also, Wu et al., Structure, Vol. 11, pp. 399-410 (2003).
However these reports focus on small molecules which bind only to proteins at the protein natural active sites. Peng et al., Bio. Organic and Medicinal Chemistry Ltrs., Vol. 13, pp. 3693-3699 (2003), and Schindler, et al., Science, Vol. 289, p. 1938 (2000) describe inhibitors of abl kinase.
These inhibitors are identified in WO Publication No. 2002/034727. This class of inhibitors binds to the ATP active site while also binding in a mode that induces movement of the kinase catalytic loop. Pargellis et al., Nature Structural Biology, Vol. 9, p. 268 (2002) reported inhibitors p38 alpha-kinase also disclosed in WO Publication No. 00/43384 and Regan et al., J. Medicinal Chemistry, Vol. 45, pp. 2994-3008 (2002). This class of inhibitors also interacts with the kinase at the ATP active site involving a concomitant movement of the kinase activation loop.
More recently, it has been disclosed that kinases utilize activation loops and kinase domain regulatory pockets to control their state of catalytic activity. This has been recently reviewed (see, e.g., M. Huse and J. Kuriyan, Cell (2002) 109:275).
SUMMARY OF THE INVENTION
The present invention is broadly concerned with new compounds for use in treating anti-inflammatory conditions and methods of treating such conditions.. In more detail, the inventive compounds have the formula ( -D-~E~Y}-Q (IA
) wherein:
R' is selected from the group consisting of aryls (preferably C6-C18, and more preferably C6 C12) and heteroaryls;
each X and Y is individually selected from the group consisting of -0-, -S-, -NR6-, -NRbSOZ-, -NR6CO-, alkynyls (preferably C,-C,g, and more preferably Ci-C1Z), alkenyls (preferably C,-C18, and more preferably C,-C,Z), alkylenes (preferably C1-C18, and more preferably C,-C12), -O(CH2)h-, and -NR6(CH2)h , where each'h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably C1-C18, and more preferably CX12), -O(CHZ)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic (preferably C6 C18, and more preferably C6 C12), monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, fu.ryl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)Z-;
jis0orl;
mis0orl;
nis0or1;
pis0or1;
q is 0 or 1;
tis0orl;
Q is selected from the group consisting of O NR, S NR, p NR, S\~ R= O N~ _O O~SI~NR=
I
~ ~0- - ~O ~O /~+ N >p /~N/S'O / I N~O
'S õ 'i/N'S ' N\ = ~ \R \R. R, Q-I 0-2 R.
0 R, R p R'' 0 p /p ~S~p R.
R.~ \ R."~ \ R,~ /S\ R. \ /~ / \ /
O NR, I_ NR Z N N Z M N
S 'L/~N~( R.
y/N H
~ ' R "+ 0 p -+ O
Q-7 S Q-8 Q-9 Q-IO Q-ll 0 O O R.' 0 R,\ 0 R. p ~~ . N NH N NH i Rs N R,\ RN
I
\ \ I \ I Rs \ O /N R.
ORs pP, Rs OR, R. p Q-12 Rs Q-15 p OH SH
R, O COH O p /\ O N. HO N W W W ~ W
Rs CO= I
't'Ll H C O CH~ H3C CHs H3C p CHs ORs H3C
H~C , H3C
~ O O O ~O N R. O NvN~3ZR.
p O N/~5 N R4 HN~NiSQZ R~ r S-O )/\ 0OII
N
~ w w l-lk~W \ I/ / / / .
/COZR SOsRs Ir p N n p N\~COZR. R. II
N
SpiN(R.): Rs ~pRs 0 R~ N (Z'R.
OR, aIO' and each R4 group is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), aminoalkyls (preferably C1-C1B, and more preferably C,-C1z), alkoxyalkyls (preferably C,-C,8, and more preferably C,-C,Z), aryls (preferably C6-C18, and more preferably C6 C,2), aralkyls (preferably Cb C,g, and more preferably C6-C12 and preferably C,-C18, and more preferably C,-C,2), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), aryls (preferably C6 C,B, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably C,-C,8, and more preferably C,-C,Z), arylaminos (preferably C6-C18, and more preferably C6-C12), cycloalkylaminos (preferably C1-C18, and more preferably C,-C,Z), heterocyclylaminos, hydroxys, alkoxys (preferably C1-C18, and more preferably C,-C1z), aryloxys (preferably C6 C,B, and more preferably C6-C,Z), alkylthios (preferably C,-C18, and more preferably C,-C,z), arylthios (preferably C6 C,g, and more preferably C6 C12), cyanos, halogens, perfluoroalkyls (preferably C,-CtB, and more preferably C,-C12), alkylcarbonyls (preferably C,-C,S, and more preferably C,-C,Z), and nitros;
each R6 is individually selected from the group consisting of -H, alkyls (preferably C,-C,g, and more preferably C,-C,Z), allyls, and (3-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls (preferably C1-C18, and more preferably C,-C,Z), phenyl, naphthyl, aralkyls (wherein the aryl is preferably C6-C18, and more preferably C6-C12, and wherein alkyl is preferably C,-C8, and more preferably C,-C,Z), heterocyclyls, and heterocyclylalkyls (wherein the alkyl is preferably C1-C18, and more preferably C,-C,Z);
each R9 group is individually selected from, the group consisting of -H, -F, and alkyls (preferably C1-C18, and more preferably C,-C,Z), wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each X and Y is individually selected from the group consisting of -0-, -S-, -NR6-, -NRbSOZ-, -NR6CO-, alkynyls (preferably C,-C,g, and more preferably Ci-C1Z), alkenyls (preferably C,-C18, and more preferably C,-C,Z), alkylenes (preferably C1-C18, and more preferably C,-C12), -O(CH2)h-, and -NR6(CH2)h , where each'h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably C1-C18, and more preferably CX12), -O(CHZ)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic (preferably C6 C18, and more preferably C6 C12), monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, fu.ryl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)Z-;
jis0orl;
mis0orl;
nis0or1;
pis0or1;
q is 0 or 1;
tis0orl;
Q is selected from the group consisting of O NR, S NR, p NR, S\~ R= O N~ _O O~SI~NR=
I
~ ~0- - ~O ~O /~+ N >p /~N/S'O / I N~O
'S õ 'i/N'S ' N\ = ~ \R \R. R, Q-I 0-2 R.
0 R, R p R'' 0 p /p ~S~p R.
R.~ \ R."~ \ R,~ /S\ R. \ /~ / \ /
O NR, I_ NR Z N N Z M N
S 'L/~N~( R.
y/N H
~ ' R "+ 0 p -+ O
Q-7 S Q-8 Q-9 Q-IO Q-ll 0 O O R.' 0 R,\ 0 R. p ~~ . N NH N NH i Rs N R,\ RN
I
\ \ I \ I Rs \ O /N R.
ORs pP, Rs OR, R. p Q-12 Rs Q-15 p OH SH
R, O COH O p /\ O N. HO N W W W ~ W
Rs CO= I
't'Ll H C O CH~ H3C CHs H3C p CHs ORs H3C
H~C , H3C
~ O O O ~O N R. O NvN~3ZR.
p O N/~5 N R4 HN~NiSQZ R~ r S-O )/\ 0OII
N
~ w w l-lk~W \ I/ / / / .
/COZR SOsRs Ir p N n p N\~COZR. R. II
N
SpiN(R.): Rs ~pRs 0 R~ N (Z'R.
OR, aIO' and each R4 group is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), aminoalkyls (preferably C1-C1B, and more preferably C,-C1z), alkoxyalkyls (preferably C,-C,8, and more preferably C,-C,Z), aryls (preferably C6-C18, and more preferably C6 C,2), aralkyls (preferably Cb C,g, and more preferably C6-C12 and preferably C,-C18, and more preferably C,-C,2), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), aryls (preferably C6 C,B, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably C,-C,8, and more preferably C,-C,Z), arylaminos (preferably C6-C18, and more preferably C6-C12), cycloalkylaminos (preferably C1-C18, and more preferably C,-C,Z), heterocyclylaminos, hydroxys, alkoxys (preferably C1-C18, and more preferably C,-C1z), aryloxys (preferably C6 C,B, and more preferably C6-C,Z), alkylthios (preferably C,-C18, and more preferably C,-C,z), arylthios (preferably C6 C,g, and more preferably C6 C12), cyanos, halogens, perfluoroalkyls (preferably C,-CtB, and more preferably C,-C12), alkylcarbonyls (preferably C,-C,S, and more preferably C,-C,Z), and nitros;
each R6 is individually selected from the group consisting of -H, alkyls (preferably C,-C,g, and more preferably C,-C,Z), allyls, and (3-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls (preferably C1-C18, and more preferably C,-C,Z), phenyl, naphthyl, aralkyls (wherein the aryl is preferably C6-C18, and more preferably C6-C12, and wherein alkyl is preferably C,-C8, and more preferably C,-C,Z), heterocyclyls, and heterocyclylalkyls (wherein the alkyl is preferably C1-C18, and more preferably C,-C,Z);
each R9 group is individually selected from, the group consisting of -H, -F, and alkyls (preferably C1-C18, and more preferably C,-C,Z), wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene (preferably C,-C8, and more preferably C,-CQ), N(R6), 0;
each Z is individually selected from the group consisting of -0- and -N(R4)-;
and each ring of formula (IA) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls (preferably C,-C18, and more preferably C,-C,Z), aryls (preferably C6-C,8, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably C,-Ct8, and more preferably C,-C12), arylaminos (preferably C6-C,8, and more preferably C6-C,Z), cycloalkylaminos (preferably C1-C18, and more preferably C1-C12), heterocyclylaminos, hydroxys, alkoxys (preferably C,-C18, and more preferably C,-C12), aryloxys (preferably C6 C,8, and more preferably C6-C,2), alkylthios (preferably C,-C18, and more preferably C,-C,Z), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls (preferably C,-C18, and more preferably C,-C,2), alkylsulfonyls (preferably C1-C18, and more preferably C,-C,2), aminosulfonyls, and perfluoroalkyls (preferably C,-C18, and more preferably C,-C,2).
In one preferred embodiment, the compound has the structure of formula (I) except that:
when Q is Q-3 or Q-4, then the compound of formula (I) is not Ph O
y O~N~O H / I O N\ / O NPh Me0 / N\H O~NN \ ~~N NH2 SX Ph/N~ or ph O Z
OEt O
when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
when Q is Q-7, R5 is -OH, Y is -0-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, then the compound of formula (I) is not 0 N Me 0 Me 0 NH ,~ rH, O 0 ~
N \ 0 O tJ y NH N ~
O
H~0 1 -O HO O 0 tOEt S ~N
S I~ S \ ~ . N~NH OJ Me HN / O I/ O ~ Me \ N HN
I N' N
0 HN F / ~ Ph ~
0 NH 0 NH.
Rso, O H, N 0 N
~ ReZ
Ret o I~
R80 is H, Me R82 is substituted phenyl R8l is substituted phenyl when Q is Q-8, then Y is not -CHZO-;
when Q is Q-8, the compound of formula (I) is not H
N~ ,~
O~ SaO H
N O
R'o / N\ or O~ S'O I ~ CF3 0 oS I\ Ri0 0 RIO = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not O Ph 40 Me'"H O\S O N
HO H, 0 ~NHO ON HZN (1\
CHz)a \% Ph S NN Rta Rta N
N R~5 Ris NO 0 N~fl O I ~NO
Rit NH 02N S ~N OZN S
O~! O R12 ' 0 R14 Rl I H, alkyl, alkoxy, nitro, halogen 1112, R13 = H, alkyl R
14= H, alkyl, allyl, propargyl RIS = H. alkyl, N )~ NH
NN~Rjs \ ~ ~ ~ Mee 0 \O ' O TN~N Me N HO
~ \ R 0 NN Rie R~"~\O
~ / ~a I , or R17 NC ~ R16=H,methyl R17,R18=alkyl R19 = H, alkyl when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-10, then the compound of formula (I) is not PM N
O O S O
N N~S O t-BuO H H 3 H
when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-1 1, then the compound of formula (I) is not i-Pr Ph H H
N~ e N~O
Os0 i-Pr Ph ~ ~
when Q is Q-15, then the compound of formula (I) is not H J I R~ H H I Ri H H Nl / O N
O/~ N N 0 N'N ~ R20 N~Ph H O ~S~R21 H O S RZ1 O~H N \ H~ I I rz\ H
R20 Ry1 , or R20 = substituted phenyl, RZi = H, alkyl when Q is Q-16 and Y is -NH-, then H
(R i-X~-A4N
~-D-E
~-L-~Np of formula (I) is not biphenyl;
when Q is Q-16 and Y is -S-, then (R I -X}--A4N~--L-(N~-D-E
m p p of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;.
when Q is Q-16 and Y is -SOZNH-, then the compound of formula (I) is not O
Ph-N~ ~ ~ HsCY N ~
N H I~ p p p H ~/qS O N ~/S 0 ~ N.S NH H II NH R22 H, ~~
H ~ C.~
H~O H O R22 = Me, OH H p Rza R26 NC N N
N \ 1 O O
I\ \ I\ O\ O I\ I~ 0 O
x S NH N~ L NH
R24 H ~ Rza H
R25 xs H 0 H ~ or N "eNH
H H,~O
R23 = OH, SH, NH2 when Q is RZy = hydrogen or one or more methoxy, hydroxy, fluoro, chloro, nitro, dimethylamino, 1 5 Q-16 or furanyl Ru = substituted phenyl, furanyl R26 = OH or CI
a n d x5 = 0, r,H;
Y is -CONH-, then (RI-X}-A4N~-L-~N~-D-E
m p p ~
of formula (I) is not imidazophenyl;
when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not Rz7 n N-N O
HzN t N OI NH
Rze H H~O
R2, = substituted phenyl, pyridylcarbonyl R=r - CN, methoxycarbonyl n0or1 when Q is Q-16 and t is 0, then (RI-XFA-()-L-(-D-E
m p P
of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
when Q is Q-17, then the compound of formula (I) is not ~
n-Bu ~ / R31 O O NR30 or N 41, R~ H N
2s ~ O
R29 = alkyl n-Bu 0 R30 = H, t-Bu, benzoyl R31 = substituted phenyl when Q is Q-2 1, then the compound of formula (I) is not HOZC R
O
N
O ~./
Ph when Q is Q-22, then the compound of formula (I) is selected from the group consisting of N N\ NHx(NH)p-A-(X-Rt)m N~ ~ Ou N H~(NH)p-A-(X-Rl)m wl.w J
OH W OH
NH-L-(NH)p-A-(X-R)m R4 NH-L-(NH)p-A-(X-Rj)m ONH
O NH
Wl%W w OH ' and W~OH
when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of \ N
N N
N CO-(NH)p-A-(X-R,)m N A-(X-R,)m NN~ CO-(NH)p-A-(X-RI)m N A-(X-RI)m I -I -I w W .W WfW I
~ ~' wOH W OH
OH OH
CO-(NH) p-A-(X-Rl)m A-(X-Rl) m CO-(NH)p-A-(X-Ri)m A-(X-RI)m X Xw yy and W w1,W w~wL~OH w'I'OH
OH OH
but excluding Ra1 H O N I\ R3s 0 R
O O / I.Rao R3B R37 = N(Me)2, I\ H R35 \ N\ R39 morpholino, OMe, OH, H
/ R34 = Me, CI I H R38 = H, CN, OMe, OH, R
HO 34 R35 = -N(Me)2, morpholino // Me benzyloxy, phenyl, nitro meta or para- R36 = H, F HO meta or para- R39 = H, OH
R40 = H, F
R41 = H, CI
O OMe 0 N
N
HN I/ HN HN
Me OMe N
\ N \ \ N \ \ N
I H I H , I H
lO HO Me HO / Me and meta or para- OH meta or para-MeO NvNHMe Me0 i'IN
O
H
~ \ N
meta or para-when Q is Q-23, then the compound of formula (I) is not R42 (CH2)yMe i I
H ~ ~ I
~ /
N N
HSI/ N~ ~ H
HS R42 - H, Me HS
-Me 0~ 0 ~N
S o / r~
i H
HS HS , HS ~
S02NHz ci t-Bu ~ N ci 15 HS O HN,S t-Bu 0 N& H H~~ SH
CI
N \
HS S O :C)-r SH
, or C11 when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of R~}}~~ W
'/~ \\ II IIW
, N/~N N' A-(x-Rt)m w N~NnA-(X-Rt)m A-(X-Rt)m ~Gt OII ~Gt O Gt pL
N//
Nl~N A-(x-Rt)m N
H "F
N -(X-Rt)m q'A-(X-Rt)m W ~W R7 0 WJLIW O W~W 0 \ JII' ~A (X Rt)m \ ~ ~ \ ~ ~I~O
' H H q A-(X-Rt)m N' S"A-(X-Rt)m o~/YWY A-(x-Rt)m O S.N~!W N'A-(X-Rt)m OyN'rW
NA-(X-Rt)m = WR~ ' I IWI~%(R , and HN W~ 'R7 wherein each W is individually selected from the group consisting of -CH- and -N-;
each G, is individually selected froni the group consisting of -0-, -S-, and -N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
0 0 o o 0 ~ O o oo \% // o 0 S. .R4 fI S. 4 Ra ~,.Z-Ra O~ Z, O H N O J~N.S.NRa HN N N HNI~N.S.NRa O~S ~S Ra Ra H Ra \ Ra H O~
Ra or~
L ~ ~* Y-J =
Q-24 Q-25 Q-26 or Q-31 wherein each Z is individually selected from the group consisting of -O-and -N(R4)-;
when Q is Q-31, then the compound of formula (I) is not /'O OS N~
S H
CI I CI HN~
CI / N' N~
~ CI
or ~
O~ 0 O
H SH I/ H
\
N N
~o s o when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not \ I \
N
\ \ \ H
N
or I I /
N, CH3 N, .CH3 O OSO
O ~ 0 .~
R46 = hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not Ph p OS ~ S
~ H
O
or N, H
N
Ph---~ ~O OS~p S O
when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not N H NS
/ N H Me Ph 0 when Q is Q-32, then ~.-D-E-Y
(Ri-X~-A4N~-L-~Np is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
when Q is Q-32, Y is -CONH-, q is 0, m is 0, and N~-L-~N~--P
of formula (I) is -CONH-, then A is not phenyl;
when Q is Q-32, q is 0, m is 0, and 4NH~L-N4 P
is -CONH-, then the compound of formula (I) is not 0 R~ de Ru R60~~' M 0 H
R60 or RgOO-.F~. N
H H
H H 0 Rss S_ /,R47 Ph \( Me N~N
Rae R5+ ssYN
Rso m/ Ru or Z+~
XN
R54 = benzoyl, phenylalkylaminocarbonyl, substituted phenylaminocarbonyl H. Br R47 = alkyl, substituted phenyl, thienyl, phenacetyl R55 = Cl, Br, SPh, benzoyl, phenylsulfonyi naphthyl R51 = H, phenylsulfonyl, phenyl, benzyl Rqa = H, alkyl, Br, substituted phenyl, benzoyl, R6 = Et, i-Pr phenylsulfonyl R53 = substituted phenyl, substituted benzyl R49 = H, alkyl, phenyl Xt = 0, N-Ph, N-alkyl, N-carbamoyl Rsn = substituted phenyl Z t= N(R50), 0 when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone;
when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
whenQisQ-32,Dispyrimidylqis0,tis0,pis0,nis0,andmis0,thenAisnot phenyl;
when Q is Q-32 and Y is an ether linkage, then ~-A--~N~--L--4N-E
(R ~ X p p of formula (I) is not biphenyl or phenyloxazolyl;
when Q is Q-32 and Y is -CH=CH-, then m p E
of formula (I) is not phenylaminophenyl;
when Q is Q-32, then the compound of formula (I) is not R56 0 Raz N
II
~I xt RaoO ~P' /~ H O
AlkylO ~ Fs H ~ N ReoO /~t\--(~~~ N
AlkylO ~~ N b H H O d Rat ~
b= 0-1 R6oO ~ p H \N
Xt = O, S RaoO ~~ N
R56 = H, CF3, Cl, imidazolyl, amino, morpholino, phenylthio, H H d R
cycloalkyl, benzyl, phenyl, phenoxy, thienyl, substituted alkyl, O e7 pyridylthio, pyrimidyl, benzylamino, N-benimidazolyl, 0 O-N
pyridylcarbonylamino, ureido,N- thiourea, substituted alkanoylamino, Rso0 - H
phenylsulfonyl, substituted benzoyl, phenylalkenoyl, furanoyl, R600 N
thienoyl, pyridinoyl, HH d R
R57 = substituted phenyl, substituted biphenyl 0 63 Ra 0 R830~P H 6111~
o0-P Ra'ON ~ or Ra O~ H H~ d R ; and H H p O R59 61 d=0-2 R58 = substituted alkylaminocarbonyl, phenylaminocarbonyl R60 = H, alkyl R59 = H, CI R61 = substittited phenyl, thienyl, Br R62= H. alkyl, phenyl R63 = substituted phenyl when Q is Q-35 as shown ~ZRjp ZRjo (G/k " u (G k I \ \
Q-35 (para) Q-35 (meta) wherein G is selected from the group consisting of -0-, -S-, -NR4-, and -CH2-, k is0or 1, and u is 1, 2, 3, or 4, then R~ X~A~N~-L---~N~D-E-Y
is selected from the group consisting of A-[(X)1-R,]m W O~y C~' ~ O w w OII 20 1R
~N ~ I', A-I(X)1-R,lm R~ a.AI(X)1Rt]m q_ o S,Y~- A-I(X)1 R,lm R7 W W~W O A W R~
O ( ~~A-I(X)1-Rt1m H~A'I(X)J Rt1m W N A- X-R m o~,aY [( )'~ ,1 R~ HN W ~ R7 W~W O A
s~ ' i 0 ~\N a~ "A-[(X)1-Rt1m H ~ A'[(X)1-R,1m N Gt OII R7~Gt 0 R7 Gt o0 Hl, A [(X)1 Rtlm N N .~"
~j ~ A-I(X)1-Rt]m ~q A-I(X)1-R,1m , =
õ
r N~A-((X)j-RI]m N~A-[(X)j-Rtlm ~N A-I(X)j-Rtjm ~ =
R7 R7 R7 ~G ~Ct Y/", ~N~A-I(X)j-Ri]m N~A-[(X)j-Rtlm NA-I(X)j-Rt]m WIIII W W'lW
A-I(X)j-Rilm \ (A-I(X)j-Rjlm \ (A-((X)j-Rj]m O4z~ zra~W A-I(X)j-Rilm O H W A-I(X)j-Ri1m Oy a W A-I(X)j-Rt1m W Ry O\'N W~% R7 , and HN W R7 except that the compound of formula (I) is not Me / I C02R71 Me COZH R
\ ia Ph ~\(CH2)nCO2R75 R71 meta, para ~W4 W N R72 28.1 R73 =-OCH2CO2H R75 = H, Et ~ W4 H R71 = H, Me R72 thiezolyl, isoxazolyl R74 = oxazolyl, imidazolyl R78 R76 = H. NH2, N02 W4 = N, CH imidazolyl, furyl 28.2 R73 C02Me n 0-1 R74= chlorophenyl CI
~ ~
CO R
X3 2 n ~COzR7a O-N
~ ~
meta, para Me Ph NH
O R77 = H, alkyl )- ~ COZH
HN NH I
HN X3=OorCH2 R78=H,alkyl 0 O /
N{
COpMe NH
NN ~ R~ O Me / O ~ 'N
HZN ~C02Et N \ N~ I R70 / WZ -~ NH RasH H I\ N O CO-Ra7 O meta, Pera / / C02Me H
O 2Me COZR65 MeO / 1 O R67 = OH, NH2 F3C I/ ~ (\ C02RS6 R68 = CF3, Me Me0 R70 = 2-MeSO2-phen-1 =yi, 2-NH2SO2-phen-I-yI, meta, para morpholino, imidazolyl, N(Et)2 OMe 0 R65 H. El R66 = alkyl W 2 CR69 or N
O N~ I
OMe ~ N \
HZN' /N OMe I H
1~ H3C NU N /
N~ I ~ I \ N 0 O
NH2 \ I / I \ COzH
R79 = H, Me C02R79 or \ I\ N ~
O
Even more preferably, R, as discussed above is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls, and even more preferably, R, is selected from the group consisting of I W N
W \
Jl . (0) ' W
L ~ ~N .N ) . N RZ W W N O O
R2 Rz H
.nnn R. 20 R~ r-{ ~--~
~ W
~W~ (W_ NYS N~ S, Ro 'N ",R4 o O, o o z ~
i \ ~N~A ~R? Dw, R ccN,R5 ~RZ
~
, R2 o a-a R4 each R2 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C1-C12), aminos, alkylaminos (preferably Ci-C18, and more preferably Ci-C~z), arylaminos (preferably C6 C,g, and more preferably C6-C12), cycloalkylaminos (preferably C,-C,8, and more preferably C1-C12), heterocyclylaminos, halogens, alkoxys (preferably C1-C18, and more preferably C1-C12), and hydroxys; and each R3 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), alkylaminos (preferably C1-C18, and more preferably C,-C,Z), arylaminos (preferably C6 C,B, and more preferably C6-C,Z), cycloalkylaminos (preferably C1-C18, and more preferably C,-C1z), heterocyclylaminos, alkoxys (preferably C,-C,g, and more preferably C,-C1z), hydroxys, cyanos, halogens, perfluoroalkyls (preferably C,-C18, and more preferably C,-C,2), alkylsulfinyls (preferably C1-C18, and more preferably C,-C,2), alkylsulfonyls (preferably C1-C1B, and more preferably C,-C,Z), R4NHSO2-, and -NHSOZR4.
Finally, in another preferred embodiment, wherein A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and w;w'~
w - J
'w, w, where each W, is individually selected from the group consisting of -CH- and -N-.
An additional class of compounds useful in the invention have the formula A-T-(L)n-(NH)p-D-(E)q-(y)t-Q
(IB) wherein:
Y is selected from the group consisting of -0-, -S-, -NRb-, -NR6S02-, -NR6CO-, alkynyls (preferably CI-C18, and more preferably CI-C12), alkenyls (preferably Ci-C18, and more preferably CI-C12), alkylenes (preferably Ci-C18, and more preferably Ci-C12), -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably Ci-Cia, and more preferably CI-C12), -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CHZ)h- the introduction of the side-chain oxo group does not fonm an ester moiety;
A is selected from the group consisting of aromatic (preferably C6-C18, and more preferably C6-C12), monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and .nnr w;wL w, W'w,- '", J
where each W 1 is individually selected form the group consisting of -CH- and N-.
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selectedfrom the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)z-;
T is NR6, 0, alkylene (preferably CI-C12, more preferably CI-C4), -O(CH2)h-, or -NR6(CH2)n-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, or T is absent wherein A is directly bonded to -(L)õ(NH) P-D-(E)q -(Y) -Q;
n is 0 or 1;
pis0or1;
qis0orl;
t is 0 or 1;
v is 1,2, or 3;
xislor2;
Q is selected from the group consisting of formulae Q36- Q59, inclusive;
each R4 group is individually selected from the group consisting of -H, alkyls (preferably CI-C18i and more preferably Cc-C12), aminoalkyls (preferably Cl-C18, and more preferably CI-C12), alkoxyalkyls (preferably CI-CIs, and more preferably Ci-C12), aryls (preferably C6-C,8, and more preferably C6-Ci2), aralkyls (preferably C6-Ci8, and more preferably C6-Cc2 and preferably CI-C18, and more preferably CI-Ci2), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R6 is individually selected from the group consisting of -H, alkyls (preferably CI-C18, and more preferably Ci-C12), allyls, and B-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls (preferably Ci-C18, and more preferably CI-Q2), phenyl, naphthyl, aralkyls (wherein the aryl is preferably C6-C]8, and more preferably C6-C]2), wherein alkyl is preferably CI-C18, and more preferably CI-CiZ), heterocyclyls, and heterocyclylalkyls (wherein the alkyl is preferably CI-C,g, and more preferably Ci-C12);
each R9 group is individually selected from the group consisting of -H, -F, and alkyls (preferably Cl-C18, and more preferably CI-C12), wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R9, group is individually selected from the group consisting of -F, and alkyls (preferably CI-C18, and more preferably Ci-C12), wherein when two R9, groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each RIo is alkyl or perfluoroalkyl;
G is alkylene (preferably CI -C8, and more preferably Ci-C4), N(R6), 0;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (1) optionally includes one or more of RT, where RT is a substituent individually selected from the group consisting of -H, alkyls (preferably Ci-Ci8i and more preferably CI-C12), aryls (preferably C6-CI8, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably CI-CI8, and more preferably CI-C12), arylaminos (preferably C6-CI8, and more preferably C6-C12), cycloalkylaminos (preferably Ci-CI8, and more preferably CI-Ci2), heterocyclylaminos, hydroxys, alkoxys (preferably C1-C18, and more preferably Ci-C1z), perfluoroalkoxys (preferably Ci-C8, more preferably Cl-C4), aryloxys (preferably C6-C18, and more preferably C6-C12), alkylthios (preferably CI-C18, and more preferably Ci-Ciz), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls (preferably Ci-C18i and more preferably CI-C12), alkylsulfonyls (preferably CI-C18, and more preferably CI-C1Z), aminosulfonyls, perfluoroalkyls (preferably CI-C18, and more preferably Cl-C12);
aminooxaloylamino; alkylaminooxaloylamino; dialkylaminooxaloylamino;
morpholinooxaloylamino; piperazinooxaloylamino; alkoxycarbonylamino;
heterocyclyloxycarbonylamino; heterocyclylalkyloxycarbonylamino;
heterocyclylcarbonylamino; heterocyclylalkylcarbonylamino;
aminoalkyloxycarbonylamino; alkylaminoalkyloxycarbonylamino; or dialkylaminoalkyloxycarbonylamino.
In a preferred embodiment, A as described above is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and N/ ~ W~
W-W
i W, where each W, is individually selected from the group consisting of -CH- and -N-.
Q groups Q-36 through Q-59 are set forth below. In an additionally preferred embodiment, Q is taken from Q-37, Q-39, Q-41, Q-42, Q-43, Q-44, Q-47, Q-48, Q-54, and Q-57; in a more preferred embodiment, Q is taken from Q-39, Q-41, Q-42, Q-43, Q-44, Q-47, Q-48, and Q-54.
O~NNrp p, p pzz( S O p S O
,N-S N-NN-N N
, , R4 R4 R4 R4 %R4 R4 R4 ~R4 rLnnr Rs' R9' ~
I
p N p OgO 0 .R4 GZ'R4 R N' H R4 A
Z' N N oz_- O
4 R4 R4 Q-40 Q-41 (N) pQ-42 vtrt. '~n' vtrt, ~~ ~
G~~ G~~ I ~ ~
V ?V ~V R9R / R4-pp ~
S.
R4 p p R60 Rlp 'V1IL, 'ViJL Ln.r1.. L.ll.lL . ~V1r\, ~
HN ON ON pN p,%-N
p R8 R _N7 1%~NH O' NH
4 R4 pz:S yf~
N, Q-49 Q-50 Q-51 R4"I N, R4 Ra R4 ~ = ~ ~õn, 0 I 'V ~~V ~ S .~ ~ ~p p ~ ~p N, N. / 'O R
O
0 Ra O~ Ra O O N R4 ) R.
R Ra Ra x R4 /N N a Ra R R4/ .Ra With respect to the method of using the novel compounds; the activation state of a kinase is determined by the interaction of switch control ligands and complemental switch control pockets. One conformation of the kinase may result from the switch control ligand's interaction with a particular switch control pocket while another conformation may result from the ligand's interaction with a different switch control pocket. Generally interaction of the ligand with one pocket, such as the "on" pocket, results in the kinase assuming an active conformation wherein the kinase is biologically active. Similarly, an inactive conformation (wherein the kinase is not biologically active) is assumed when the ligand interacts with another of the switch control pockets, such as the "off' pocket. The switch control pocket can be selected from the group consisting of simple, composite and combined switch control pockets.
Interaction between the switch control ligand and the switch control pockets is dynamic and therefore, the ligand is not always interacting with a switch control pocket. In some instances, the ligand is not in a switch control pocket (such as occurs when the protein is changing from an active conformation to an inactive conformation). In other instances, such as when the ligand is interacting with the environment surrounding the protein in order to determine with which switch control pocket to interact, the ligand is not in a switch control pocket. Interaction of the ligand with particular switch control pockets is controlled in part by the charge status of the amino acid residues of the switch control ligand. When the ligand is in a neutral charge state, it interacts with one of the switch control pockets and when it is in a charged state, it interacts with the other of the switch control pockets. For example, the switch control ligand may have a plurality of OH groups and be in a neutral charge state. This neutral charge state results in a ligand that is more likely to interact with one of the switch control pockets through hydrogen boding between the OH groups and selected residues of the pocket, thereby resulting in whichever protein conformation results from that interaction. However, if the OH groups of the switch control ligand become charged through phosphorylation or some other means, the propensity of the ligand to interact with the other of the switch control pockets will increase and the ligand will interact with this other switch control pocket through complementary covalent binding between the negatively or positively charged residues of the pocket and ligand. This will result in the protein assuming the opposite conformation assumed when the ligand was in a neutral charge state and interacting with the other switch control pocket.
Of course, the conformation of the protein determines the activation state of the protein and can therefore play a role in protein-related diseases, processes; and conditions. For example, if a metabolic process requires a biologically active protein but the protein's switch control ligand reinains-iri tfie swi"tch control pocket the "offl' pocketYtliat results "in a biologically inactive protein, that metabolic process cannot occur at a normal rate. Similarly, if a disease is exacerbated by a biologically active protein and the protein's switch control ligand remains in the switch control pocket (i.e. the "on" pocket) that results in the biologically active protein conformation, the disease condition will be worsened. Accordingly, as demonstrated by the present invention, selective modulation of the switch control pocket and switch control ligand by the selective administration of a molecule will play an important role in the treatment and control of protein-related diseases, processes, and conditions.
One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 a-kinase and including both the consensus wild type sequence and disease polymorphs thereof. The activation state is generally selected from an upregulated or downregulated state. The method generally comprises the step of contacting the kinase with a molecule having the general formula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and a lesser propensity to interact with the occupied switch control pocket. As a result, the protein will have a greater propensity to assume either an active or inactive conformation (and consequenctly be upregulated or downregulated), depending upon which of the switch control pockets is occupied by the molecule. Thus, contacting the kinase with a molecule modulates that protein's activation state. The molecule can act as an antagonist or an agonist of either switch control pocket. The contact between the molecule and the kinase preferably occurs at a region of a switch control pocket of the kinase and more preferably in an interlobe oxyanion pocket of the kinase. In some instances, the contact between the molecule and the pocket also results in the alteration of the conformation of other adjacent sites and pockets, such as an ATP active site.
Such an alteration can also effect regulation and modulation of the active state of the protein.
Preferably, the region of the switch_control _pocket of_the_kinase comprises an amino acid r.esidue_sequence operable for binding to the Formula I molecule. Such binding can occur between the molecule and a specific region of the switch control pocket with preferred regions including the a-C helix, the a-D helix, the catalytic loop, the activation loop, and the C-terminal residues or C-lobe residues (all residues located downstream (toward the C-end) from the Activation loop), the glycine rich loop, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence IIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (SEQ
ID NO. 3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ
ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. When the binding region is in the C-lobe residues, one preferred binding sequence is WMHY (SEQ ID NO. 6).
When the binding region is in the glycine rich loop one preferred binding sequence is YGSV (SEQ ID NO.
7). When a biologically inactive protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically active protein conformation (when interacting with the switch control ligand) will be selected. Similarly, when a biologically active protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically inactive protein conformation (when interacting with the switch control ligand) will be selected. Thus, the propensity of the protein to assume a desired conformation will be modulated by administration of the molecule. In preferred forms, the molecule will be administered to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. In such forms, it will be desired to select molecules that interact with the switch control pocket that generally leads to a biologically active protein conformation so that the protein will have the propensity to assume the biologically inactive form and thereby alleviate the condition. It is contemplated that the molecules of the present invention will be administerable in any conventional form including oral, parenteral, inhalation, and subcutaneous. It is preferred for the administration to be in the oral form. Preferred molecules include the preferred compounds of formula (I), as discussed above.
Another aspect of the present invention provides a method of treating an inflammatory condition of an individual comprising the step of administering a molecule having the general formula (I) to the individual: Such conditions are often the result of an overproduction of the biologically active form of a protein, including kinases. The administering step generally includes the step of causing said molecule to contact a kinase involved with the inflammatory process, preferably p38 a-kinase. When the contact is between the molecule and a kinase, the contact preferably occurs in an interlobe oxyanion pocket of the kinase that includes an amino acid residue sequence operable for binding to the Formula I molecule.
Preferred bindirig regions of the interlobe oxyanion pocket include the a-C helix region, the a-D helix region, the catalytic loop, the activation loop, the C-terminal residues, the glycine rich loop residues, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence IIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (SEQ ID NO.
3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. Such a method permits treatment of the condition by virtue of the modulation of the activation state of a kinase by contacting the kinase with a molecule that associates with the switch control pocket that normally leads to a biologically active form of the kinase when interacting with the switch control ligand.
Because the ligand cannot easily interact with the switch control pocket associated with or occupied by the molecule, the ligand tends to interact with the switch control pocket leading to the biologically inactive form of the protein, with the attendant result of a decrease in the amount of biologically active protein. Preferably, the inflammatory condition is selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive -diseases,-graft-versus-host_r.eaction,_Chron'-s_disease,_ulcerative_colitis,_inflammatory-- bowel disease, pyresis, and combinations thereof. As with the other methods of the invention, the molecules may be administered in any conventional form, with any convention excipients or ingredients. However, it is preferred to administer the molecule in an oral dosage form.
Preferred molecules are again selected from the group consisting of the preferred formula (I) compounds discussed above.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic. representation of a naturally occurring mammalian protein in accordance with the invention including "on" and "off' switch control pockets 102 and 104, respectively, a transiently modifiable switch control ligand 106, and an active ATP site 108;
Fig. 2 is a schematic representation of the protein of Fig. 1, wherein the switch control ligand 106 is illustrated in a binding relationship with the off switch control pocket 104, thereby causing the protein to assume a first biologically downregulated conformation;
Fig. 3 is a view similar to that of Fig. 1, but illustrating the switch control ligand 106 in its charged-modified condition wherein the OH groups 110 of certain amino acid residues have been phosphorylated;
Fig. 4 is a view similar to that of Fig. 2, but depicting the protein wherein the phosphorylated switch control ligand 106 is in a binding relationship with the on switch control pocket 102, thereby causing the protein to assume a second biologically-active conformation different than the first conformation of Fig. 2;
Fig. 4a is an enlarged schematic view illustrating a representative binding between the phosphorylated residues of the switch control ligand 106, and complemental residues Z+ from the on switch control pocket 102;
Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic form possible small molecule compounds 116 and 118 in a binding relationship with the off and on switch control pockets 104 and 102, respectively;
Fig. 6 is a schematic view of the protein in a situation where a composite switch control pocket 120 is formed with portions of the switch control ligand 106 and the on switch control pocket 102, and with a small molecule 122 in binding relationship with the composite pocket;
and Fig. 7 is a schematic view of the protein in a situation where a combined switch control pocket 124 is formed with portions of the on switch control pocket 102, the switch control ligand sequence 106, and the active ATP site 108, and with a small molecule 126 in binding relationship with the combined switch control pocket.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a way of rationally developing new small molecule modulators which interact with riaturally occurring proteins (e.-g,-mammalian,-and especially human proteins) in order to modulate the activity of the proteins. Novel-protein-small molecule adducts are also provided. The invention preferably makes use of naturally occurring proteins having a conformational property whereby the proteins change their conformations in vivo with a corresponding change in protein activity. For example, a given enzyme protein in one conformation may be biologically upregulated, while in another conformation, the same protein may be biologically downregulated. The invention preferably makes use of one mechanism of conformation change utilized by naturally occurring proteins, through the interaction of what are termed "switch control ligands" and "switch control pockets" within the protein.
As used herein, "switch control ligand" means a region or domain within a naturally occurring protein and having one or more amino acid residues therein which are transiently modified in vivo between individual states by biochemical modification, typically phosphorylation, sulfation, acylation or oxidation: Similarly, "switch control pocket" means a plurality of contiguous or non-contiguous amino acid residues within a naturally occurring protein and comprising residues capable of binding in vivo with transiently modified residues of a switch control ligand in one of the individual states thereof in order to induce or restrict the conformation of the protein and thereby modulate the biological activity of the protein, and/or which is capable of binding with a non-naturally occurring switch control modulator molecule to induce or restrict a protein conformation and thereby modulate the biological activity of the protein.
A protein-modulator adduct in accordance with the invention comprises a naturally occurring protein having a switch control pocket with a non-naturally occurring molecule bound to the protein at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein. Preferably, the protein also has a corresponding switch control -ligand,-the_ligand.interacting_in vivo.with_the.pocket to regulate the conformation and biological activity of the protein such that the protein will assume a first conformation and a first biological activity upon the ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of the ligand-pocket interaction.
The nature of the switch control ligand/switch control pocket interaction may be understood from a consideration of schematic Figs. 1-4. Specifically, in Fig.
1, a protein 100 is illustrated in schematic form to include an "on" switch control pocket 102, and "off" switch control pocket 104, and a switch control ligand 106. In addition, the schematically depicted protein also includes an ATP active site 108. In the exemplary protein of Fig.
1, the ligand 106 has three amino acid residues with side chain OH groups 110. The off pocket 104 contains corresponding X residues 112 and the on pocket 102 has Z residues 114. In the exemplary instance, the protein 100 will change its conformation depending upon the charge status of the OH groups 110 on ligand 106, i.e., when the OH groups are unmodified, a neut ral charge is presented, but when these groups are phosphorylated a negative charge is presented.
The functionality of the pockets 102, 104 and ligand 106 can be understood from a consideration of Figs. 2-4. In Fig. 2, the ligand 106 is shown operatively interacted with the off pocket 104 such that the OH groups 110 interact with the X residues 112 forming a part of the pocket 104. Such interaction is primarily by virtue of hydrogen bonding between the OH groups 110 and the residues 112. As seen, this ligand/pocket interaction causes the protein 100 to assume a conformation different from that seen in Fig. 1 and corresponding to the off or biologically downregulated conformation of the protein.
Fig. 3 illustrates the situation where the ligand 106 has shifted from the off pocket interaction conformation of Fig. 2 and the OH groups 110 have been phosphorylated, giving a negative charge to the ligand. In this condition, the ligand has a strong propensity to interact with on pocket 102, to thereby change the protein conformation to the on or biologically upregulated state (Fig. 4). Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted to positively charged residues 114 to achieve an ionic-like stabilizing bond.
Note that in the on conformation of Fig. 4, the protein conformation is different than the off conformation of Fig.
2, and that the ATP active site is available and the protein is functional as a kinase enzyme.
Figs. 1-4 illustrate a simple situation where the protein exhibits discrete pockets 102 and 104 and ligand 106. However, in many cases a more complex switch control pocket pattern is observed. -Fig._6_illustrates.a situation where_an_appro.priate_pocket.for_small molecule interaction is formed from amino acid residues taken both from ligand 106 and, for example, from pocket 102. This is termed a "composite switch control pocket" made up of residues from both the ligand 106 and a pocket, and is referred to by the numeral 120. A small molecule 122 is illustrated which interacts with the pocket 120 for protein modulation purposes.
Another more complex switch pocket is depicted in Fig. 7 wherein the pocket includes residues from ori pockef 1-02; and ATP -site 108 to dreate what-is ternied a"combined -switch control pocket." Such a combined pocket is referred to as numeral 124 and may also include -residues from ligand 106. An appropriate small molecule 126 is illustrated with pocket 124 for protein modulation purposes.
It will thus be appreciated that while in the simple pocket situation.of Figs.
1-4, the small molecule will interact with the simple pocket 102 or 104, in the more complex situations of Figs.
6 and 7 the interactive pockets are in the regions of the pockets 120 or124.
Thus, broadly the the small molecules interact "at the region" of the respective switch control pocket.
MATERIALS AND METHODS
General Synthesis of Compounds.
In the synthetic schemes of this section, q is 0 or 1. When q = 0, the substituent is replaced by a synthetically non-interfering group R7.
Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are prepared according to the synthetic route shown in Scheme 1.1. Reaction of isothiocyanate 1 with chlorine, followed by addition of isocyanate 2 affords 3-oxo-thiadiazolium salt 3.
Quenching of the reaction with air affords compounds of Formula 1-4.
Alternatively, reaction of isothiocyanate 1 with isothiocyanate 5 under the reaction conditions gives rise to compounds of Formula I=7. See A. Martinez et al, Journal of Medicinal Chemistry (2002) 45: 1292.
Intermediates 1, 2 and 5 are commercially available or prepared according to Scheme 1.2. Reaction of amine 8 with phosgene or a phosgene equivalent affords isocyanate 2.
Similarly, reaction of amine 8 with thiophosgene affords isothiocyanate 5.
Amine 8 is prepared by palladium(0)-catalyzed amination of 9 wherein M is a group capable of oxidative insertion into palladium(0), according to methodology reported by S.
Buchwald.
See M. Wolter et al, Organic Letters (2002) 4:973; B.H. Yang and S. Buchwald, Journal of Organometallic Chemistry (1999) 576(1-2):125. In this reaction sequence, P is a suitable amine protecting group. Use of and removal of amine protecting groups is accomplished by methodology reported in the literature (Protective Groups in Organic Synthesis, Peter G.M.
Wutts, Theodora Greene (Editors) 3rd edition (April 1999) Wiley, John & Sons, Incorporated; ISBN: 0471160199). Starting compounds 9 are commercially available or readily prepared by one of ordinary skill in the art: See March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith & Jerry March (Editors) 5th edition (January 2001) Wiley John & Sons; ISBN : 0471585890.
Scheme 1.1 E) R,4 1) ClZ + R4 CI ~ N Cl 3) air, RT _ O~ NO
R4-N=C=S O -1 2) [R6O2C-(NH)P]q-D-E-Y-N=C=O S-~
, S-N Y-E-D [(NH)p-C02R6]c 2 Y-E-D-[(NH)p-C02R6]q 3 1~4 _ R4 1) CIZ R4 ClO , RT
O N S
R4-N=C=S C~ /N g 3) air, _ ~ ~
2) [R602C-(NH)P]q D-E-Y N=C=S S_~' Y-E-D-[(NH)p-C02R6]q Y-E-D-[(NH)p-C02R6]q Scheme 1.2 NH2 phosgene ,N=C=O
[R602C-(NH)p]q-D-E-Y -~ Base [R602C-(NH)p]q-D-E-Y
8 ?
NH thiophosgene N=C=S
[R602C-(NH)p]q-D-E-Y 2 --~ [R602C-(NH)p]q-D-E-Y"
Base R602C-NH-D-E-Y-NHP deprotection M-D-E-Y-NHP =~ --Pd(O) catalysis Compounds of Formula I wherein Q is taken from Q1 or Q-2 and Y is alkylene are also available via the synthetic route shown in Scheme 1.3. Reaction of amine 8 with isocyanate or isothiocyanate 2a yields the urea/thiourea 8a which can be cyclized by the 10 addition of chlorocarbonyl sulfenyl chloride. See GB1115350 and US3818024, Revankar et.
al US Patent 4,093,624, and Klayman et. al JOC 1972, 37(10), 1532 for further details.
Where R4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of I-4 (X=0) and I-7 (X=S).
Scheme 1.3 - -- x .eNH2 X=O, S HN N.1 Ra [R602C-(NH)p]q-D-E-Y
2a [R602C-(NH)p]q-D-E-Y' H
8 8a, X=O, S
O X
~ ~CI
CI S 'N 'k N' R4 Deprotection [R602C-(NH)p]q-D-E-Y S--,\\O
1-4 X=O
1-7 X=S
X
~N~NH
[R6O2C-(NH)p]q-D-E-Y S
I-4 X=O
1-7 X=S
1-7 is also available as shown in Scheme 1.4. Condensation of isocyariate or isothiocyanate 2a with amine R5NH2 yields urea/thiourea 2b, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2c. Where R4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of 2d. Reaction of 2d with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-4 (X=O) and 1-7 (X=S).
Scheme 1.4 O O
R5NH2R4HN N- RS CIS'CI R,N ~~R Deprotection of R4 s R4NCX Y a y X=O, S X II
X
2a x=o, s x=O, S
2b 2c ~O 0 S
~ NaH/DMF S
HNy N-RS N N, [R602C-(NH)p]q-D-E-Y Y R5 X [R602C-(NH)p]q-D-E-Y'M X
X=O, S
2d 1-4 X=0 8a I-T X=S
Compounds of Formula I wherein Q is taken from Q-1' or Q-2' and Y is alkylene are available via the synthetic route shown in Scheme 1.3. Condensation of isocyanate or isothiocyanate 2a with ammonia yields urea/thiourea 2e, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2f.
Reaction of 2f with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields yields I-4' (X=0) and I-7' (X=S).
Scheme 1.5 O O
NH3 R4HN N-H CI)tIS'CI ~--~~, R NCX - H ~N "'H
~
X=O, S ~ ~ x X
2a x=o, s x=o, s 2e 2f NaH/DMF S
, T N
[R602C-(NH)p]q-D-E-Y N
Ra [R60zC-(N H) p]q-D-E-Y 'M I-4' X=0 8a I-T X=S
Compounds of Formula I wherein Q is taken from Q-3 or Q-4 and Y is alkylene, are prepared according to the synthetic route shown in Schemes 2.1 and 2.2, respectively.
Reaction of 12, wherein M is a suitable leaving group, with the carbaniate-protected hydrazine 13 affords intermediate 14. Reaction of 14 with an isocyanate gives rise to intermediate 15. Thermal cyclization of 15 affords 1,2,4-triazolidinedione of Formula 1-16.
--By. analogy, scheme 2.2 illustrates the preparation of 3-thio-5-oxo-1,2,4-triazolidines of Formula I-18 by reaction of intermediate 14 with an isothiocyanate and subsequent thermal cyclization.
Scheme 2.1 O
)-ORjo H2N-N, R4 R4 D Y N OR 11 iD~ /Y- 1 [R602C-(NH)PIq~ ~E/ \H~ ~ 10 [R602C-(NH)p]q E M ~
R -N=C=O I 4 [R602C-(NH)plq~E/Y\NNyORIo heat O
O NH
[R602C-(NH)P]qDE~Y\N N
~O
O ~
Scheme 2.2 -~
R4-N=C=S [R602C-(NH)p]9 D\E,Y~N~ y ORto heat 14 ? S~NH 0 Ra [R6O2C-(NH)P]qDE/Y\NN
/N
Intermediates 12 wherein p is 1 are readily available or are prepared by reaction of 19 with carbamates 10 under palladium(0)-catalyzed conditions. M, is a group which oxidatively inserts. palladium(0), preferably iodo or bromo, and is of greater reactivity than M. Compounds 19 are either commercially available or prepared by one of ordinary skill in the art.
Scheme 2.3 Mi\DY~M ---> R602C-NH.pEY'M
Pd(O) catalysis;
19 Base 12 -Compounds of Formula I wherein D is taken from Q-3 or Q-4 and Y is alkylene, are also 10 prepared according to the synthetic route shown in Scheme 2.4. Oxidation of amine R4NH2 to the corresponding hydrazine, condensation with ethyl chloroformate subsequent heating yieldsl,2,4-triazolidinedione 15a. After the action of NaH in DMF, displacement wherein M
is a suitable leaving group such as chloride, bromide or iodide yields 1-16 (X=O) and 1-18 (X=S).
Scheme 2.4 1. NaNO2 0 O RSNCX
2. SnCI2 AR4NHZ R4NHNH2 CI OEt R4NHNHOEt X=O, S heat 2a O
HN-{ NaH/DMF [R6O2C-(NH)p]q-D-E-Y, O
N N- N
R4 ~ Rs -NN
.M Ra Rs x [R602C-(NH)plq-D-E-Y y 8a x 15a 1-16 X=0 1-18 X=S
O
HN NaH/DMF NH
R4 N NH [R802C-(NH)p]q-D-E-Y-N~N-R4 Deprotection of R5 Y [R602C-(NH)p]q-D-E-Y
X 8a X
15b I-16' X=0 I-18' X=S
Compounds of Formula I wherein D is taken from D-3' or D-4' and Y is alkylene, are also prepared according to the synthetic route shown in Scheme 2.4. When R5 is a readily removable-protecting-group-(e.g. R. =-3;4-d-methoxybenzyl amine),-the_action-of_mild, acidic deprotection conditions such as CAN or TFA on 15a will reveal 1,2,4-triazolidinedione 15b.
After deprotonation of 15b by NaH in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16' (X=O) and 1-18' (X=S).
Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y is alkylene are prepared according to the synthetic route shown in Scheme 3. Reaction of hydrazine 20 with chlorosulfonylisocyanate and base, such as triethylamine, gives rise to a mixture of intermediates 21A and 21B which are not isolated but undergo cyclization in situ to afford compounds of Formulae I-22A and I-22B. Compounds I-22A and I-22B are separated by chromatography or fractional crystallization. Optionally, compounds 1-22A and 1-22B can undergo Mitsunobu reaction with alcohols R4OH to give compounds of Formulae I-23A and 1-23B. Compounds 20 are prepared by acid-catalyzed deprotection of t-butyl carbamates of structure 14, wherein RIo is t-butyl.
Scheme 3 R4 CISOZ-N=C=O
[R6O2C-(HN)p]q-D-E-Y,,, N"NH
20 H Base [R6O2C-(HN)p]q-D-E-Y~N~NH [R6O2C-(HN)p]q-D-E-Y~ N ~N
O
~
H
O NH + ----CI~ /NH
O jS~CI S 0 R4 Ra [R6O2C-(HN)p]q-D-E-Y,~N~N~ O [R6O2C-(HN)p]q-D-E-Y~,N~N
~NH~O + 0=S-NH
Ph3P ph3p Diethyl azodicarboxylate Diethyl azodicarboxylate [R602C-(HN)p]q-D-E-Y, NN\ yO [R602C-(HN)p]q-D-E-Y~N,N~O
SO +
O~- N O 'p NN
R
~ a Compounds of Formula I wherein Q is Q-7 and Y is alkylene are prepared as shown in Scheme 4. Reaction of amine 8 with maleimide 24, wherein M is a suitable leaving group, affords compounds of Formula I-25. Reaction of compound 26, wherein M is a group. which can oxidatively insert Pd(O), can participate in a Heck reaction with maleimide 27, affording compounds of Formula I-28. Maleimides 24 and 27 are commercially available or prepared by one of ordinary skill in the art.
Scheme 4 0 'Ra N
-O R
a O N
Q O
[R602C-(NH)p]q-D-E-Y~N2 24 R5 [R602C-(NH)p]q-D-E-Y~N (E) 8 Base H R5 Ra O N
Ra O O N
D M (z) O
[R6O2C-(NH)p]q ~E~ 27 R5 [R6O2C-(NH)p]qfZl 26 Pd(O), Base 1-28 Heck Reaction -Compounds of Formula I wherein Q is Q-8 and Y is alkylene are prepared as shown in Scheme 5, according to methods reported by M. Tremblay et al, Journal of Combinatorial Chemistry (2002) 4:429. Reaction of polymer-bound activated ester 29 (polymer linkage is oxime activated-ester) with chlorosulfonylisocyante and t-butanol affords N-BOC
sulfonylurea 30. Subjection of 30 to the Mitsunobu reaction with R4OH gives rise to 31.
BOC-group removal with acid, preferably trifluoroacetic acid, and then treatment with base, preferably triethylamine, provides the desired sulfahydantoin I-32.
Optionally, intermediate 30 is treated with acid, preferably trifluoroacetic acid, to afford the N-unsubstituted sulfahydantoin I-33. -Scheme 5 R4 R4 CISO2-N=C=O
[R602C-(NH)p]q-D-E-Y~NH OQ t-BuOH
R4 Ra [RsOzC-(NH)P]q-D-E-Y,,, N 0~ Ph3P diethyl azodicarboxylate BOC
R4 Ra [R602C-(NH)P]q-D-E-Y,, N O 1) H+ Ra Ra I ~ [R602C-(NH)PIq-D-E-Y~N
O~S~ Ra 0 2) Triethylamine 0'S O
31 O N I-32 ~~ ~ N
a [R602C-(NH)p]q-D-E-Y,, N
H+ O~S__ 0 Compounds of Formula I wherein Q is Q-8 and Y is alkylene are also prepared as shown in Scheme 5a. Amine 8 is condensed with the glyoxal hemiester to yield 31a.
Reaction of chlorosulphonyl isocyanate first with benzyl alcohol then 31a yields 31b, which after heating yields 1-32.
Scheme 5.1 O
H-ly OEt O
(R602C-(NH)p]q-D-E-YNH2 [R602C-(NH)p]q-D-E-Y~N v OEt 8 NaCHBH3 31a HZN,S~O O
1.
CISO2NCO [R602C-(NH)p]q-D-E-Y~N OEt OH
2. H O
31b [R602C-(NH)p]q-D-E-Y' OEt 31a 3. 5% Pd/C
O~\S~N O
I ~
heat [R60zC-(NH)p]q-D-E-Y"' Compounds of Formula I wherein Q is taken from Q-8', are prepared according to the synthetic route shown in Scheme 5.2. Formation of 31c by the method of Muller and DuBois JOC 1989, 54, 4471 and its deprotonation with NaH/DMF or NaH/DMF and subsequently alkylation wherein M is a suitable leaving group such as chloride, bromide or iodide yields I-32'. Alternatively, I-32' is also available as shown in Scheme 5.3. Mitsunobu reaction of boc-sulfamide amino ethyl ester with alcohol 8b (made by methods analogous to that for amine 8) yields 31c, which after Boc removal with 2N HCl in dioxane is cyclized by the action of NaH on 31d results in I-32'.
Scheme 5.2 O\O
S-NH
NaN O
S-NH
[R602C-(NH)p]q-D-E-Y"M O [R602C-(NH)p]q-D-E-Y' N
31c - O
8a 1-32' Scheme 5.3 H O [ReO2C-(NH)p]q-D-E-Y OH N ~
Boc-N,S~O O 8b [RsOzC(NH)p]q-D-E-Y- 'S~O O
I
HN-~-K
HN----OEt DEADCAT, Ph3P 31d OEt O.ii ~S-NH
heat N
[Rs02C-(NH)p]q-D-E-Y~
O
1-32' Compounds of Formula I wherein Q is Q-9 and Y is alkylene are prepared as shown in Scheme 6. Reaction of polymer-bound amino acid ester 34 with an isocyanate affords intermediate urea 35. Treatment of 35 with base, preferably pyridine or, ttriethylamine, with optional heating, gives rise to compounds of Formula 1-36.
Scheme 6 [R602C-(NH)p]q-D-E-Y~,NH )K1_o-_Q R4-N=C=O
Ra R4 [R602C-(NH)p]q-D-E-Y,, N O Base ~
O ___~ NH
[ R6 O2 C-( N H) p] q-D-E-Y~,, N
O
I-36 O/j-_N
Compounds of Formula I wherein Q is Q-9 and Y is alkylene are also prepared as shown in Scheme 6.1. Reaction of aldehyde 8c under reductive amination conditions with the t-butyl ester of glycine yields 35a. Isocyanate 2a is condensed with p-nitrophenol (or the corresponding R4NH2 amine is condensed with p-nitrophenyl chloroformate) to yield the carbamic acid p-nitrophenyl ester, which when reacted with deprotonated 35a and yields the urea that when deprotected with acid yields 35b. Formula 1-36 is directly available from 35b by the action of NaH and heat.
Scheme 6.1 O
0 HZN-,-A Ot-Bu N~
~
(R602C-(NH)plq-D-E-YH [RsOZC-(NH)p]q-D-E-Y, Ot Bu NaCHBH3 8c 35a O Oa;~-N02 Ifl, 1. R4HN
2. 2N HCI/Dioxane [RsO2C-(NH)P]q-D-E-Y"~ O [~-- RsO2C-(NH)P]q-D-E-Y" --AOH
1-36 35b Compounds of Formula I wherein Q is taken from Q-9', are prepared according to the synthetic route shown in Scheme 6.2. Formation of 35c by the method described in JP10007804A2 and Zvilichovsky and Zucker, Israel Journal of Chemistry, 1969, 7(4), 547-54 and its deprotonation with NaHIDMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide, yields I-36'.
Scheme 6.2 p ~--NH
NaN~ O~-NH
[R602C-(NH)p]q-D-E-Y 'M 0 [R602C-(NH)p]q-D-E-Y~ N -?
35c 0 8a 1-36' Compounds of Formula I wherein Q is Q-10 or Q-1 1, and Y is alkylene are prepared as shown in Schemes 7.1 and 7.2, respectively. Treatment of alcohol 37 (Z = 0) or amine 37 (Z =. NH) with chlorosulfonylisocyanate affords intermediate carbamate or urea of structure 38. -Treatment of 38 witif an amine of-st-ructui-e HN(R4)Z and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula I-39. Reaction of chlorosulonylisocyanate with an alcohol (Z = 0) or amine (Z = NR4) 40 affords intermediate 41. Treatment of 41 with an amine 8 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-42.
Scheme 7.1 O
CISOZ-N=C=O
[R602C-(NH)p]q-D-E-Y~ZH [R802C-(NH)p]q-D-E-Y-, ~ Z N i-S02CI
N ~O
Ra [Rs02C-(NH)P]q-D-E-Y~ ~ i ~ S~NiR4 N Base Z H I
Scheme 7.2 Ra H-Z O
CISO2-N=C=O 40 R41 Z A H iSO2CI
[R602C'(NH)p]q-D-E-Y,, N-~R5 0 /Y-D-E-q[(NH)PC02Rs 8 H Ra1 Z A H O S, N 0 - ---Base R5 Compounds of Formula I wherein Q is taken from Q-12 are prepared according to the synthetic route shown in Scheme 8. Alkylation of pyridine 43, wherein TIPS is tri-isopropylsilyl, under standard conditions (K2CO3, DMF, Ra-I or Mitsunobu conditions employing R4-OH) yields pyridine derivative 44 which is reacted with compound 12, wherein ] 0 M is a suitable leaving group, to afford pyridones of formula I-45.
Scheme 8 R
~ ReQ KZC03 DM For Acetone TIPS\ I ~ o~ TIPS
O N RaOH, Ph3P O N
Diethyl azodicarboxylate [ReO2C'(NH)p]q-D-E-Y~, M
O N
Base Y-QE-[(NH)pCO2R8]q Compounds of Formula I wherein Q is taken from Q-13 are prepared according to the synthetic route shown in Scheme 9. Starting from readily available pyridine 46, alkylation under standard conditions (K2CO3, DMF, R4-I or Mitsunobu conditions employing R4-OH) yields pyridine derivative 47. N-alkylation with K2CO3, DMF, R4-I affords pyridones of formula 48. Intermediate 48 is partitioned to undergo a Heck reaction, giving I-49; a Buchwald amination reaction, giving I-51; or a Buchwald Cu(I) catalyzed 0-arylation reaction, to give J. The Heck reaction product I-49 may be optionally hydrogenated to afford the saturated compound I-50. Wherein the phenyl ether R4 group is methyl, compounds of formula I-49, I-50, I-51, or I-52 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-53, wherein R4 is hydrogen.
Scheme 9 R5 R40, K2COs Rs ORq \ DMForAcetone_- R
I I Rql, K2CO3 / s DMF or Acetone TIPS~O N/ CI R4OH, Ph3P TIPSO N CI
Diethyl azodicarboxylate O N CI
q ED/[(NH)pC02~]q R OR4 n s Hydrogenation Rs 48 E.D[(NH)PC02Rs]q -' I
Heck reaction 0 R N n O N E, D-[(NH)pC02R6]t Pd(0) q I-49 Rq Base n+2 ORq I-50 H E~ ,[(NH)pCO2R6]q boron tribromide ~ D R5 or lithium chloride boron tribromide n I or lithium chloride N N/~
'1 rE[(NH)PC02Re]q Buchwald amination H n Pd(0) R4 I-51 boron tribromide OH
Base - or lithium chloride / Rs HO E~D,[(NH)pCO2R6]q OR4 boron tribromide ~E, D~[(NH)pCO
48 n R5 or lithium chloride O N Y
' R4 Buchwald arylation 1-53 Cu(I) O N 0 nED~[(NH)PC02R6]q Base R4 I-52 Compounds of Formula I wherein Q is taken from Q-14 are prepared according to the synthetic route shown in Scheme 10. Starting from readily available pyridine 54, alkylation under standard conditions (K2C03, DMF, Rq-I or Mitsunobu conditions employing R4-OH) yields pyridine derivativ_e_55. N-alkylation with K2CO3, DMF, R4-I affords pyridones of formula 56. Intermediate 56, wherein M is a suitable leaving group, preferably bromine or chlorine, is partitioned to undergo a Heck reaction, giving I-57; a Buchwald amination reaction , giving I-59; or a Buchwald Cu(I) catalyzed 0-arylation reaction, to give I-60. The Heck reaction product I-57 may be optionally hydrogenated to afford the saturated compound 1-58. Wherein R4 is methyl, compounds of formula I-57, 1-58, I-59, or I-60 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-61, wherein R4 is hydrogen.
Scheme 10 R40, K2CO3 M OR4 DMAetoe R41; K2CO3 TIPS CXM
I
. ~ TIPS DMF or Acetone RqOH, Ph3P \
O N R5 Diethyl azodicarboxylate O N Rg O N RS
RS
E, iI(NH)p-C02Rr.]q OR4 n+
' D / EID, [(NH)p-C02Ra]q Hydrog ~ tion D
n ' 56 =~ (~n E [(NH)P C02~]q Heck reaction pd(0) O RN 4 RS 0 N. R5 Base I-57 R4 1-58 H2N E~, ,[(NH)p-C02Rs]q N E. /[(NH)P-C02Rs]q BBr3o~LiC1 D r D BBr3 or LiCI
56 ~ I n Buchwald amination 0 N R5 BBr3 or LiCI OH
Base 4 I-59 Y E~D~[(NH)p-CC
HO,W ~ ~[(NH)p-CO2R6]q OR4 D O-yED,[(NH)p-CO2R6]q BBr3 or LiCI 0 RN 4 R5 n C/
56 -~ I n Buchwald arylation 1-61 Cu(I) 0 N Re Base R 1-60 Compounds of Formula I wherein Q is taken from Q-15 are prepared according to the synthetic routes shown in Schemes 11 and 12. Starting esters 62 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions.
Reaction of protected secoester 62 with Meerwin's salt produces the vinyl ether 63 as a pair of regioisomers. Alternatively, reaction of 62 with dimethylamine affords the vinylogous carbamate 64. Formation of the dihydropyrimidinedione 66 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol.
Dihydropyrimidinedione 66 may optionally be further substituted by Mitsunobu reaction with alcohols R4OH
to give rise to compounds 67.
Scheme 12 illustrates the further synthetic elaboration of intermediates 67.
Removal of the silyl protecting group (TBS) is accomplished by treatment of 67 with flouride (tetra-n-butylammonium fluoride or cesium flouride) to give primary alcohols 68.
Reaction of 68 with isocyanates 2 gives rise to compounds of Formula 1-69. Alternatively, reaction of 68 with [R6O2C(NH)p]q-D-E-M, wherein M is a suitable leaving group, affords compounds of Formula I-70. Oxidation of 68 using the Dess-Martin periodinane (D. Dess, J.
Martin, J. Am.
Chem. Soc. (1991) 113:7277) or tetra-n-alkyl peruthenate (W. Griffith, S. Ley, Aldrichimica Acta (1990) 23:13) gives the aldehydes 71. Reductive amination of 71 with amines 8 gives rise to compounds of_Formula 1-72. Alternatively, aldehydes 71 may be reacted with ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73.
Reaction of 73 with isocyanates 2 affords compounds of Formula I-74.
Scheme 11 '-O O
O O Meer'"'in's. TBSO 0 O
Reagent OMe R4HN/~=NH2 TBSO OMe 63 R5 65 R4~N
R5 N(Me)2 0 TBSO
Dimethylami-te TBSO n 62 4A sieves' OMe R5 n R40H R4~N)~ NR4 Ph3P TBSO O
diethyl azodicarboxylate Scheme 12 R4\ 'i-1, 1IR4- R-r\ NpIC-(NH)p)q-D-C-N=C-0 R4\ N J, N N N NH
-- /NH' /O TBSO ~ 0 HO (R602C'(NH)p)q-D-E ~II/
n Q n n O RS
R5 [R602C-(NH)plq-D-E- 68 Re 1-69 O Oxidation R41~1 N NH O 0 1-0 ~ R4~ ~ [~02C-(NH~)q-D-C-NHZ R~\ ~
[RgOZC'(NH)P]q-D-E n 0 N NH g N
Reductive amination 0 (ReOzC"(NH)p]q-D-E
n n ammonium acetate (reductive amination) [R60:c-(NH)P)q-D-C-N=C-O R4 N
N 'J~ NH
H2N [RBOiC"(NH)p)q-D-E' NH y N
Rs RS
Compounds of Formula I wherein Q is taken from Q-16 are prepared according to the synthetic routes shown in Schemes 13 and 14. Starting esters 75 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions.
Reaction of protected secoester 75 with Meerwin's salt produces the vinyl ether 76 as a pair of regioisomers. Alternatively, reaction of 75 with dimethylamine affords the vinylogous carbamate 77. Formation of the dihydropyrimidinedione 78 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol.
Dihydropyrimidinedione 78 may optionally be further substituted by Mitsunobu reaction with alcohols R4OH
to give rise to compounds 79. Compounds of Formulae 1-81, 1-82, I-84, and 1-86 are prepared as shown in Scheme 14 by analogy to the sequence previously described in Scheme 12.
Scheme 13 11-1 o 0 0 Meerwin's RS OMe 0 O
ea gen Rs OMe 76TBS0 )n 65 R,, N NH
-- --+
Dimethylamine,} N(Me)2 0 R
TBSO n 4A sieves s 0 75 R5 OMe TBSO J n TBSO n ~ 0 ~ ,,Ra R4OH R4-_ N N
--=.
Ph3P
diethyl azodicarboxylate RS O
TBSO 'n Scheme 14 0 N N
FZ.-,~ NJ~ NR, (R602C-(NH)p]q-D-E-N=C=0 2 RS 0 r I-81 n \ OTBS [R602C-(NH)p]q-D-E-M gp OH NH-C-O-[(NH)pC02R, n n Oxidation R,~, /R4 R4,11, ,lia 1L )~ ~ [R60ZC-(NH~]q-D-E-NHZ
N N N N~ 8 R 0 Reduciive amination 1 RS O Rs O \ NH-C-D (NH)pCOyRe)c 1 ( I-84 O-E-D-[(NH)pCOpReJq 83 ' CHO O
ammonium acetate R,111AN"IR4 (reductive arnination) R4~ R4 [R60ZC-(NH)pJq-D-E-Nc C-O ~
N N 2 n NH
h--NH-E-D-((NH)p( N)4z _ -86 n Alkyl acetoacetates 87 are commercially available and are directly converted into the esters 88 as shown in Scheme 15. Treatment of 87 with NaHMDS in THF, followed by quench with formaldehyde and TBSCI (n = 1) or Q-(CH2)n-OTBS (n = 2-4), gives rise to compounds 88.
Scheme 15 ~We 1. NaHMDS, THF
RS 2. CH2O quench; R5 OMe 87 or Q-(CH2)n-OTBS ~
n OTBS
88, n> 1 O O
(for n = 1) R5 OMe TBS-Cl, pyridine, OTBS
CHZCIZ 8+ n = 1 Compounds of Formula I wherein Q is taken from Q-17 are prepared according to the synthetic routes shown in Schemes 16.1 and 16.2, and starts with the BOC-protected hydrazine 13, which is converted to the 1,2-disubstituted hydrazine 89 by a reductive alkylation with a glyoxal derivative mediated by sodium cyanoborohydride and acidic workup. Condensation of 89 with diethyl malonate in benzene under reflux yields the heterocycle 90. Oxidation with N204 in benzene (see Cardillo, Merlini and Boeri Gazz.
Chim. Ital., (1966) 9:8) to the nitromalonohydrazide 91 and further treatment with P205 in benzene (see: Cardillo,G. et al, Gazz.Chim.Ital. (1966) 9:973-985) yields the tricarbonyl 92.
Alternatively; treatment of 90 with Brederick's reagent (t-BuOCH(N(Me2)2, gives rise to 93, which is subjected to ozonolysis, with a DMS and methanol workup, to afford the protected tricarbonyl 92. Copound 92 is readily deprotected by the action of sF in THF
to yield the primary alcohol 94. Alcohol 94 is optionally converted into the primary amine 95 by a sequence involving tosylate formation, azide displacement, and hydrogenation.
Scheme 16.1 1)~,OTBS EtO OEt O '1~~ O
H O
BOC NaCNBH3, CH3CN /~ ,OTBS O O N24 -R4N-NH2 H+ - RHN-H~ ~/ -y R4N-N R N-N
13 2) 89 90 \'~OTBS 4 \--~OT
t-BuO-CH(NMe)z)z PzOs (Me)ZN
~ Me0 OMe 0 oxonolysis O
MeOH/DMS
~~OTBS
CsF, THF
MeO OMe 1) tosyl chloride, base O O MeO OMe -2) NaN, O
R4N-N 3) hydrogenation \/\NH2 R4N-N
Reaction of 94 with (hetero)aryl halide 26, wherein M is iodo, bromo, or chloro, under copper(I) catalysis affords compounds I-96. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Formula J. By analogy, reaction of 5 amine 95 with 26 under palladium(O) catalysis affords compounds of Formula I-97. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Formula I-99.
Scheme 16.2 MeO OMe HO OH
Me0 OMe NOZC (NH)p]q-D-E'M 0 0 O" O
26_ H+ HzO
Cu(I), base R N-N\_'.~O~-E-D-[(NH)pCO2R6]q \'--\0."E-D-[(NH)pCo;
\--'OH 1-98 M Me0 OMe HO OH
Me0 OMe [R6OZC-(NH) O ~ H20 p]q-D-E~ 0\\~/~O
0~~~~~0 26 ---i R4N-N Pd(0), base R4N-N~~NH~E-D-I(NH)pC02Rs)q R4N-N~~NH~D E I(NH)pCC
'\,"\NH2 Compounds of Formula I wherein Q is taken from Q-17 are also prepared according to the synthetic route shown in Scheme 16.3. Deprotonation of 4,4-dimethyl-3,5-dioxo-pyrazolidine (95a, prepared according to the method described in Zinner and Boese, D.
Pharmazie 1970, 25(5-6), 309-12 and Bausch, M. J.et.al J. Org. Chem. 1991, 56(19), 5643) with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide yields I-99a.
Scheme 16.3 O
HN
ICI HN-NH ~_N
[R602C-(NH)p]q-D-E-Y [R6O2C-(NH)p]q-D-E-Y
8a 95a 0 I-99a Compounds of Formula I wherein Q is taken from Q-18 are prepared as shown in Schemes 17.1 and 17.2. Aminoesters 100 are subjected to reductive alkylation conditions to give rise to intennediates 101. Condensation of amines 101 with carboxylic acids using an acid activating reagent such as dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOBt) affords intermediate amides 102. Cyclization of amides 102 to tetramic acids 104 is mediated by Amberlyst A-26 hydroxide resin after trapping of the in situ generated alkoxide 103 and submitting 103 to an acetic acid-mediated resin-release.
Scheme 17.1 R5 o 0 R4CH0 0 RSCHZCOZH 0 ~
NHZ _ R60)1-lr-- NH-/R4 0 ~O~NR4 R60-1~ c M' DCC, HOBt M
M. NaBH(OA)3 102 NMe3+ OH O O C H+, R4OH O
~-NMe3 0 Z) R40 N,R4 NRn M. M
M' is t-BuOCH2-, BOCNH(CH2)3-, BOCNH(CH2)4-, HC-C-CH2- 103 M is HOCH2-; HZN-(CHZ) H2N-(CH2)4-; HC=C
Scheme 17.2 illustrates the synthetic sequences for converting intermediates 104 to compounds of Formula I. Reaction of alcohol 104.1 with aryl or heteroaryl halide 26 (Q =
halogen) under copper(I) catalysis gives rise to compounds of Formula 1-105.1.
Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(0) catalyzed amination conditions affords compounds of Formulae 1-105.2 and 1-105.3. Reaction of acetylene 104.4 with 26 under. Sonogashira coupling conditions affords compounds of Formula 1-105.4.
Compounds I-105.4 may optionally be reduced to the corresponding saturated analogs I-105.5 by standard hydrogenation.
Scheme 17.2 Rs O R5 O
O ~
~O ~ IReO2C-(NH)PIq-D-E'M R4 N Rn 6 N~ R4 Cu(1), base OH ~--E-D-I(NH)pC02R6]q 104.1 1-105.1 / [R602C-(NH)p]q-D-E' ~
Ra0 N\/ Ra 26 N~ R4 Pd(O), base n NH~E-D-I(NH)PC02R61q NHz 1-105.2, n = 3 104.2,n=3 I-105.3,n=4 104.3, n = 4 RS IReO2C-(NH)PIq-D-E'M R5 O R5 O 26 Hydrogenation R,4 0 R4O --~ N ~
R"O N R PdC12(Ph3P)Z, Cul N~R
~ 4 Base \ (Sonogashira Coupling) E-D-[(NH)pCO2R6)q qIR6O2Cp(HN)]-D-E
104.4 1-105.4 1-105.5 Compounds of Formula I wherein Q is taken from Q-19, Q-20, or Q-21 are prepared as illustrated in Scheme 18. Commercially available Kemp's acid 106 is converted to its anhydride 107 using a dehydrating reagent, preferably di-isopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Reaction of 107 with amines affords the intermediate amides which are cyclized to the imides 108 by reaction with DIC or EDC. Alternatively, 107 is reacted with amines 8 to afford amides of Formula 1-110.
Amides 1-110 may optionally be further reacted with DIC or EDC to give rise to compounds of Formula 1-111. Acid 108 is further reacted with amines 8 to give compounds of Formula 1-109.
Scheme 18 O Ra O
CO2H COZH DIC or EDC HO~ f O O 1) IZ,qNH2 HO~jO N
b3C0 CH3 O I O H3C CH CH3 H3C 3 2) DIC or EDC 3C
[R602C-(NH)p]q-D-E R4 0 [R602C-(NH)p]q-D-ENH HN~O N
O
DIC, HOAt [R602C-(NH)p]q-D-E [R602C-(NH)p]q-D- i [R602C-(NH)p]q-D-E 1.
NHz NH O CO2H DIC or EDC HO~O N
Compounds of Formula I wherein Q is taken from Q-22 or Q-23 are prepared as shown in Schemes 19.1 through 19.3. Preparation of intermediates 113 and 114 are prepared as shown in Scheme 19.1 from di-halo(hetero)aryls 112, wherein M2 is a more robust leaving group than Mi. Reaction of 112 with amines 37 (Z = NH) either thermally in the presence of base or by palladium(0) catalysis in the presence of base and phosphine ligand affords compounds 113. Alternatively, reaction of 112 with alcohols 37 (X = 0) either thermally in the presence of base or by copper(I) catalysis in the presence of base affords compounds 114.
Scheme 19.1 [R6O2C-(NH)p]q-D-E-Y,-IZH
M Mi W/Z~Iw 37, Z = NH WII\W
M2 I~ Base [~OzC (NH)plq D E Y~N I /
H
M, [R6O2C-(NH)p]q-D-E-Y-IZH W 111~w 37, Z = O [R602C-(NH)plq-D-E-Y~O~
Base 114 Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117. Treatment of 113 with aqueous copper oxide or an alkaline hydroxide affords compounds of Formula 1-115. Alternatively, treatment of 113 with t-butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517. Treatment of the t-butyl sulfide 116 with acid affords the desired thiols of Formula 1-118. Alternatively, 113 may be treated with excess ammonia under pressurized conditions to afford compound 117.
Mi Scheme 19.2 w~w [RsOZC (NH)p]q-D-E-Y,, N I Z
H
aq CuO t-BuSH excess NH3, or Cul, K2COJ base KOH ethylene glycol /~.u NH2 w ~w w w ww [R6O2C-(NH)p]q-D-E-Y, N I 0~ [R802C-(NH)p]q-D-E-Y,~ N I / [R602C-(NH)p]q-D-E-Y,, N I 0 H
H+
SH
w~w [R602C-(NH)p]q-D-E-Y,, N ~.
H
Scheme 19.3 illustrates the conversion of intermediate 114 into compounds of Formula I-119. I-122, and 121, by analogy to the sequence described in Scheme 19.2.
W ~W
Scheme 19.3 I) R602 C- ( N H) p]q-D-E-Y~ O/o) aq CuO t-BuSH excess NH3, or Cul base ethylene glycol OH StBu NH2 W \W W111~W VNl-k~lW
R602C-(NH)p]q-D-E-Y,,O ~ R602C-(NH)p]q-D-E-Y,, O)L"O~ R602C-(NH)p]q-D-E-Y,, O
I ~
H+
SH
WW
R602C-(NH)plq-D-E-Y,, O I /
Compounds of Formula I wherein q is taken from Q-24, Q-25, or Q-26 are prepared as shown in Scheme 20. Reaction of compounds 1-115 or 1-119 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R4)2 gives rise to compounds of Formulae 1-123 or 1-124. Reaction of compounds 1-118 or 1-122 with a peracid, preferably peracetic acid or trifluoroperacetic acid, affords compounds of Formula I-125 or 1-126. Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R4)2 or alcohols R4OH, affords compounds of Formulae I-127, 1-128, I-129, or 1-130.
Scheme 20 /~ /\
W. W W W i W
R802C-(NH)p)q-D-E-Y_, Zlyl") R802C-(NH)pjq-D-E-Y~,Z~ ReOzC-(NH)plq-D-E-YNZ' V
I-115,Z=NH I-118,Z=NH 117,Z=NH
1_119,Z=O 1-122,Z=O 121,Z=O
1) Chlorosulfonyl- 1) Chlorosulfonyl-isocyanate Peracetic acid isocyanate 2) HN(R4)2 2) HN(R4)2 or R4OH
0 o p 0 \\ 1j D/ 'NS/N~Ra j O3H HN~H~S\ i/Ra H /\
~ Ra W~W R " \, R602C-(NH)p)q-D-E-Y / I1'V W ~W
I~ ~ ReD2C'(NH)plq-D-E-Y~Z / ReO2C-(NH)plq-D-E-Y~ Z
Z/p~j I/
~
11_123,Z=NH 1-125,Z=NH 1-127,Z=NH
I-128, Z = O
I_124, Z= 0 I-126, Z= 0 O \\ 0 /INIg' OR4 HN H
WlkW
Z
RsOZC-(NH)plq-D-E-Y., I /
1-129, Z = NH
1-130, Z = 0 Compounds of Formula I wherein Q is taken from Q-27 are prepared as illustrated in Scheme 21. Reductive alkylation of thiomorpholine with aldehydes 131 affords benzylic amines 132, which are then subjected to peracid oxidation to give rise to the thiomorpholine sulfones 133 (see C. R. Johnson et al, Tetrahedron (1969) 25: 5649).
Intermediates 133 are reacted with amines 8(Z = NH2) under Buchwald palladium-catalyzed amination conditions to give rise to compounds of Formula I-134. Alternatively, compounds 133 are reacted with alcohols 8(Z = OH) under Buchwald copper(I) catalyzed conditions to afford compounds of Formula 1-135. Alternatively, intermediates 133 are reacted with alkenes under palladium(0)-catalyzed Heck reaction conditions to give compounds of Formula I-136.
Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide.
s OS s-o Scheme 21 CHO (N) peracid NaBH(OAc)3 oxidation O Q Q
- - ~~
[ReOsC (NH)p]q D E Y,, IRs02C-(NH)p1q-D-E 7/
NH2 S~O n \
8 ~/
133 pd(0), phosphine, \ 133 Pd(0), Ph3P, base I base ~. / IRe02C (NH)p)q D E F 1-136 [R802C-(NH)p]q-D-E-Y-NH n reduction (hydrogenatio:
diimide) [R802C-(NH)p]q-D-E-Y~ O
OH ~S-~O
133 8 N,,) Cu(I), base N
[R602C-(NH)p]q-D-E-Y-d IR602C-(NH)plq-D-E r)n 1-137 Compounds of Formula I wherein Q is taken from Q-27 are also prepared. as illustrated in Scheme 21.1. Aldehyde 8c is reductively aminated with ammonia, and the resultant amine condensed with divinyl sulphone to yield 1-134. Intermediate 134a is also available by reduction of amide 8d under a variety of standard conditions.
Scheme 21.1 [R602C7(NH)p]q-D-E-Y_ - _H._. _.[R6O2C-(NH)p]q-D-E-Y~NH2 8c NaCHBH3 134a Amide reduction 0 i.e. LAH
S
0 [R602C-(NH)p]q-D-E-Y NH2 [R602C-(NH)p]q-D-E-Y ~ OS-\~- 8d O
More generally, amines 134c are available via the reduction of amides 134b as shown in Scheme 21.2. The morpholine amide analogues 134d and morpholine analogues 134e are also available as shown in Scheme 21.2.
Scheme 21.2 [R602C-(NH)p]q-D-E-YOH R, R2NH [R602C-(NH)p)q-D-EY'k NRjRZ
DIC coupling 8e 134b H
N
C Amide reduction OJ DIC coupling i.e. LAH
[R602C-(NH)p]q-D-E-YN--~) [R602C-(NH)p]q-D-E-Y~NRI R2 134c 134d Amide reduction i.e. LAH
[R6O2C-(NH)p]q-D-E-Y "I-, N
134e Compounds of Formula I wherein Q is taken from Q-28 or Q-29 are prepared according to the sequences illustrated in Scheme 22. Readily available amides 138 are reacted with chlorosulfonylisocyanate to give intermediates 140, which are Teacted in situ with amines HN(R4)Z or alcohols R4OH to afford compounds of Formulae 1-141 or 1-142, respectively. Alternatively, amides 138 are reacted with sulfonylchlorides to give compounds of Formula 1-139.
H N CI
O N~ ISO
Scheme 22 CONH2 O O HN(R4)2'or I \ C1SO2-N=C=O R40H
base [ReO2C-(NH)p]q-D-E _Y [R602C-(NH)p]q-D-E , Y
R4 Ra I
H
O
O N~N / S R4 N N to [Re02C-(NH)p]q-D-E~ Y/ [R602C-(NH)p]q-D-E~Y
O HN-S
::~O
each Z is individually selected from the group consisting of -0- and -N(R4)-;
and each ring of formula (IA) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls (preferably C,-C18, and more preferably C,-C,Z), aryls (preferably C6-C,8, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably C,-Ct8, and more preferably C,-C12), arylaminos (preferably C6-C,8, and more preferably C6-C,Z), cycloalkylaminos (preferably C1-C18, and more preferably C1-C12), heterocyclylaminos, hydroxys, alkoxys (preferably C,-C18, and more preferably C,-C12), aryloxys (preferably C6 C,8, and more preferably C6-C,2), alkylthios (preferably C,-C18, and more preferably C,-C,Z), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls (preferably C,-C18, and more preferably C,-C,2), alkylsulfonyls (preferably C1-C18, and more preferably C,-C,2), aminosulfonyls, and perfluoroalkyls (preferably C,-C18, and more preferably C,-C,2).
In one preferred embodiment, the compound has the structure of formula (I) except that:
when Q is Q-3 or Q-4, then the compound of formula (I) is not Ph O
y O~N~O H / I O N\ / O NPh Me0 / N\H O~NN \ ~~N NH2 SX Ph/N~ or ph O Z
OEt O
when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
when Q is Q-7, R5 is -OH, Y is -0-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, then the compound of formula (I) is not 0 N Me 0 Me 0 NH ,~ rH, O 0 ~
N \ 0 O tJ y NH N ~
O
H~0 1 -O HO O 0 tOEt S ~N
S I~ S \ ~ . N~NH OJ Me HN / O I/ O ~ Me \ N HN
I N' N
0 HN F / ~ Ph ~
0 NH 0 NH.
Rso, O H, N 0 N
~ ReZ
Ret o I~
R80 is H, Me R82 is substituted phenyl R8l is substituted phenyl when Q is Q-8, then Y is not -CHZO-;
when Q is Q-8, the compound of formula (I) is not H
N~ ,~
O~ SaO H
N O
R'o / N\ or O~ S'O I ~ CF3 0 oS I\ Ri0 0 RIO = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not O Ph 40 Me'"H O\S O N
HO H, 0 ~NHO ON HZN (1\
CHz)a \% Ph S NN Rta Rta N
N R~5 Ris NO 0 N~fl O I ~NO
Rit NH 02N S ~N OZN S
O~! O R12 ' 0 R14 Rl I H, alkyl, alkoxy, nitro, halogen 1112, R13 = H, alkyl R
14= H, alkyl, allyl, propargyl RIS = H. alkyl, N )~ NH
NN~Rjs \ ~ ~ ~ Mee 0 \O ' O TN~N Me N HO
~ \ R 0 NN Rie R~"~\O
~ / ~a I , or R17 NC ~ R16=H,methyl R17,R18=alkyl R19 = H, alkyl when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-10, then the compound of formula (I) is not PM N
O O S O
N N~S O t-BuO H H 3 H
when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-1 1, then the compound of formula (I) is not i-Pr Ph H H
N~ e N~O
Os0 i-Pr Ph ~ ~
when Q is Q-15, then the compound of formula (I) is not H J I R~ H H I Ri H H Nl / O N
O/~ N N 0 N'N ~ R20 N~Ph H O ~S~R21 H O S RZ1 O~H N \ H~ I I rz\ H
R20 Ry1 , or R20 = substituted phenyl, RZi = H, alkyl when Q is Q-16 and Y is -NH-, then H
(R i-X~-A4N
~-D-E
~-L-~Np of formula (I) is not biphenyl;
when Q is Q-16 and Y is -S-, then (R I -X}--A4N~--L-(N~-D-E
m p p of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;.
when Q is Q-16 and Y is -SOZNH-, then the compound of formula (I) is not O
Ph-N~ ~ ~ HsCY N ~
N H I~ p p p H ~/qS O N ~/S 0 ~ N.S NH H II NH R22 H, ~~
H ~ C.~
H~O H O R22 = Me, OH H p Rza R26 NC N N
N \ 1 O O
I\ \ I\ O\ O I\ I~ 0 O
x S NH N~ L NH
R24 H ~ Rza H
R25 xs H 0 H ~ or N "eNH
H H,~O
R23 = OH, SH, NH2 when Q is RZy = hydrogen or one or more methoxy, hydroxy, fluoro, chloro, nitro, dimethylamino, 1 5 Q-16 or furanyl Ru = substituted phenyl, furanyl R26 = OH or CI
a n d x5 = 0, r,H;
Y is -CONH-, then (RI-X}-A4N~-L-~N~-D-E
m p p ~
of formula (I) is not imidazophenyl;
when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not Rz7 n N-N O
HzN t N OI NH
Rze H H~O
R2, = substituted phenyl, pyridylcarbonyl R=r - CN, methoxycarbonyl n0or1 when Q is Q-16 and t is 0, then (RI-XFA-()-L-(-D-E
m p P
of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
when Q is Q-17, then the compound of formula (I) is not ~
n-Bu ~ / R31 O O NR30 or N 41, R~ H N
2s ~ O
R29 = alkyl n-Bu 0 R30 = H, t-Bu, benzoyl R31 = substituted phenyl when Q is Q-2 1, then the compound of formula (I) is not HOZC R
O
N
O ~./
Ph when Q is Q-22, then the compound of formula (I) is selected from the group consisting of N N\ NHx(NH)p-A-(X-Rt)m N~ ~ Ou N H~(NH)p-A-(X-Rl)m wl.w J
OH W OH
NH-L-(NH)p-A-(X-R)m R4 NH-L-(NH)p-A-(X-Rj)m ONH
O NH
Wl%W w OH ' and W~OH
when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of \ N
N N
N CO-(NH)p-A-(X-R,)m N A-(X-R,)m NN~ CO-(NH)p-A-(X-RI)m N A-(X-RI)m I -I -I w W .W WfW I
~ ~' wOH W OH
OH OH
CO-(NH) p-A-(X-Rl)m A-(X-Rl) m CO-(NH)p-A-(X-Ri)m A-(X-RI)m X Xw yy and W w1,W w~wL~OH w'I'OH
OH OH
but excluding Ra1 H O N I\ R3s 0 R
O O / I.Rao R3B R37 = N(Me)2, I\ H R35 \ N\ R39 morpholino, OMe, OH, H
/ R34 = Me, CI I H R38 = H, CN, OMe, OH, R
HO 34 R35 = -N(Me)2, morpholino // Me benzyloxy, phenyl, nitro meta or para- R36 = H, F HO meta or para- R39 = H, OH
R40 = H, F
R41 = H, CI
O OMe 0 N
N
HN I/ HN HN
Me OMe N
\ N \ \ N \ \ N
I H I H , I H
lO HO Me HO / Me and meta or para- OH meta or para-MeO NvNHMe Me0 i'IN
O
H
~ \ N
meta or para-when Q is Q-23, then the compound of formula (I) is not R42 (CH2)yMe i I
H ~ ~ I
~ /
N N
HSI/ N~ ~ H
HS R42 - H, Me HS
-Me 0~ 0 ~N
S o / r~
i H
HS HS , HS ~
S02NHz ci t-Bu ~ N ci 15 HS O HN,S t-Bu 0 N& H H~~ SH
CI
N \
HS S O :C)-r SH
, or C11 when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of R~}}~~ W
'/~ \\ II IIW
, N/~N N' A-(x-Rt)m w N~NnA-(X-Rt)m A-(X-Rt)m ~Gt OII ~Gt O Gt pL
N//
Nl~N A-(x-Rt)m N
H "F
N -(X-Rt)m q'A-(X-Rt)m W ~W R7 0 WJLIW O W~W 0 \ JII' ~A (X Rt)m \ ~ ~ \ ~ ~I~O
' H H q A-(X-Rt)m N' S"A-(X-Rt)m o~/YWY A-(x-Rt)m O S.N~!W N'A-(X-Rt)m OyN'rW
NA-(X-Rt)m = WR~ ' I IWI~%(R , and HN W~ 'R7 wherein each W is individually selected from the group consisting of -CH- and -N-;
each G, is individually selected froni the group consisting of -0-, -S-, and -N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
0 0 o o 0 ~ O o oo \% // o 0 S. .R4 fI S. 4 Ra ~,.Z-Ra O~ Z, O H N O J~N.S.NRa HN N N HNI~N.S.NRa O~S ~S Ra Ra H Ra \ Ra H O~
Ra or~
L ~ ~* Y-J =
Q-24 Q-25 Q-26 or Q-31 wherein each Z is individually selected from the group consisting of -O-and -N(R4)-;
when Q is Q-31, then the compound of formula (I) is not /'O OS N~
S H
CI I CI HN~
CI / N' N~
~ CI
or ~
O~ 0 O
H SH I/ H
\
N N
~o s o when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not \ I \
N
\ \ \ H
N
or I I /
N, CH3 N, .CH3 O OSO
O ~ 0 .~
R46 = hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not Ph p OS ~ S
~ H
O
or N, H
N
Ph---~ ~O OS~p S O
when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not N H NS
/ N H Me Ph 0 when Q is Q-32, then ~.-D-E-Y
(Ri-X~-A4N~-L-~Np is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
when Q is Q-32, Y is -CONH-, q is 0, m is 0, and N~-L-~N~--P
of formula (I) is -CONH-, then A is not phenyl;
when Q is Q-32, q is 0, m is 0, and 4NH~L-N4 P
is -CONH-, then the compound of formula (I) is not 0 R~ de Ru R60~~' M 0 H
R60 or RgOO-.F~. N
H H
H H 0 Rss S_ /,R47 Ph \( Me N~N
Rae R5+ ssYN
Rso m/ Ru or Z+~
XN
R54 = benzoyl, phenylalkylaminocarbonyl, substituted phenylaminocarbonyl H. Br R47 = alkyl, substituted phenyl, thienyl, phenacetyl R55 = Cl, Br, SPh, benzoyl, phenylsulfonyi naphthyl R51 = H, phenylsulfonyl, phenyl, benzyl Rqa = H, alkyl, Br, substituted phenyl, benzoyl, R6 = Et, i-Pr phenylsulfonyl R53 = substituted phenyl, substituted benzyl R49 = H, alkyl, phenyl Xt = 0, N-Ph, N-alkyl, N-carbamoyl Rsn = substituted phenyl Z t= N(R50), 0 when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone;
when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
whenQisQ-32,Dispyrimidylqis0,tis0,pis0,nis0,andmis0,thenAisnot phenyl;
when Q is Q-32 and Y is an ether linkage, then ~-A--~N~--L--4N-E
(R ~ X p p of formula (I) is not biphenyl or phenyloxazolyl;
when Q is Q-32 and Y is -CH=CH-, then m p E
of formula (I) is not phenylaminophenyl;
when Q is Q-32, then the compound of formula (I) is not R56 0 Raz N
II
~I xt RaoO ~P' /~ H O
AlkylO ~ Fs H ~ N ReoO /~t\--(~~~ N
AlkylO ~~ N b H H O d Rat ~
b= 0-1 R6oO ~ p H \N
Xt = O, S RaoO ~~ N
R56 = H, CF3, Cl, imidazolyl, amino, morpholino, phenylthio, H H d R
cycloalkyl, benzyl, phenyl, phenoxy, thienyl, substituted alkyl, O e7 pyridylthio, pyrimidyl, benzylamino, N-benimidazolyl, 0 O-N
pyridylcarbonylamino, ureido,N- thiourea, substituted alkanoylamino, Rso0 - H
phenylsulfonyl, substituted benzoyl, phenylalkenoyl, furanoyl, R600 N
thienoyl, pyridinoyl, HH d R
R57 = substituted phenyl, substituted biphenyl 0 63 Ra 0 R830~P H 6111~
o0-P Ra'ON ~ or Ra O~ H H~ d R ; and H H p O R59 61 d=0-2 R58 = substituted alkylaminocarbonyl, phenylaminocarbonyl R60 = H, alkyl R59 = H, CI R61 = substittited phenyl, thienyl, Br R62= H. alkyl, phenyl R63 = substituted phenyl when Q is Q-35 as shown ~ZRjp ZRjo (G/k " u (G k I \ \
Q-35 (para) Q-35 (meta) wherein G is selected from the group consisting of -0-, -S-, -NR4-, and -CH2-, k is0or 1, and u is 1, 2, 3, or 4, then R~ X~A~N~-L---~N~D-E-Y
is selected from the group consisting of A-[(X)1-R,]m W O~y C~' ~ O w w OII 20 1R
~N ~ I', A-I(X)1-R,lm R~ a.AI(X)1Rt]m q_ o S,Y~- A-I(X)1 R,lm R7 W W~W O A W R~
O ( ~~A-I(X)1-Rt1m H~A'I(X)J Rt1m W N A- X-R m o~,aY [( )'~ ,1 R~ HN W ~ R7 W~W O A
s~ ' i 0 ~\N a~ "A-[(X)1-Rt1m H ~ A'[(X)1-R,1m N Gt OII R7~Gt 0 R7 Gt o0 Hl, A [(X)1 Rtlm N N .~"
~j ~ A-I(X)1-Rt]m ~q A-I(X)1-R,1m , =
õ
r N~A-((X)j-RI]m N~A-[(X)j-Rtlm ~N A-I(X)j-Rtjm ~ =
R7 R7 R7 ~G ~Ct Y/", ~N~A-I(X)j-Ri]m N~A-[(X)j-Rtlm NA-I(X)j-Rt]m WIIII W W'lW
A-I(X)j-Rilm \ (A-I(X)j-Rjlm \ (A-((X)j-Rj]m O4z~ zra~W A-I(X)j-Rilm O H W A-I(X)j-Ri1m Oy a W A-I(X)j-Rt1m W Ry O\'N W~% R7 , and HN W R7 except that the compound of formula (I) is not Me / I C02R71 Me COZH R
\ ia Ph ~\(CH2)nCO2R75 R71 meta, para ~W4 W N R72 28.1 R73 =-OCH2CO2H R75 = H, Et ~ W4 H R71 = H, Me R72 thiezolyl, isoxazolyl R74 = oxazolyl, imidazolyl R78 R76 = H. NH2, N02 W4 = N, CH imidazolyl, furyl 28.2 R73 C02Me n 0-1 R74= chlorophenyl CI
~ ~
CO R
X3 2 n ~COzR7a O-N
~ ~
meta, para Me Ph NH
O R77 = H, alkyl )- ~ COZH
HN NH I
HN X3=OorCH2 R78=H,alkyl 0 O /
N{
COpMe NH
NN ~ R~ O Me / O ~ 'N
HZN ~C02Et N \ N~ I R70 / WZ -~ NH RasH H I\ N O CO-Ra7 O meta, Pera / / C02Me H
O 2Me COZR65 MeO / 1 O R67 = OH, NH2 F3C I/ ~ (\ C02RS6 R68 = CF3, Me Me0 R70 = 2-MeSO2-phen-1 =yi, 2-NH2SO2-phen-I-yI, meta, para morpholino, imidazolyl, N(Et)2 OMe 0 R65 H. El R66 = alkyl W 2 CR69 or N
O N~ I
OMe ~ N \
HZN' /N OMe I H
1~ H3C NU N /
N~ I ~ I \ N 0 O
NH2 \ I / I \ COzH
R79 = H, Me C02R79 or \ I\ N ~
O
Even more preferably, R, as discussed above is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls, and even more preferably, R, is selected from the group consisting of I W N
W \
Jl . (0) ' W
L ~ ~N .N ) . N RZ W W N O O
R2 Rz H
.nnn R. 20 R~ r-{ ~--~
~ W
~W~ (W_ NYS N~ S, Ro 'N ",R4 o O, o o z ~
i \ ~N~A ~R? Dw, R ccN,R5 ~RZ
~
, R2 o a-a R4 each R2 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C1-C12), aminos, alkylaminos (preferably Ci-C18, and more preferably Ci-C~z), arylaminos (preferably C6 C,g, and more preferably C6-C12), cycloalkylaminos (preferably C,-C,8, and more preferably C1-C12), heterocyclylaminos, halogens, alkoxys (preferably C1-C18, and more preferably C1-C12), and hydroxys; and each R3 is individually selected from the group consisting of -H, alkyls (preferably C1-C18, and more preferably C,-C,Z), alkylaminos (preferably C1-C18, and more preferably C,-C,Z), arylaminos (preferably C6 C,B, and more preferably C6-C,Z), cycloalkylaminos (preferably C1-C18, and more preferably C,-C1z), heterocyclylaminos, alkoxys (preferably C,-C,g, and more preferably C,-C1z), hydroxys, cyanos, halogens, perfluoroalkyls (preferably C,-C18, and more preferably C,-C,2), alkylsulfinyls (preferably C1-C18, and more preferably C,-C,2), alkylsulfonyls (preferably C1-C1B, and more preferably C,-C,Z), R4NHSO2-, and -NHSOZR4.
Finally, in another preferred embodiment, wherein A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and w;w'~
w - J
'w, w, where each W, is individually selected from the group consisting of -CH- and -N-.
An additional class of compounds useful in the invention have the formula A-T-(L)n-(NH)p-D-(E)q-(y)t-Q
(IB) wherein:
Y is selected from the group consisting of -0-, -S-, -NRb-, -NR6S02-, -NR6CO-, alkynyls (preferably CI-C18, and more preferably CI-C12), alkenyls (preferably Ci-C18, and more preferably CI-C12), alkylenes (preferably Ci-C18, and more preferably Ci-C12), -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably Ci-Cia, and more preferably CI-C12), -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CHZ)h- the introduction of the side-chain oxo group does not fonm an ester moiety;
A is selected from the group consisting of aromatic (preferably C6-C18, and more preferably C6-C12), monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and .nnr w;wL w, W'w,- '", J
where each W 1 is individually selected form the group consisting of -CH- and N-.
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selectedfrom the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)z-;
T is NR6, 0, alkylene (preferably CI-C12, more preferably CI-C4), -O(CH2)h-, or -NR6(CH2)n-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, or T is absent wherein A is directly bonded to -(L)õ(NH) P-D-(E)q -(Y) -Q;
n is 0 or 1;
pis0or1;
qis0orl;
t is 0 or 1;
v is 1,2, or 3;
xislor2;
Q is selected from the group consisting of formulae Q36- Q59, inclusive;
each R4 group is individually selected from the group consisting of -H, alkyls (preferably CI-C18i and more preferably Cc-C12), aminoalkyls (preferably Cl-C18, and more preferably CI-C12), alkoxyalkyls (preferably CI-CIs, and more preferably Ci-C12), aryls (preferably C6-C,8, and more preferably C6-Ci2), aralkyls (preferably C6-Ci8, and more preferably C6-Cc2 and preferably CI-C18, and more preferably CI-Ci2), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R6 is individually selected from the group consisting of -H, alkyls (preferably CI-C18, and more preferably Ci-C12), allyls, and B-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls (preferably Ci-C18, and more preferably CI-Q2), phenyl, naphthyl, aralkyls (wherein the aryl is preferably C6-C]8, and more preferably C6-C]2), wherein alkyl is preferably CI-C18, and more preferably CI-CiZ), heterocyclyls, and heterocyclylalkyls (wherein the alkyl is preferably CI-C,g, and more preferably Ci-C12);
each R9 group is individually selected from the group consisting of -H, -F, and alkyls (preferably Cl-C18, and more preferably CI-C12), wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R9, group is individually selected from the group consisting of -F, and alkyls (preferably CI-C18, and more preferably Ci-C12), wherein when two R9, groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each RIo is alkyl or perfluoroalkyl;
G is alkylene (preferably CI -C8, and more preferably Ci-C4), N(R6), 0;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (1) optionally includes one or more of RT, where RT is a substituent individually selected from the group consisting of -H, alkyls (preferably Ci-Ci8i and more preferably CI-C12), aryls (preferably C6-CI8, and more preferably C6-C12), heterocyclyls, alkylaminos (preferably CI-CI8, and more preferably CI-C12), arylaminos (preferably C6-CI8, and more preferably C6-C12), cycloalkylaminos (preferably Ci-CI8, and more preferably CI-Ci2), heterocyclylaminos, hydroxys, alkoxys (preferably C1-C18, and more preferably Ci-C1z), perfluoroalkoxys (preferably Ci-C8, more preferably Cl-C4), aryloxys (preferably C6-C18, and more preferably C6-C12), alkylthios (preferably CI-C18, and more preferably Ci-Ciz), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls (preferably Ci-C18i and more preferably CI-C12), alkylsulfonyls (preferably CI-C18, and more preferably CI-C1Z), aminosulfonyls, perfluoroalkyls (preferably CI-C18, and more preferably Cl-C12);
aminooxaloylamino; alkylaminooxaloylamino; dialkylaminooxaloylamino;
morpholinooxaloylamino; piperazinooxaloylamino; alkoxycarbonylamino;
heterocyclyloxycarbonylamino; heterocyclylalkyloxycarbonylamino;
heterocyclylcarbonylamino; heterocyclylalkylcarbonylamino;
aminoalkyloxycarbonylamino; alkylaminoalkyloxycarbonylamino; or dialkylaminoalkyloxycarbonylamino.
In a preferred embodiment, A as described above is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and N/ ~ W~
W-W
i W, where each W, is individually selected from the group consisting of -CH- and -N-.
Q groups Q-36 through Q-59 are set forth below. In an additionally preferred embodiment, Q is taken from Q-37, Q-39, Q-41, Q-42, Q-43, Q-44, Q-47, Q-48, Q-54, and Q-57; in a more preferred embodiment, Q is taken from Q-39, Q-41, Q-42, Q-43, Q-44, Q-47, Q-48, and Q-54.
O~NNrp p, p pzz( S O p S O
,N-S N-NN-N N
, , R4 R4 R4 R4 %R4 R4 R4 ~R4 rLnnr Rs' R9' ~
I
p N p OgO 0 .R4 GZ'R4 R N' H R4 A
Z' N N oz_- O
4 R4 R4 Q-40 Q-41 (N) pQ-42 vtrt. '~n' vtrt, ~~ ~
G~~ G~~ I ~ ~
V ?V ~V R9R / R4-pp ~
S.
R4 p p R60 Rlp 'V1IL, 'ViJL Ln.r1.. L.ll.lL . ~V1r\, ~
HN ON ON pN p,%-N
p R8 R _N7 1%~NH O' NH
4 R4 pz:S yf~
N, Q-49 Q-50 Q-51 R4"I N, R4 Ra R4 ~ = ~ ~õn, 0 I 'V ~~V ~ S .~ ~ ~p p ~ ~p N, N. / 'O R
O
0 Ra O~ Ra O O N R4 ) R.
R Ra Ra x R4 /N N a Ra R R4/ .Ra With respect to the method of using the novel compounds; the activation state of a kinase is determined by the interaction of switch control ligands and complemental switch control pockets. One conformation of the kinase may result from the switch control ligand's interaction with a particular switch control pocket while another conformation may result from the ligand's interaction with a different switch control pocket. Generally interaction of the ligand with one pocket, such as the "on" pocket, results in the kinase assuming an active conformation wherein the kinase is biologically active. Similarly, an inactive conformation (wherein the kinase is not biologically active) is assumed when the ligand interacts with another of the switch control pockets, such as the "off' pocket. The switch control pocket can be selected from the group consisting of simple, composite and combined switch control pockets.
Interaction between the switch control ligand and the switch control pockets is dynamic and therefore, the ligand is not always interacting with a switch control pocket. In some instances, the ligand is not in a switch control pocket (such as occurs when the protein is changing from an active conformation to an inactive conformation). In other instances, such as when the ligand is interacting with the environment surrounding the protein in order to determine with which switch control pocket to interact, the ligand is not in a switch control pocket. Interaction of the ligand with particular switch control pockets is controlled in part by the charge status of the amino acid residues of the switch control ligand. When the ligand is in a neutral charge state, it interacts with one of the switch control pockets and when it is in a charged state, it interacts with the other of the switch control pockets. For example, the switch control ligand may have a plurality of OH groups and be in a neutral charge state. This neutral charge state results in a ligand that is more likely to interact with one of the switch control pockets through hydrogen boding between the OH groups and selected residues of the pocket, thereby resulting in whichever protein conformation results from that interaction. However, if the OH groups of the switch control ligand become charged through phosphorylation or some other means, the propensity of the ligand to interact with the other of the switch control pockets will increase and the ligand will interact with this other switch control pocket through complementary covalent binding between the negatively or positively charged residues of the pocket and ligand. This will result in the protein assuming the opposite conformation assumed when the ligand was in a neutral charge state and interacting with the other switch control pocket.
Of course, the conformation of the protein determines the activation state of the protein and can therefore play a role in protein-related diseases, processes; and conditions. For example, if a metabolic process requires a biologically active protein but the protein's switch control ligand reinains-iri tfie swi"tch control pocket the "offl' pocketYtliat results "in a biologically inactive protein, that metabolic process cannot occur at a normal rate. Similarly, if a disease is exacerbated by a biologically active protein and the protein's switch control ligand remains in the switch control pocket (i.e. the "on" pocket) that results in the biologically active protein conformation, the disease condition will be worsened. Accordingly, as demonstrated by the present invention, selective modulation of the switch control pocket and switch control ligand by the selective administration of a molecule will play an important role in the treatment and control of protein-related diseases, processes, and conditions.
One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 a-kinase and including both the consensus wild type sequence and disease polymorphs thereof. The activation state is generally selected from an upregulated or downregulated state. The method generally comprises the step of contacting the kinase with a molecule having the general formula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and a lesser propensity to interact with the occupied switch control pocket. As a result, the protein will have a greater propensity to assume either an active or inactive conformation (and consequenctly be upregulated or downregulated), depending upon which of the switch control pockets is occupied by the molecule. Thus, contacting the kinase with a molecule modulates that protein's activation state. The molecule can act as an antagonist or an agonist of either switch control pocket. The contact between the molecule and the kinase preferably occurs at a region of a switch control pocket of the kinase and more preferably in an interlobe oxyanion pocket of the kinase. In some instances, the contact between the molecule and the pocket also results in the alteration of the conformation of other adjacent sites and pockets, such as an ATP active site.
Such an alteration can also effect regulation and modulation of the active state of the protein.
Preferably, the region of the switch_control _pocket of_the_kinase comprises an amino acid r.esidue_sequence operable for binding to the Formula I molecule. Such binding can occur between the molecule and a specific region of the switch control pocket with preferred regions including the a-C helix, the a-D helix, the catalytic loop, the activation loop, and the C-terminal residues or C-lobe residues (all residues located downstream (toward the C-end) from the Activation loop), the glycine rich loop, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence IIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (SEQ
ID NO. 3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ
ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. When the binding region is in the C-lobe residues, one preferred binding sequence is WMHY (SEQ ID NO. 6).
When the binding region is in the glycine rich loop one preferred binding sequence is YGSV (SEQ ID NO.
7). When a biologically inactive protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically active protein conformation (when interacting with the switch control ligand) will be selected. Similarly, when a biologically active protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically inactive protein conformation (when interacting with the switch control ligand) will be selected. Thus, the propensity of the protein to assume a desired conformation will be modulated by administration of the molecule. In preferred forms, the molecule will be administered to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. In such forms, it will be desired to select molecules that interact with the switch control pocket that generally leads to a biologically active protein conformation so that the protein will have the propensity to assume the biologically inactive form and thereby alleviate the condition. It is contemplated that the molecules of the present invention will be administerable in any conventional form including oral, parenteral, inhalation, and subcutaneous. It is preferred for the administration to be in the oral form. Preferred molecules include the preferred compounds of formula (I), as discussed above.
Another aspect of the present invention provides a method of treating an inflammatory condition of an individual comprising the step of administering a molecule having the general formula (I) to the individual: Such conditions are often the result of an overproduction of the biologically active form of a protein, including kinases. The administering step generally includes the step of causing said molecule to contact a kinase involved with the inflammatory process, preferably p38 a-kinase. When the contact is between the molecule and a kinase, the contact preferably occurs in an interlobe oxyanion pocket of the kinase that includes an amino acid residue sequence operable for binding to the Formula I molecule.
Preferred bindirig regions of the interlobe oxyanion pocket include the a-C helix region, the a-D helix region, the catalytic loop, the activation loop, the C-terminal residues, the glycine rich loop residues, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence IIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (SEQ ID NO.
3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. Such a method permits treatment of the condition by virtue of the modulation of the activation state of a kinase by contacting the kinase with a molecule that associates with the switch control pocket that normally leads to a biologically active form of the kinase when interacting with the switch control ligand.
Because the ligand cannot easily interact with the switch control pocket associated with or occupied by the molecule, the ligand tends to interact with the switch control pocket leading to the biologically inactive form of the protein, with the attendant result of a decrease in the amount of biologically active protein. Preferably, the inflammatory condition is selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive -diseases,-graft-versus-host_r.eaction,_Chron'-s_disease,_ulcerative_colitis,_inflammatory-- bowel disease, pyresis, and combinations thereof. As with the other methods of the invention, the molecules may be administered in any conventional form, with any convention excipients or ingredients. However, it is preferred to administer the molecule in an oral dosage form.
Preferred molecules are again selected from the group consisting of the preferred formula (I) compounds discussed above.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic. representation of a naturally occurring mammalian protein in accordance with the invention including "on" and "off' switch control pockets 102 and 104, respectively, a transiently modifiable switch control ligand 106, and an active ATP site 108;
Fig. 2 is a schematic representation of the protein of Fig. 1, wherein the switch control ligand 106 is illustrated in a binding relationship with the off switch control pocket 104, thereby causing the protein to assume a first biologically downregulated conformation;
Fig. 3 is a view similar to that of Fig. 1, but illustrating the switch control ligand 106 in its charged-modified condition wherein the OH groups 110 of certain amino acid residues have been phosphorylated;
Fig. 4 is a view similar to that of Fig. 2, but depicting the protein wherein the phosphorylated switch control ligand 106 is in a binding relationship with the on switch control pocket 102, thereby causing the protein to assume a second biologically-active conformation different than the first conformation of Fig. 2;
Fig. 4a is an enlarged schematic view illustrating a representative binding between the phosphorylated residues of the switch control ligand 106, and complemental residues Z+ from the on switch control pocket 102;
Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic form possible small molecule compounds 116 and 118 in a binding relationship with the off and on switch control pockets 104 and 102, respectively;
Fig. 6 is a schematic view of the protein in a situation where a composite switch control pocket 120 is formed with portions of the switch control ligand 106 and the on switch control pocket 102, and with a small molecule 122 in binding relationship with the composite pocket;
and Fig. 7 is a schematic view of the protein in a situation where a combined switch control pocket 124 is formed with portions of the on switch control pocket 102, the switch control ligand sequence 106, and the active ATP site 108, and with a small molecule 126 in binding relationship with the combined switch control pocket.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a way of rationally developing new small molecule modulators which interact with riaturally occurring proteins (e.-g,-mammalian,-and especially human proteins) in order to modulate the activity of the proteins. Novel-protein-small molecule adducts are also provided. The invention preferably makes use of naturally occurring proteins having a conformational property whereby the proteins change their conformations in vivo with a corresponding change in protein activity. For example, a given enzyme protein in one conformation may be biologically upregulated, while in another conformation, the same protein may be biologically downregulated. The invention preferably makes use of one mechanism of conformation change utilized by naturally occurring proteins, through the interaction of what are termed "switch control ligands" and "switch control pockets" within the protein.
As used herein, "switch control ligand" means a region or domain within a naturally occurring protein and having one or more amino acid residues therein which are transiently modified in vivo between individual states by biochemical modification, typically phosphorylation, sulfation, acylation or oxidation: Similarly, "switch control pocket" means a plurality of contiguous or non-contiguous amino acid residues within a naturally occurring protein and comprising residues capable of binding in vivo with transiently modified residues of a switch control ligand in one of the individual states thereof in order to induce or restrict the conformation of the protein and thereby modulate the biological activity of the protein, and/or which is capable of binding with a non-naturally occurring switch control modulator molecule to induce or restrict a protein conformation and thereby modulate the biological activity of the protein.
A protein-modulator adduct in accordance with the invention comprises a naturally occurring protein having a switch control pocket with a non-naturally occurring molecule bound to the protein at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein. Preferably, the protein also has a corresponding switch control -ligand,-the_ligand.interacting_in vivo.with_the.pocket to regulate the conformation and biological activity of the protein such that the protein will assume a first conformation and a first biological activity upon the ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of the ligand-pocket interaction.
The nature of the switch control ligand/switch control pocket interaction may be understood from a consideration of schematic Figs. 1-4. Specifically, in Fig.
1, a protein 100 is illustrated in schematic form to include an "on" switch control pocket 102, and "off" switch control pocket 104, and a switch control ligand 106. In addition, the schematically depicted protein also includes an ATP active site 108. In the exemplary protein of Fig.
1, the ligand 106 has three amino acid residues with side chain OH groups 110. The off pocket 104 contains corresponding X residues 112 and the on pocket 102 has Z residues 114. In the exemplary instance, the protein 100 will change its conformation depending upon the charge status of the OH groups 110 on ligand 106, i.e., when the OH groups are unmodified, a neut ral charge is presented, but when these groups are phosphorylated a negative charge is presented.
The functionality of the pockets 102, 104 and ligand 106 can be understood from a consideration of Figs. 2-4. In Fig. 2, the ligand 106 is shown operatively interacted with the off pocket 104 such that the OH groups 110 interact with the X residues 112 forming a part of the pocket 104. Such interaction is primarily by virtue of hydrogen bonding between the OH groups 110 and the residues 112. As seen, this ligand/pocket interaction causes the protein 100 to assume a conformation different from that seen in Fig. 1 and corresponding to the off or biologically downregulated conformation of the protein.
Fig. 3 illustrates the situation where the ligand 106 has shifted from the off pocket interaction conformation of Fig. 2 and the OH groups 110 have been phosphorylated, giving a negative charge to the ligand. In this condition, the ligand has a strong propensity to interact with on pocket 102, to thereby change the protein conformation to the on or biologically upregulated state (Fig. 4). Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted to positively charged residues 114 to achieve an ionic-like stabilizing bond.
Note that in the on conformation of Fig. 4, the protein conformation is different than the off conformation of Fig.
2, and that the ATP active site is available and the protein is functional as a kinase enzyme.
Figs. 1-4 illustrate a simple situation where the protein exhibits discrete pockets 102 and 104 and ligand 106. However, in many cases a more complex switch control pocket pattern is observed. -Fig._6_illustrates.a situation where_an_appro.priate_pocket.for_small molecule interaction is formed from amino acid residues taken both from ligand 106 and, for example, from pocket 102. This is termed a "composite switch control pocket" made up of residues from both the ligand 106 and a pocket, and is referred to by the numeral 120. A small molecule 122 is illustrated which interacts with the pocket 120 for protein modulation purposes.
Another more complex switch pocket is depicted in Fig. 7 wherein the pocket includes residues from ori pockef 1-02; and ATP -site 108 to dreate what-is ternied a"combined -switch control pocket." Such a combined pocket is referred to as numeral 124 and may also include -residues from ligand 106. An appropriate small molecule 126 is illustrated with pocket 124 for protein modulation purposes.
It will thus be appreciated that while in the simple pocket situation.of Figs.
1-4, the small molecule will interact with the simple pocket 102 or 104, in the more complex situations of Figs.
6 and 7 the interactive pockets are in the regions of the pockets 120 or124.
Thus, broadly the the small molecules interact "at the region" of the respective switch control pocket.
MATERIALS AND METHODS
General Synthesis of Compounds.
In the synthetic schemes of this section, q is 0 or 1. When q = 0, the substituent is replaced by a synthetically non-interfering group R7.
Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are prepared according to the synthetic route shown in Scheme 1.1. Reaction of isothiocyanate 1 with chlorine, followed by addition of isocyanate 2 affords 3-oxo-thiadiazolium salt 3.
Quenching of the reaction with air affords compounds of Formula 1-4.
Alternatively, reaction of isothiocyanate 1 with isothiocyanate 5 under the reaction conditions gives rise to compounds of Formula I=7. See A. Martinez et al, Journal of Medicinal Chemistry (2002) 45: 1292.
Intermediates 1, 2 and 5 are commercially available or prepared according to Scheme 1.2. Reaction of amine 8 with phosgene or a phosgene equivalent affords isocyanate 2.
Similarly, reaction of amine 8 with thiophosgene affords isothiocyanate 5.
Amine 8 is prepared by palladium(0)-catalyzed amination of 9 wherein M is a group capable of oxidative insertion into palladium(0), according to methodology reported by S.
Buchwald.
See M. Wolter et al, Organic Letters (2002) 4:973; B.H. Yang and S. Buchwald, Journal of Organometallic Chemistry (1999) 576(1-2):125. In this reaction sequence, P is a suitable amine protecting group. Use of and removal of amine protecting groups is accomplished by methodology reported in the literature (Protective Groups in Organic Synthesis, Peter G.M.
Wutts, Theodora Greene (Editors) 3rd edition (April 1999) Wiley, John & Sons, Incorporated; ISBN: 0471160199). Starting compounds 9 are commercially available or readily prepared by one of ordinary skill in the art: See March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith & Jerry March (Editors) 5th edition (January 2001) Wiley John & Sons; ISBN : 0471585890.
Scheme 1.1 E) R,4 1) ClZ + R4 CI ~ N Cl 3) air, RT _ O~ NO
R4-N=C=S O -1 2) [R6O2C-(NH)P]q-D-E-Y-N=C=O S-~
, S-N Y-E-D [(NH)p-C02R6]c 2 Y-E-D-[(NH)p-C02R6]q 3 1~4 _ R4 1) CIZ R4 ClO , RT
O N S
R4-N=C=S C~ /N g 3) air, _ ~ ~
2) [R602C-(NH)P]q D-E-Y N=C=S S_~' Y-E-D-[(NH)p-C02R6]q Y-E-D-[(NH)p-C02R6]q Scheme 1.2 NH2 phosgene ,N=C=O
[R602C-(NH)p]q-D-E-Y -~ Base [R602C-(NH)p]q-D-E-Y
8 ?
NH thiophosgene N=C=S
[R602C-(NH)p]q-D-E-Y 2 --~ [R602C-(NH)p]q-D-E-Y"
Base R602C-NH-D-E-Y-NHP deprotection M-D-E-Y-NHP =~ --Pd(O) catalysis Compounds of Formula I wherein Q is taken from Q1 or Q-2 and Y is alkylene are also available via the synthetic route shown in Scheme 1.3. Reaction of amine 8 with isocyanate or isothiocyanate 2a yields the urea/thiourea 8a which can be cyclized by the 10 addition of chlorocarbonyl sulfenyl chloride. See GB1115350 and US3818024, Revankar et.
al US Patent 4,093,624, and Klayman et. al JOC 1972, 37(10), 1532 for further details.
Where R4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of I-4 (X=0) and I-7 (X=S).
Scheme 1.3 - -- x .eNH2 X=O, S HN N.1 Ra [R602C-(NH)p]q-D-E-Y
2a [R602C-(NH)p]q-D-E-Y' H
8 8a, X=O, S
O X
~ ~CI
CI S 'N 'k N' R4 Deprotection [R602C-(NH)p]q-D-E-Y S--,\\O
1-4 X=O
1-7 X=S
X
~N~NH
[R6O2C-(NH)p]q-D-E-Y S
I-4 X=O
1-7 X=S
1-7 is also available as shown in Scheme 1.4. Condensation of isocyariate or isothiocyanate 2a with amine R5NH2 yields urea/thiourea 2b, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2c. Where R4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of 2d. Reaction of 2d with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-4 (X=O) and 1-7 (X=S).
Scheme 1.4 O O
R5NH2R4HN N- RS CIS'CI R,N ~~R Deprotection of R4 s R4NCX Y a y X=O, S X II
X
2a x=o, s x=O, S
2b 2c ~O 0 S
~ NaH/DMF S
HNy N-RS N N, [R602C-(NH)p]q-D-E-Y Y R5 X [R602C-(NH)p]q-D-E-Y'M X
X=O, S
2d 1-4 X=0 8a I-T X=S
Compounds of Formula I wherein Q is taken from Q-1' or Q-2' and Y is alkylene are available via the synthetic route shown in Scheme 1.3. Condensation of isocyanate or isothiocyanate 2a with ammonia yields urea/thiourea 2e, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2f.
Reaction of 2f with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields yields I-4' (X=0) and I-7' (X=S).
Scheme 1.5 O O
NH3 R4HN N-H CI)tIS'CI ~--~~, R NCX - H ~N "'H
~
X=O, S ~ ~ x X
2a x=o, s x=o, s 2e 2f NaH/DMF S
, T N
[R602C-(NH)p]q-D-E-Y N
Ra [R60zC-(N H) p]q-D-E-Y 'M I-4' X=0 8a I-T X=S
Compounds of Formula I wherein Q is taken from Q-3 or Q-4 and Y is alkylene, are prepared according to the synthetic route shown in Schemes 2.1 and 2.2, respectively.
Reaction of 12, wherein M is a suitable leaving group, with the carbaniate-protected hydrazine 13 affords intermediate 14. Reaction of 14 with an isocyanate gives rise to intermediate 15. Thermal cyclization of 15 affords 1,2,4-triazolidinedione of Formula 1-16.
--By. analogy, scheme 2.2 illustrates the preparation of 3-thio-5-oxo-1,2,4-triazolidines of Formula I-18 by reaction of intermediate 14 with an isothiocyanate and subsequent thermal cyclization.
Scheme 2.1 O
)-ORjo H2N-N, R4 R4 D Y N OR 11 iD~ /Y- 1 [R602C-(NH)PIq~ ~E/ \H~ ~ 10 [R602C-(NH)p]q E M ~
R -N=C=O I 4 [R602C-(NH)plq~E/Y\NNyORIo heat O
O NH
[R602C-(NH)P]qDE~Y\N N
~O
O ~
Scheme 2.2 -~
R4-N=C=S [R602C-(NH)p]9 D\E,Y~N~ y ORto heat 14 ? S~NH 0 Ra [R6O2C-(NH)P]qDE/Y\NN
/N
Intermediates 12 wherein p is 1 are readily available or are prepared by reaction of 19 with carbamates 10 under palladium(0)-catalyzed conditions. M, is a group which oxidatively inserts. palladium(0), preferably iodo or bromo, and is of greater reactivity than M. Compounds 19 are either commercially available or prepared by one of ordinary skill in the art.
Scheme 2.3 Mi\DY~M ---> R602C-NH.pEY'M
Pd(O) catalysis;
19 Base 12 -Compounds of Formula I wherein D is taken from Q-3 or Q-4 and Y is alkylene, are also 10 prepared according to the synthetic route shown in Scheme 2.4. Oxidation of amine R4NH2 to the corresponding hydrazine, condensation with ethyl chloroformate subsequent heating yieldsl,2,4-triazolidinedione 15a. After the action of NaH in DMF, displacement wherein M
is a suitable leaving group such as chloride, bromide or iodide yields 1-16 (X=O) and 1-18 (X=S).
Scheme 2.4 1. NaNO2 0 O RSNCX
2. SnCI2 AR4NHZ R4NHNH2 CI OEt R4NHNHOEt X=O, S heat 2a O
HN-{ NaH/DMF [R6O2C-(NH)p]q-D-E-Y, O
N N- N
R4 ~ Rs -NN
.M Ra Rs x [R602C-(NH)plq-D-E-Y y 8a x 15a 1-16 X=0 1-18 X=S
O
HN NaH/DMF NH
R4 N NH [R802C-(NH)p]q-D-E-Y-N~N-R4 Deprotection of R5 Y [R602C-(NH)p]q-D-E-Y
X 8a X
15b I-16' X=0 I-18' X=S
Compounds of Formula I wherein D is taken from D-3' or D-4' and Y is alkylene, are also prepared according to the synthetic route shown in Scheme 2.4. When R5 is a readily removable-protecting-group-(e.g. R. =-3;4-d-methoxybenzyl amine),-the_action-of_mild, acidic deprotection conditions such as CAN or TFA on 15a will reveal 1,2,4-triazolidinedione 15b.
After deprotonation of 15b by NaH in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16' (X=O) and 1-18' (X=S).
Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y is alkylene are prepared according to the synthetic route shown in Scheme 3. Reaction of hydrazine 20 with chlorosulfonylisocyanate and base, such as triethylamine, gives rise to a mixture of intermediates 21A and 21B which are not isolated but undergo cyclization in situ to afford compounds of Formulae I-22A and I-22B. Compounds I-22A and I-22B are separated by chromatography or fractional crystallization. Optionally, compounds 1-22A and 1-22B can undergo Mitsunobu reaction with alcohols R4OH to give compounds of Formulae I-23A and 1-23B. Compounds 20 are prepared by acid-catalyzed deprotection of t-butyl carbamates of structure 14, wherein RIo is t-butyl.
Scheme 3 R4 CISOZ-N=C=O
[R6O2C-(HN)p]q-D-E-Y,,, N"NH
20 H Base [R6O2C-(HN)p]q-D-E-Y~N~NH [R6O2C-(HN)p]q-D-E-Y~ N ~N
O
~
H
O NH + ----CI~ /NH
O jS~CI S 0 R4 Ra [R6O2C-(HN)p]q-D-E-Y,~N~N~ O [R6O2C-(HN)p]q-D-E-Y~,N~N
~NH~O + 0=S-NH
Ph3P ph3p Diethyl azodicarboxylate Diethyl azodicarboxylate [R602C-(HN)p]q-D-E-Y, NN\ yO [R602C-(HN)p]q-D-E-Y~N,N~O
SO +
O~- N O 'p NN
R
~ a Compounds of Formula I wherein Q is Q-7 and Y is alkylene are prepared as shown in Scheme 4. Reaction of amine 8 with maleimide 24, wherein M is a suitable leaving group, affords compounds of Formula I-25. Reaction of compound 26, wherein M is a group. which can oxidatively insert Pd(O), can participate in a Heck reaction with maleimide 27, affording compounds of Formula I-28. Maleimides 24 and 27 are commercially available or prepared by one of ordinary skill in the art.
Scheme 4 0 'Ra N
-O R
a O N
Q O
[R602C-(NH)p]q-D-E-Y~N2 24 R5 [R602C-(NH)p]q-D-E-Y~N (E) 8 Base H R5 Ra O N
Ra O O N
D M (z) O
[R6O2C-(NH)p]q ~E~ 27 R5 [R6O2C-(NH)p]qfZl 26 Pd(O), Base 1-28 Heck Reaction -Compounds of Formula I wherein Q is Q-8 and Y is alkylene are prepared as shown in Scheme 5, according to methods reported by M. Tremblay et al, Journal of Combinatorial Chemistry (2002) 4:429. Reaction of polymer-bound activated ester 29 (polymer linkage is oxime activated-ester) with chlorosulfonylisocyante and t-butanol affords N-BOC
sulfonylurea 30. Subjection of 30 to the Mitsunobu reaction with R4OH gives rise to 31.
BOC-group removal with acid, preferably trifluoroacetic acid, and then treatment with base, preferably triethylamine, provides the desired sulfahydantoin I-32.
Optionally, intermediate 30 is treated with acid, preferably trifluoroacetic acid, to afford the N-unsubstituted sulfahydantoin I-33. -Scheme 5 R4 R4 CISO2-N=C=O
[R602C-(NH)p]q-D-E-Y~NH OQ t-BuOH
R4 Ra [RsOzC-(NH)P]q-D-E-Y,,, N 0~ Ph3P diethyl azodicarboxylate BOC
R4 Ra [R602C-(NH)P]q-D-E-Y,, N O 1) H+ Ra Ra I ~ [R602C-(NH)PIq-D-E-Y~N
O~S~ Ra 0 2) Triethylamine 0'S O
31 O N I-32 ~~ ~ N
a [R602C-(NH)p]q-D-E-Y,, N
H+ O~S__ 0 Compounds of Formula I wherein Q is Q-8 and Y is alkylene are also prepared as shown in Scheme 5a. Amine 8 is condensed with the glyoxal hemiester to yield 31a.
Reaction of chlorosulphonyl isocyanate first with benzyl alcohol then 31a yields 31b, which after heating yields 1-32.
Scheme 5.1 O
H-ly OEt O
(R602C-(NH)p]q-D-E-YNH2 [R602C-(NH)p]q-D-E-Y~N v OEt 8 NaCHBH3 31a HZN,S~O O
1.
CISO2NCO [R602C-(NH)p]q-D-E-Y~N OEt OH
2. H O
31b [R602C-(NH)p]q-D-E-Y' OEt 31a 3. 5% Pd/C
O~\S~N O
I ~
heat [R60zC-(NH)p]q-D-E-Y"' Compounds of Formula I wherein Q is taken from Q-8', are prepared according to the synthetic route shown in Scheme 5.2. Formation of 31c by the method of Muller and DuBois JOC 1989, 54, 4471 and its deprotonation with NaH/DMF or NaH/DMF and subsequently alkylation wherein M is a suitable leaving group such as chloride, bromide or iodide yields I-32'. Alternatively, I-32' is also available as shown in Scheme 5.3. Mitsunobu reaction of boc-sulfamide amino ethyl ester with alcohol 8b (made by methods analogous to that for amine 8) yields 31c, which after Boc removal with 2N HCl in dioxane is cyclized by the action of NaH on 31d results in I-32'.
Scheme 5.2 O\O
S-NH
NaN O
S-NH
[R602C-(NH)p]q-D-E-Y"M O [R602C-(NH)p]q-D-E-Y' N
31c - O
8a 1-32' Scheme 5.3 H O [ReO2C-(NH)p]q-D-E-Y OH N ~
Boc-N,S~O O 8b [RsOzC(NH)p]q-D-E-Y- 'S~O O
I
HN-~-K
HN----OEt DEADCAT, Ph3P 31d OEt O.ii ~S-NH
heat N
[Rs02C-(NH)p]q-D-E-Y~
O
1-32' Compounds of Formula I wherein Q is Q-9 and Y is alkylene are prepared as shown in Scheme 6. Reaction of polymer-bound amino acid ester 34 with an isocyanate affords intermediate urea 35. Treatment of 35 with base, preferably pyridine or, ttriethylamine, with optional heating, gives rise to compounds of Formula 1-36.
Scheme 6 [R602C-(NH)p]q-D-E-Y~,NH )K1_o-_Q R4-N=C=O
Ra R4 [R602C-(NH)p]q-D-E-Y,, N O Base ~
O ___~ NH
[ R6 O2 C-( N H) p] q-D-E-Y~,, N
O
I-36 O/j-_N
Compounds of Formula I wherein Q is Q-9 and Y is alkylene are also prepared as shown in Scheme 6.1. Reaction of aldehyde 8c under reductive amination conditions with the t-butyl ester of glycine yields 35a. Isocyanate 2a is condensed with p-nitrophenol (or the corresponding R4NH2 amine is condensed with p-nitrophenyl chloroformate) to yield the carbamic acid p-nitrophenyl ester, which when reacted with deprotonated 35a and yields the urea that when deprotected with acid yields 35b. Formula 1-36 is directly available from 35b by the action of NaH and heat.
Scheme 6.1 O
0 HZN-,-A Ot-Bu N~
~
(R602C-(NH)plq-D-E-YH [RsOZC-(NH)p]q-D-E-Y, Ot Bu NaCHBH3 8c 35a O Oa;~-N02 Ifl, 1. R4HN
2. 2N HCI/Dioxane [RsO2C-(NH)P]q-D-E-Y"~ O [~-- RsO2C-(NH)P]q-D-E-Y" --AOH
1-36 35b Compounds of Formula I wherein Q is taken from Q-9', are prepared according to the synthetic route shown in Scheme 6.2. Formation of 35c by the method described in JP10007804A2 and Zvilichovsky and Zucker, Israel Journal of Chemistry, 1969, 7(4), 547-54 and its deprotonation with NaHIDMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide, yields I-36'.
Scheme 6.2 p ~--NH
NaN~ O~-NH
[R602C-(NH)p]q-D-E-Y 'M 0 [R602C-(NH)p]q-D-E-Y~ N -?
35c 0 8a 1-36' Compounds of Formula I wherein Q is Q-10 or Q-1 1, and Y is alkylene are prepared as shown in Schemes 7.1 and 7.2, respectively. Treatment of alcohol 37 (Z = 0) or amine 37 (Z =. NH) with chlorosulfonylisocyanate affords intermediate carbamate or urea of structure 38. -Treatment of 38 witif an amine of-st-ructui-e HN(R4)Z and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula I-39. Reaction of chlorosulonylisocyanate with an alcohol (Z = 0) or amine (Z = NR4) 40 affords intermediate 41. Treatment of 41 with an amine 8 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-42.
Scheme 7.1 O
CISOZ-N=C=O
[R602C-(NH)p]q-D-E-Y~ZH [R802C-(NH)p]q-D-E-Y-, ~ Z N i-S02CI
N ~O
Ra [Rs02C-(NH)P]q-D-E-Y~ ~ i ~ S~NiR4 N Base Z H I
Scheme 7.2 Ra H-Z O
CISO2-N=C=O 40 R41 Z A H iSO2CI
[R602C'(NH)p]q-D-E-Y,, N-~R5 0 /Y-D-E-q[(NH)PC02Rs 8 H Ra1 Z A H O S, N 0 - ---Base R5 Compounds of Formula I wherein Q is taken from Q-12 are prepared according to the synthetic route shown in Scheme 8. Alkylation of pyridine 43, wherein TIPS is tri-isopropylsilyl, under standard conditions (K2CO3, DMF, Ra-I or Mitsunobu conditions employing R4-OH) yields pyridine derivative 44 which is reacted with compound 12, wherein ] 0 M is a suitable leaving group, to afford pyridones of formula I-45.
Scheme 8 R
~ ReQ KZC03 DM For Acetone TIPS\ I ~ o~ TIPS
O N RaOH, Ph3P O N
Diethyl azodicarboxylate [ReO2C'(NH)p]q-D-E-Y~, M
O N
Base Y-QE-[(NH)pCO2R8]q Compounds of Formula I wherein Q is taken from Q-13 are prepared according to the synthetic route shown in Scheme 9. Starting from readily available pyridine 46, alkylation under standard conditions (K2CO3, DMF, R4-I or Mitsunobu conditions employing R4-OH) yields pyridine derivative 47. N-alkylation with K2CO3, DMF, R4-I affords pyridones of formula 48. Intermediate 48 is partitioned to undergo a Heck reaction, giving I-49; a Buchwald amination reaction, giving I-51; or a Buchwald Cu(I) catalyzed 0-arylation reaction, to give J. The Heck reaction product I-49 may be optionally hydrogenated to afford the saturated compound I-50. Wherein the phenyl ether R4 group is methyl, compounds of formula I-49, I-50, I-51, or I-52 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-53, wherein R4 is hydrogen.
Scheme 9 R5 R40, K2COs Rs ORq \ DMForAcetone_- R
I I Rql, K2CO3 / s DMF or Acetone TIPS~O N/ CI R4OH, Ph3P TIPSO N CI
Diethyl azodicarboxylate O N CI
q ED/[(NH)pC02~]q R OR4 n s Hydrogenation Rs 48 E.D[(NH)PC02Rs]q -' I
Heck reaction 0 R N n O N E, D-[(NH)pC02R6]t Pd(0) q I-49 Rq Base n+2 ORq I-50 H E~ ,[(NH)pCO2R6]q boron tribromide ~ D R5 or lithium chloride boron tribromide n I or lithium chloride N N/~
'1 rE[(NH)PC02Re]q Buchwald amination H n Pd(0) R4 I-51 boron tribromide OH
Base - or lithium chloride / Rs HO E~D,[(NH)pCO2R6]q OR4 boron tribromide ~E, D~[(NH)pCO
48 n R5 or lithium chloride O N Y
' R4 Buchwald arylation 1-53 Cu(I) O N 0 nED~[(NH)PC02R6]q Base R4 I-52 Compounds of Formula I wherein Q is taken from Q-14 are prepared according to the synthetic route shown in Scheme 10. Starting from readily available pyridine 54, alkylation under standard conditions (K2C03, DMF, Rq-I or Mitsunobu conditions employing R4-OH) yields pyridine derivativ_e_55. N-alkylation with K2CO3, DMF, R4-I affords pyridones of formula 56. Intermediate 56, wherein M is a suitable leaving group, preferably bromine or chlorine, is partitioned to undergo a Heck reaction, giving I-57; a Buchwald amination reaction , giving I-59; or a Buchwald Cu(I) catalyzed 0-arylation reaction, to give I-60. The Heck reaction product I-57 may be optionally hydrogenated to afford the saturated compound 1-58. Wherein R4 is methyl, compounds of formula I-57, 1-58, I-59, or I-60 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-61, wherein R4 is hydrogen.
Scheme 10 R40, K2CO3 M OR4 DMAetoe R41; K2CO3 TIPS CXM
I
. ~ TIPS DMF or Acetone RqOH, Ph3P \
O N R5 Diethyl azodicarboxylate O N Rg O N RS
RS
E, iI(NH)p-C02Rr.]q OR4 n+
' D / EID, [(NH)p-C02Ra]q Hydrog ~ tion D
n ' 56 =~ (~n E [(NH)P C02~]q Heck reaction pd(0) O RN 4 RS 0 N. R5 Base I-57 R4 1-58 H2N E~, ,[(NH)p-C02Rs]q N E. /[(NH)P-C02Rs]q BBr3o~LiC1 D r D BBr3 or LiCI
56 ~ I n Buchwald amination 0 N R5 BBr3 or LiCI OH
Base 4 I-59 Y E~D~[(NH)p-CC
HO,W ~ ~[(NH)p-CO2R6]q OR4 D O-yED,[(NH)p-CO2R6]q BBr3 or LiCI 0 RN 4 R5 n C/
56 -~ I n Buchwald arylation 1-61 Cu(I) 0 N Re Base R 1-60 Compounds of Formula I wherein Q is taken from Q-15 are prepared according to the synthetic routes shown in Schemes 11 and 12. Starting esters 62 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions.
Reaction of protected secoester 62 with Meerwin's salt produces the vinyl ether 63 as a pair of regioisomers. Alternatively, reaction of 62 with dimethylamine affords the vinylogous carbamate 64. Formation of the dihydropyrimidinedione 66 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol.
Dihydropyrimidinedione 66 may optionally be further substituted by Mitsunobu reaction with alcohols R4OH
to give rise to compounds 67.
Scheme 12 illustrates the further synthetic elaboration of intermediates 67.
Removal of the silyl protecting group (TBS) is accomplished by treatment of 67 with flouride (tetra-n-butylammonium fluoride or cesium flouride) to give primary alcohols 68.
Reaction of 68 with isocyanates 2 gives rise to compounds of Formula 1-69. Alternatively, reaction of 68 with [R6O2C(NH)p]q-D-E-M, wherein M is a suitable leaving group, affords compounds of Formula I-70. Oxidation of 68 using the Dess-Martin periodinane (D. Dess, J.
Martin, J. Am.
Chem. Soc. (1991) 113:7277) or tetra-n-alkyl peruthenate (W. Griffith, S. Ley, Aldrichimica Acta (1990) 23:13) gives the aldehydes 71. Reductive amination of 71 with amines 8 gives rise to compounds of_Formula 1-72. Alternatively, aldehydes 71 may be reacted with ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73.
Reaction of 73 with isocyanates 2 affords compounds of Formula I-74.
Scheme 11 '-O O
O O Meer'"'in's. TBSO 0 O
Reagent OMe R4HN/~=NH2 TBSO OMe 63 R5 65 R4~N
R5 N(Me)2 0 TBSO
Dimethylami-te TBSO n 62 4A sieves' OMe R5 n R40H R4~N)~ NR4 Ph3P TBSO O
diethyl azodicarboxylate Scheme 12 R4\ 'i-1, 1IR4- R-r\ NpIC-(NH)p)q-D-C-N=C-0 R4\ N J, N N N NH
-- /NH' /O TBSO ~ 0 HO (R602C'(NH)p)q-D-E ~II/
n Q n n O RS
R5 [R602C-(NH)plq-D-E- 68 Re 1-69 O Oxidation R41~1 N NH O 0 1-0 ~ R4~ ~ [~02C-(NH~)q-D-C-NHZ R~\ ~
[RgOZC'(NH)P]q-D-E n 0 N NH g N
Reductive amination 0 (ReOzC"(NH)p]q-D-E
n n ammonium acetate (reductive amination) [R60:c-(NH)P)q-D-C-N=C-O R4 N
N 'J~ NH
H2N [RBOiC"(NH)p)q-D-E' NH y N
Rs RS
Compounds of Formula I wherein Q is taken from Q-16 are prepared according to the synthetic routes shown in Schemes 13 and 14. Starting esters 75 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions.
Reaction of protected secoester 75 with Meerwin's salt produces the vinyl ether 76 as a pair of regioisomers. Alternatively, reaction of 75 with dimethylamine affords the vinylogous carbamate 77. Formation of the dihydropyrimidinedione 78 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol.
Dihydropyrimidinedione 78 may optionally be further substituted by Mitsunobu reaction with alcohols R4OH
to give rise to compounds 79. Compounds of Formulae 1-81, 1-82, I-84, and 1-86 are prepared as shown in Scheme 14 by analogy to the sequence previously described in Scheme 12.
Scheme 13 11-1 o 0 0 Meerwin's RS OMe 0 O
ea gen Rs OMe 76TBS0 )n 65 R,, N NH
-- --+
Dimethylamine,} N(Me)2 0 R
TBSO n 4A sieves s 0 75 R5 OMe TBSO J n TBSO n ~ 0 ~ ,,Ra R4OH R4-_ N N
--=.
Ph3P
diethyl azodicarboxylate RS O
TBSO 'n Scheme 14 0 N N
FZ.-,~ NJ~ NR, (R602C-(NH)p]q-D-E-N=C=0 2 RS 0 r I-81 n \ OTBS [R602C-(NH)p]q-D-E-M gp OH NH-C-O-[(NH)pC02R, n n Oxidation R,~, /R4 R4,11, ,lia 1L )~ ~ [R60ZC-(NH~]q-D-E-NHZ
N N N N~ 8 R 0 Reduciive amination 1 RS O Rs O \ NH-C-D (NH)pCOyRe)c 1 ( I-84 O-E-D-[(NH)pCOpReJq 83 ' CHO O
ammonium acetate R,111AN"IR4 (reductive arnination) R4~ R4 [R60ZC-(NH)pJq-D-E-Nc C-O ~
N N 2 n NH
h--NH-E-D-((NH)p( N)4z _ -86 n Alkyl acetoacetates 87 are commercially available and are directly converted into the esters 88 as shown in Scheme 15. Treatment of 87 with NaHMDS in THF, followed by quench with formaldehyde and TBSCI (n = 1) or Q-(CH2)n-OTBS (n = 2-4), gives rise to compounds 88.
Scheme 15 ~We 1. NaHMDS, THF
RS 2. CH2O quench; R5 OMe 87 or Q-(CH2)n-OTBS ~
n OTBS
88, n> 1 O O
(for n = 1) R5 OMe TBS-Cl, pyridine, OTBS
CHZCIZ 8+ n = 1 Compounds of Formula I wherein Q is taken from Q-17 are prepared according to the synthetic routes shown in Schemes 16.1 and 16.2, and starts with the BOC-protected hydrazine 13, which is converted to the 1,2-disubstituted hydrazine 89 by a reductive alkylation with a glyoxal derivative mediated by sodium cyanoborohydride and acidic workup. Condensation of 89 with diethyl malonate in benzene under reflux yields the heterocycle 90. Oxidation with N204 in benzene (see Cardillo, Merlini and Boeri Gazz.
Chim. Ital., (1966) 9:8) to the nitromalonohydrazide 91 and further treatment with P205 in benzene (see: Cardillo,G. et al, Gazz.Chim.Ital. (1966) 9:973-985) yields the tricarbonyl 92.
Alternatively; treatment of 90 with Brederick's reagent (t-BuOCH(N(Me2)2, gives rise to 93, which is subjected to ozonolysis, with a DMS and methanol workup, to afford the protected tricarbonyl 92. Copound 92 is readily deprotected by the action of sF in THF
to yield the primary alcohol 94. Alcohol 94 is optionally converted into the primary amine 95 by a sequence involving tosylate formation, azide displacement, and hydrogenation.
Scheme 16.1 1)~,OTBS EtO OEt O '1~~ O
H O
BOC NaCNBH3, CH3CN /~ ,OTBS O O N24 -R4N-NH2 H+ - RHN-H~ ~/ -y R4N-N R N-N
13 2) 89 90 \'~OTBS 4 \--~OT
t-BuO-CH(NMe)z)z PzOs (Me)ZN
~ Me0 OMe 0 oxonolysis O
MeOH/DMS
~~OTBS
CsF, THF
MeO OMe 1) tosyl chloride, base O O MeO OMe -2) NaN, O
R4N-N 3) hydrogenation \/\NH2 R4N-N
Reaction of 94 with (hetero)aryl halide 26, wherein M is iodo, bromo, or chloro, under copper(I) catalysis affords compounds I-96. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Formula J. By analogy, reaction of 5 amine 95 with 26 under palladium(O) catalysis affords compounds of Formula I-97. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Formula I-99.
Scheme 16.2 MeO OMe HO OH
Me0 OMe NOZC (NH)p]q-D-E'M 0 0 O" O
26_ H+ HzO
Cu(I), base R N-N\_'.~O~-E-D-[(NH)pCO2R6]q \'--\0."E-D-[(NH)pCo;
\--'OH 1-98 M Me0 OMe HO OH
Me0 OMe [R6OZC-(NH) O ~ H20 p]q-D-E~ 0\\~/~O
0~~~~~0 26 ---i R4N-N Pd(0), base R4N-N~~NH~E-D-I(NH)pC02Rs)q R4N-N~~NH~D E I(NH)pCC
'\,"\NH2 Compounds of Formula I wherein Q is taken from Q-17 are also prepared according to the synthetic route shown in Scheme 16.3. Deprotonation of 4,4-dimethyl-3,5-dioxo-pyrazolidine (95a, prepared according to the method described in Zinner and Boese, D.
Pharmazie 1970, 25(5-6), 309-12 and Bausch, M. J.et.al J. Org. Chem. 1991, 56(19), 5643) with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide yields I-99a.
Scheme 16.3 O
HN
ICI HN-NH ~_N
[R602C-(NH)p]q-D-E-Y [R6O2C-(NH)p]q-D-E-Y
8a 95a 0 I-99a Compounds of Formula I wherein Q is taken from Q-18 are prepared as shown in Schemes 17.1 and 17.2. Aminoesters 100 are subjected to reductive alkylation conditions to give rise to intennediates 101. Condensation of amines 101 with carboxylic acids using an acid activating reagent such as dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOBt) affords intermediate amides 102. Cyclization of amides 102 to tetramic acids 104 is mediated by Amberlyst A-26 hydroxide resin after trapping of the in situ generated alkoxide 103 and submitting 103 to an acetic acid-mediated resin-release.
Scheme 17.1 R5 o 0 R4CH0 0 RSCHZCOZH 0 ~
NHZ _ R60)1-lr-- NH-/R4 0 ~O~NR4 R60-1~ c M' DCC, HOBt M
M. NaBH(OA)3 102 NMe3+ OH O O C H+, R4OH O
~-NMe3 0 Z) R40 N,R4 NRn M. M
M' is t-BuOCH2-, BOCNH(CH2)3-, BOCNH(CH2)4-, HC-C-CH2- 103 M is HOCH2-; HZN-(CHZ) H2N-(CH2)4-; HC=C
Scheme 17.2 illustrates the synthetic sequences for converting intermediates 104 to compounds of Formula I. Reaction of alcohol 104.1 with aryl or heteroaryl halide 26 (Q =
halogen) under copper(I) catalysis gives rise to compounds of Formula 1-105.1.
Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(0) catalyzed amination conditions affords compounds of Formulae 1-105.2 and 1-105.3. Reaction of acetylene 104.4 with 26 under. Sonogashira coupling conditions affords compounds of Formula 1-105.4.
Compounds I-105.4 may optionally be reduced to the corresponding saturated analogs I-105.5 by standard hydrogenation.
Scheme 17.2 Rs O R5 O
O ~
~O ~ IReO2C-(NH)PIq-D-E'M R4 N Rn 6 N~ R4 Cu(1), base OH ~--E-D-I(NH)pC02R6]q 104.1 1-105.1 / [R602C-(NH)p]q-D-E' ~
Ra0 N\/ Ra 26 N~ R4 Pd(O), base n NH~E-D-I(NH)PC02R61q NHz 1-105.2, n = 3 104.2,n=3 I-105.3,n=4 104.3, n = 4 RS IReO2C-(NH)PIq-D-E'M R5 O R5 O 26 Hydrogenation R,4 0 R4O --~ N ~
R"O N R PdC12(Ph3P)Z, Cul N~R
~ 4 Base \ (Sonogashira Coupling) E-D-[(NH)pCO2R6)q qIR6O2Cp(HN)]-D-E
104.4 1-105.4 1-105.5 Compounds of Formula I wherein Q is taken from Q-19, Q-20, or Q-21 are prepared as illustrated in Scheme 18. Commercially available Kemp's acid 106 is converted to its anhydride 107 using a dehydrating reagent, preferably di-isopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Reaction of 107 with amines affords the intermediate amides which are cyclized to the imides 108 by reaction with DIC or EDC. Alternatively, 107 is reacted with amines 8 to afford amides of Formula 1-110.
Amides 1-110 may optionally be further reacted with DIC or EDC to give rise to compounds of Formula 1-111. Acid 108 is further reacted with amines 8 to give compounds of Formula 1-109.
Scheme 18 O Ra O
CO2H COZH DIC or EDC HO~ f O O 1) IZ,qNH2 HO~jO N
b3C0 CH3 O I O H3C CH CH3 H3C 3 2) DIC or EDC 3C
[R602C-(NH)p]q-D-E R4 0 [R602C-(NH)p]q-D-ENH HN~O N
O
DIC, HOAt [R602C-(NH)p]q-D-E [R602C-(NH)p]q-D- i [R602C-(NH)p]q-D-E 1.
NHz NH O CO2H DIC or EDC HO~O N
Compounds of Formula I wherein Q is taken from Q-22 or Q-23 are prepared as shown in Schemes 19.1 through 19.3. Preparation of intermediates 113 and 114 are prepared as shown in Scheme 19.1 from di-halo(hetero)aryls 112, wherein M2 is a more robust leaving group than Mi. Reaction of 112 with amines 37 (Z = NH) either thermally in the presence of base or by palladium(0) catalysis in the presence of base and phosphine ligand affords compounds 113. Alternatively, reaction of 112 with alcohols 37 (X = 0) either thermally in the presence of base or by copper(I) catalysis in the presence of base affords compounds 114.
Scheme 19.1 [R6O2C-(NH)p]q-D-E-Y,-IZH
M Mi W/Z~Iw 37, Z = NH WII\W
M2 I~ Base [~OzC (NH)plq D E Y~N I /
H
M, [R6O2C-(NH)p]q-D-E-Y-IZH W 111~w 37, Z = O [R602C-(NH)plq-D-E-Y~O~
Base 114 Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117. Treatment of 113 with aqueous copper oxide or an alkaline hydroxide affords compounds of Formula 1-115. Alternatively, treatment of 113 with t-butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517. Treatment of the t-butyl sulfide 116 with acid affords the desired thiols of Formula 1-118. Alternatively, 113 may be treated with excess ammonia under pressurized conditions to afford compound 117.
Mi Scheme 19.2 w~w [RsOZC (NH)p]q-D-E-Y,, N I Z
H
aq CuO t-BuSH excess NH3, or Cul, K2COJ base KOH ethylene glycol /~.u NH2 w ~w w w ww [R6O2C-(NH)p]q-D-E-Y, N I 0~ [R802C-(NH)p]q-D-E-Y,~ N I / [R602C-(NH)p]q-D-E-Y,, N I 0 H
H+
SH
w~w [R602C-(NH)p]q-D-E-Y,, N ~.
H
Scheme 19.3 illustrates the conversion of intermediate 114 into compounds of Formula I-119. I-122, and 121, by analogy to the sequence described in Scheme 19.2.
W ~W
Scheme 19.3 I) R602 C- ( N H) p]q-D-E-Y~ O/o) aq CuO t-BuSH excess NH3, or Cul base ethylene glycol OH StBu NH2 W \W W111~W VNl-k~lW
R602C-(NH)p]q-D-E-Y,,O ~ R602C-(NH)p]q-D-E-Y,, O)L"O~ R602C-(NH)p]q-D-E-Y,, O
I ~
H+
SH
WW
R602C-(NH)plq-D-E-Y,, O I /
Compounds of Formula I wherein q is taken from Q-24, Q-25, or Q-26 are prepared as shown in Scheme 20. Reaction of compounds 1-115 or 1-119 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R4)2 gives rise to compounds of Formulae 1-123 or 1-124. Reaction of compounds 1-118 or 1-122 with a peracid, preferably peracetic acid or trifluoroperacetic acid, affords compounds of Formula I-125 or 1-126. Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R4)2 or alcohols R4OH, affords compounds of Formulae I-127, 1-128, I-129, or 1-130.
Scheme 20 /~ /\
W. W W W i W
R802C-(NH)p)q-D-E-Y_, Zlyl") R802C-(NH)pjq-D-E-Y~,Z~ ReOzC-(NH)plq-D-E-YNZ' V
I-115,Z=NH I-118,Z=NH 117,Z=NH
1_119,Z=O 1-122,Z=O 121,Z=O
1) Chlorosulfonyl- 1) Chlorosulfonyl-isocyanate Peracetic acid isocyanate 2) HN(R4)2 2) HN(R4)2 or R4OH
0 o p 0 \\ 1j D/ 'NS/N~Ra j O3H HN~H~S\ i/Ra H /\
~ Ra W~W R " \, R602C-(NH)p)q-D-E-Y / I1'V W ~W
I~ ~ ReD2C'(NH)plq-D-E-Y~Z / ReO2C-(NH)plq-D-E-Y~ Z
Z/p~j I/
~
11_123,Z=NH 1-125,Z=NH 1-127,Z=NH
I-128, Z = O
I_124, Z= 0 I-126, Z= 0 O \\ 0 /INIg' OR4 HN H
WlkW
Z
RsOZC-(NH)plq-D-E-Y., I /
1-129, Z = NH
1-130, Z = 0 Compounds of Formula I wherein Q is taken from Q-27 are prepared as illustrated in Scheme 21. Reductive alkylation of thiomorpholine with aldehydes 131 affords benzylic amines 132, which are then subjected to peracid oxidation to give rise to the thiomorpholine sulfones 133 (see C. R. Johnson et al, Tetrahedron (1969) 25: 5649).
Intermediates 133 are reacted with amines 8(Z = NH2) under Buchwald palladium-catalyzed amination conditions to give rise to compounds of Formula I-134. Alternatively, compounds 133 are reacted with alcohols 8(Z = OH) under Buchwald copper(I) catalyzed conditions to afford compounds of Formula 1-135. Alternatively, intermediates 133 are reacted with alkenes under palladium(0)-catalyzed Heck reaction conditions to give compounds of Formula I-136.
Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide.
s OS s-o Scheme 21 CHO (N) peracid NaBH(OAc)3 oxidation O Q Q
- - ~~
[ReOsC (NH)p]q D E Y,, IRs02C-(NH)p1q-D-E 7/
NH2 S~O n \
8 ~/
133 pd(0), phosphine, \ 133 Pd(0), Ph3P, base I base ~. / IRe02C (NH)p)q D E F 1-136 [R802C-(NH)p]q-D-E-Y-NH n reduction (hydrogenatio:
diimide) [R802C-(NH)p]q-D-E-Y~ O
OH ~S-~O
133 8 N,,) Cu(I), base N
[R602C-(NH)p]q-D-E-Y-d IR602C-(NH)plq-D-E r)n 1-137 Compounds of Formula I wherein Q is taken from Q-27 are also prepared. as illustrated in Scheme 21.1. Aldehyde 8c is reductively aminated with ammonia, and the resultant amine condensed with divinyl sulphone to yield 1-134. Intermediate 134a is also available by reduction of amide 8d under a variety of standard conditions.
Scheme 21.1 [R602C7(NH)p]q-D-E-Y_ - _H._. _.[R6O2C-(NH)p]q-D-E-Y~NH2 8c NaCHBH3 134a Amide reduction 0 i.e. LAH
S
0 [R602C-(NH)p]q-D-E-Y NH2 [R602C-(NH)p]q-D-E-Y ~ OS-\~- 8d O
More generally, amines 134c are available via the reduction of amides 134b as shown in Scheme 21.2. The morpholine amide analogues 134d and morpholine analogues 134e are also available as shown in Scheme 21.2.
Scheme 21.2 [R602C-(NH)p]q-D-E-YOH R, R2NH [R602C-(NH)p)q-D-EY'k NRjRZ
DIC coupling 8e 134b H
N
C Amide reduction OJ DIC coupling i.e. LAH
[R602C-(NH)p]q-D-E-YN--~) [R602C-(NH)p]q-D-E-Y~NRI R2 134c 134d Amide reduction i.e. LAH
[R6O2C-(NH)p]q-D-E-Y "I-, N
134e Compounds of Formula I wherein Q is taken from Q-28 or Q-29 are prepared according to the sequences illustrated in Scheme 22. Readily available amides 138 are reacted with chlorosulfonylisocyanate to give intermediates 140, which are Teacted in situ with amines HN(R4)Z or alcohols R4OH to afford compounds of Formulae 1-141 or 1-142, respectively. Alternatively, amides 138 are reacted with sulfonylchlorides to give compounds of Formula 1-139.
H N CI
O N~ ISO
Scheme 22 CONH2 O O HN(R4)2'or I \ C1SO2-N=C=O R40H
base [ReO2C-(NH)p]q-D-E _Y [R602C-(NH)p]q-D-E , Y
R4 Ra I
H
O
O N~N / S R4 N N to [Re02C-(NH)p]q-D-E~ Y/ [R602C-(NH)p]q-D-E~Y
O HN-S
::~O
138 base [R602C-(NH)p]q-D-E -- Y
Compounds of Formula I wherein Q is taken from Q-30 are prepared as shown in Scheme 23. Readily available N-BOC anhydride 143 (see S. Chen et al, J. Am.
Chem. Soc.
(1996) 118:2567) is reacted with amines HN(R4)2 or alcohols R6OH to afford acids 144 or 145, respectively. Intermediates 144 or 145 are further reacted with amines HN(R4)2 in the presence-of-an acid-activating reagent, preferably PyBOP-and-di-isopropylethylamine, to give diamides 146 or ester-amides 147. Intermediate 145 is converted to the diesters 148 by reaction with an alkyl iodide in the presence of base, preferably potassium carbonate.
Intermediates 146-148 are treated with HCI/dioxane to give the secondary amines 149-151, which are then condensed with acids 152 in the presence of PyBOP and di-isopropylethylamine to give compounds of Formula 1-153.
Scheme 23 HOZ C ON(R4)2 2(R4)NC O 0 N(Ra O O 0 NN(It4)2 N 1) PyBOP, i-Pr2NEt NJ
~. ~ -i BOC 144 BOC L4 N or R60H 0 ORe 2) HN(R4)2 O
BOC HO2C 2(R4)NCO OR6 143 N' 145 BOC N 14;
BOC
R61, base 0 OR6 R602C ~ N 148 BOC
HCI, die CO-X, \ /
2(Ra)NC O O ~1' N(R, N
0 ~ PyBOP, i-Pr2NEt 0 OH J
\\ /
2(R4)NC O OF
[Rs '~' 02G(NH)p14-D-E Y IRs02C-(NH)p1Q-D-E ,Y J
li XI, XZ are N(R4)2 O OR
XI is N(R4)2, X2 is OR6 R602C
XI,XzareOR6 N 151 H
Compounds of Formula I wherein Q is taken from Q-31 or Q-32 are prepared according to the sequences illustrated in Scheme 24. Treatment of readily available sulfenamides 154 with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =-CH=CH2), gives rise to compounds of Formula 1-155. Treatment of sulfenamides 1-155 with iodosobenzene in the-presence of alcohols R~OH gives rise to the sulfonimidates of Formula 1-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively, compounds 1-155 (Z
=-CH=CH) may be optionally reduced to the saturated analogs 1-156 (Z = CH2-CH2-), which are converted to the corresponding sulfonimidates 1-157.
Treatment of readily available sulfonylchlorides 154.1 with amines HN(R4)2 and base gives rise to compounds of Formula 1-154.2.
Scheme 24 [ReOZC-(NH)pjq-D-E-Y,, ZH
37, Z = NH
Pd(O), phosphine, base O\
0\S/ NH2 SONH2 PhI=O
[RBOyC-(NH)p)q-D-E-Y~
ZH --~ i/
37,Z=0 R60H, Cu(I), base [Rso2C-(NH)pjq-D-E-Y-Z
M [RBO2C-(NH)pjq-D-E-Y-Z MeCN I-157 [ReO2C-(NH)p1q-D-E-Y~ Ph ZH R6' 37, Z = CH=CH2 Mf Pd(0), phosphine, O"S/
base Z = CH=CH-Hydrogenation [R6O2C-(NH)pjq-D-E-Y-(CH2);
S02NH2 SOZN(R4)2 I \ HN(4)z [R602C-(NH)pjq-D-E-Y [R602C-(NH)pjq-D-E-Y
154.1 1-154.2 Compounds of Formula I wherein Q is taken from Q-33 are prepared as shown in Scheme 25. Readily available nitriles 158 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =-CH=CH2) to afford compounds of Formula 1-159.
Compounds 1-159 (wherein Z = CH=CH-) are optionally reduced to their saturated analogs 1-160 by standard catalytic hydrogenation conditions. Treatment of compounds 1-159 or 1-160 with a metal-azide (preferably sodium -azide- or -zinc-azide)- gives rise to-tetrazoles of Formula 1-161.
Scheme 25 [R6O2C-(N H)p]q-D-E-Y~, ZH
37, Z = NH
N_ Pd(0),phosphine, N
base CN
CN ~3 [R6O2C-(NH)p]q-D-E-Y~
ZH
[R602C-(NH)p]q-D-E-Y-Z
I ~ 37,Z=0 [R602C-(NH)p)q-D-E-Y-Z 1-159 1-16 M Cu(1), base [R6O2C-(N H)p]q-D-E-Y,, ZH
37, Z = CH=CH2 =
Pd(O), phosphine, Z CH=CH-.
~
base Hydrogenation ~
i [ R602C-( N H) p]q-D-E-Y -(C H;
Compounds of Formula I wherein Q is taken from Q-34 are prepared as shown in Scheme 26. Readily available esters 162 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z = -CH=CH2) to afford compounds of Formula 1-163.
Compounds 1-163 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-164 by standard hydrogenation conditions. Compounds 1-163 or 1-164 are converted to the desired phosphonates 1-165 by an Arbuzov reaction sequence involving reduction of the esters to benzylic alcohols, conversion of the alcohols to the benzylic bromides, and treatment of the bromides with a tri-alkylphosphite. Optionally, phosphonates 1-165 are converted to the flourinated analogs 1-166 by treatment with diethylaminosulfur trifluoride (DAST).
COZZ = CH=CH- 6R6 Scheme 26 Hydrogenation [ReOzC-(NH)p}q-D-E-Y-(CH2)Z
[ReOzC-(NH)p)q-D-E-Y1.1 ZH 1-164 37, Z= NH 1) reduction to alcc (LiBH4) Pd(0), phosphine, 2) CBr4, Ph3P
base 3) P(OR6)3 C02R6 1) reduction to alcohol 0\\ /
IR602C-(NH)plq-D-E-Y~1 I \ (LiBH4) P-ORe 37,Z=0 . ZH / _ [R602C-(NH)plq-D-E-Y-Z 2) CBr4, Ph3P
M C~(I), base 3) P(OR6)3 ~
162 1-163 [ReO2C-(NH)plq-D-E-Y-Z
[R602C-(NH)p]q-D-E-Y~ZH . 1-165 37, Z = CH=CH2 ~ DAST
Pd(O), phosphine, base ORB
O~P OR6 F
[R602C-(NH)p)q-D-E-Y-Z
Compounds of Fonnula I wherein Q is taken from Q-35 are prepared according to Scheme 27. Readily available acid chlorides 167 are reacted with oxazolidones in the presence of base to afford the N-acyl oxazolidinones 168. Intermediate 168 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =.-CH=CH2) to afford the N-acyl oxazolidinones of Formula 1-169. Compounds I-169 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-170 under standard hydrogenation conditions.
Scheme 27 [R602C-(NH)p]q-D-E-Y,,, ZH
37,Z=NH
Pd(O), phosphine, OO
O O base O N
HN~O O COCI R4 t R4 [R602C-(NH)p]q-D-E-Y~, ZH I \
\ R4 37, Z= 0 I1~/ base Cu(I), base [R602C-(NH)p]q-D-E-Y-Z
[R6O2C-(N H)p]q-D-E-Y,, ZH hydrogenation 37, Z = CH=CH2 (Z = CH=CH) Pd(O), phosphine, base O~
O
O N
I \
[R602C-(N H)p]q-D-E-Y-(CHZ)2 Compounds of Formula I wherein Q is taken from Q-35 are also prepared as illustrated in Scheme 27.1. Intermediate 8a, wherein M is a suitable leaving group such as chloride, bromide or iodide, is refluxed with triethyl phosphite and the resulting phosphoryl intermediate saponified under mild conditions to yield 1-165.
Scheme 27.1 ~~OH
[R602C-(NH)p]q-D-E-Y'M 1. P(OEt)3 [R602C-(NH)p]q-D-E-Y~ OH
8a 2. saponification 1-165 Compounds of Formula I wherein Q is taken from Q-36 are prepared as illustrated in Schemes 28.1 and 28.2. Reductive alkylation of the t-butylsulfide substituted piperazines with the readily 'available aldehydes 131 gives rise to the benzylic piperazines 171.
Intermediates 171 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z
_-CH=CH2) to give compounds 172, 173, or 174, respectively. Optionally, intermediates 174 are converted to the saturated analogs 175 under standard hydrogenation conditions.
CHO HN~N-\-St-Bu N \_/N-St-Bu Scheme 28.1 I NaBH(OAc)3 ' I \
M M
r-1 N N-~
IRsO2C-(NH)p1q-D-E-Y~. V S
37. Z = NH ZH ~/N,-St-Bu 37, Z CH=CH2 171 \ - 171 (E
Pd(0), phosphine, I Pd(0), phosphine, ~ 174 base [~02C (NH)pjq D-E-Y-N / 17Z base [R602C-(NH)p]q-D-E-Y
reduction (hydrogenation or diimide) N \-/N-\-St-Bu [R602C-(N H)p]q-D-E-Y,, ZH
37,Z=0 171 L VN-\-St-8u Cu(I), base IR602C-(NH)pjq-D-E-Y-O
[R602C-(NH)p]q-D-E-Y
Scheme 28.2 illustrates the conversion of intermediate t-butylsulfides 172-175 to the sulfonic acids, employing a two step process involving acid-catalyzed deprotection of the t-butyl sulfide to the corresponding mercaptans, and subsequent peracid oxidation (preferably with peracetic acid or trifluoroperacetic acid) of the mercaptans to the desired sulfonic acids of Formula 1-176.
Scheme 28.2 N \-N
N N-'- 1 St-Bu ] ) H+
\ - I \
2) peracid oxidation [R602C-(NH)p]q-D-E-Y-Z
[R602C-(NH)p]q-D-E-Y - Z
Z = NH, 0, CH=CH, CH2-CH2 In some instances a hybrid p38-alpha kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety RI-X-A.
The synthesis of functionalized intermediates of-formula Ri-X-A are accomplished as shown in Scheme 29. Readily available intermediates 177, which contain a group M
capable of oxidative addition to palladium(0), are reacted with amines 178 (X = NH) under Buchwald Pd(0) amination conditions to afford 179. Alternatively amines or alcohols 178 (X = NH or 0) are reacted thermally with 177 in the presence of base under nuclear aromatic substitution reaction conditions to afford 179. Alternatively, alcohols 178 (X = 0) are reacted with with 177 under Buchwald copper(I)-catalyzed conditions to afford 179. In cases where p = 1, the carbamate of 179 is removed, preferably under acidic conditions when R6 is t-butyl, to afford amines 180. In cases where p = 0, the esters 179 are converted to the acids 181 preferably under acidic conditions when R6 is t-butyl.
Scheme 29 Rj-XH
M-A-(NH)p-C02R6 178 R X-A- NH CO R
-~ ~ ( )P- z s 177 heat or Pd(O) catalysis 179 H+ H+
RjX-A-NHZ RjX-A-CO2H
Another sequence for preparing amines 180 is illustrated in Scheme 30.
Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 wherein M is a leaving group, preferably M is fluoride, or M is a group capable of oxidative insertion into palladium(0), preferably M
is bromo, chloro, or iodo, gives intermediates 183. Reduction of the nitro group under standard hydrogenation conditions or treatment with a reducing metal, such as stannous chloride, gives amines 180.
Scheme 30 Rj-XH
reduction M-A-N02 - 178 RiX-A-N02 RjX-A-NH2 182 heator 183 180 Pd(0) catalysis In instances when hybrid p38-alpha kinase inhibitors are prepared, compounds of Formula 1-184 wherein q is I may be converted to amines 1-185 (p = 1) or acids I-186 (p = 0) by analogy to the conditions described in Scheme 29. Compounds of Formula 1-184 are prepared as illustrated in previous schemes 1.1, 2.1, 2.2, 3, 4, 5, 6; 7.1, 7.2, 8, 9, 10, 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, or 28.2.
Scheme 31 [R602C-(NH)plq-D" E, Y'Q
q H+ H+
~ i H N-D~ E. Y .Q HO2C-D~ E. Y .Q
Compounds 1-184 are taken from schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24,.25, 26, 27, 28.2 The preparation of inhibitors of Formula I which contain an amide linkage -CO-NH-connecting the oxyanion pocket binding moieties and Rj-X-A moieties are shown in Scheme 32. Treatment of acids 181 with an activating agent, preferably PyBOP in the presence of di-iso-propylethylamine, and amines 1-185 gives compounds of Formula I.
Alternatively, retroamides of Formula I are formed by treatment of acids 1-186-with PyBOP in the presence of di-iso-propylethylamine and amines 180.
Scheme 32 O
H N-D,E, Y'Q RtX-A-CO2H PyBop, i-Pr2NEt ~
z + R~X-A N" D~E~Y.
~ H
Compounds 1-185 taken Compounds 181 taken from scheme 31 from scheme 29 Amides of Formula I
(hybrid inhibitors, possessing oxyanioi pocket-binding moiety Q and moiety RI-) ~E, ~Q RIX-A-NHz HOZC-D Y + PyBop, i-Pr2NEt R,X-A-NH D'E~Y'O
Compounds I-186 taken Compounds 180 taken from from scheme 31 schemes 29 or 30 RetroamideFormula I
(hybrid inhibitors, possessing oxyanic pocket-binding moiety Q and moiety Ri-:
The preparation of inhibitors of Formula I which contain an urea linkage NH-CO-NH- connecting the oxyanion pocket binding moieties and the RI-X-A moieties are shown in Scheme 33. Treatment of amines 1-185 with p-nitrophenyl chloroformate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I.
Scheme 33 ,E, Q p-nitrophenyl chloroformate R,X-A-NHz HZN-D Y - a;'- O HN.DE, YQ
base I0 Compounds 180 taken fi Compounds I-185 taken O2Nschemes 29 or 30 from scheme 31 187 O-R,, X.1 A11 N"k NDll~ E"Y.Q
H H
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RI-X-A) Alternatively, inhibitors of Formula I which contain an urea linkage NH-CO-NH-connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are prepared as shown in Scheme 33. Treatment of amines 180 with p-nitrophenyl chloroformate and base affords carbamates 188. Reaction of 188 with amines 1-185 gives ureas of Formula I.
Scheme 34 RIX-A-NH2 p-nitrophenyl chloroformate H2N-D Y
(oyHNAXRl Compounds 10 taken from base schemes 29 or 30 I/ O Compounds 1-185 ta}
OZN from scheme 31 Rt, XA1~ N"k N,D~EiY'Q
H H
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RI-X-A) The preparation of inhibitors of Formula IB can be generally accomplished starting from a variety of readily available beta-ketonitriles 189, wherein R40 is alkyl, phenyl, or perfluoroalkyl. As illustrated in Scheme 35, reaction of 189 with an alcohol R4OH, preferably methanol or ethanol, under anhydrous acidic conditions, preferably anhydrous HCI, leads to the formation of imidates 190. Reaction of 190 with acyl chlorides, isocyanates, para-nitrophenylcarbamates, or substituted chloroform.ates in the presence of a base, preferably pyridine, triethylamine, di-iso-propylethylamine, Barton's base, or an alkali metal carbonate, affords key intermediates 191 and 192 as a mixture of tautomers, wherein T
is alkylene, NH, 0, or when T is absent, then the carbonyl side chain and A
are connected by a direct bond.
Scheme 35 p 0 HN ~T'A
O O NH. HX ~ jj ~ T ~ +
~CN Rao~OR41 tR40'0R41 Rao /
Rao H2N-NH-(E)y(Y)t-Q
O
H
N~ N 1, TA
Q,, (Y)t (E)4 The mixture of tautomers 191/192 are not separated from each other, but are reacted as,a mixture with a substituted hydrazine 193, wherein the Q moiety is optionally protected by a protecting group that diminishes its reactivity with the 191/192 mixture.
This cyclodehydration reaction is performed in the presence of base, acid catalysis, or under neutral conditions optionally in the presence of a dehydrating agent to afford the desired pyrazoles 194. Preferable reaction solvents include dichloromethane, ethyl acetate, acetonitrile, or an alcoholic solvent taken from methanol, ethanol, or 2-propanol.
The reaction sequence initiating from 190 and yielding 194 may take place as two separate reactions, wherein the tautomeric mixture 191/192 is isolated, and then in a second reaction step this 191/192 mixture is reacted with a substituted hydrazine 193 to afford the desired pyrazoles 194. Alternatively, the reaction sequence initiating from 190 and yielding 194 may take place in a one-pot procedure, without isolation of the intermediate 191/192 mixture.
In a further modification, the reaction sequence initiating from 190 and yielding 194 may take place in a parallel array format, wherein phase-trafficking reagents, including scavenging reagents, are utilized to allow purification and isolation of intermediates and products. Scheme 36 illustrates this modification. Excess imidate 190 is reacted with a limiting amount of electrophile in the presence of a polymer-supported base 195 to afford the acylated imidates 191/192 as a mixture of tautomers. The crude mixture of 191/192 is optionally purified by incubation with a polymer-supported electrophile 196, preferably a polymer-supported isocyanate or acid chloride. Reaction of 196 with any remaining imidate 190 sequesters this imidate as polymer-supported 197. Filtration- gives purified 191/192. In the second step, purified acylated imidates 191/192 are reacted with the substituted hydrazines 193 to afford desired crude products 194. A polymer-supported hydrazine 198 is optionally utilized to scavenge any remaining 191/192 from solution phase as derivatized 199. Filtration gives rise to purified desired pyrazoles 194.
Scheme 36 E)ectriles Q-Base O JO
O- - NH ..HX -- -- A--- -- --- / IT'A
II II Acid chloride, 15 0 N ~T" 0 HN
R~o/~/~OR~~ + Isocyanate, --, ~ ~I +
p-Nitrophenylcarbamate, R40 \/ ~OR41 R4o / ORfl 190 Anhydride, or - Substituted chloroformate Excess relative 191 192 to Electrophile Quenching of Electrophile excess Imidate 190 %dF-Electrophile-quenched imidate 190 HzN-NH-(E)a(Yk-0 -~ ~
191/192 + N O
N NIUIT"A
(puri5ed) 193 O'(Y)t(E)q H
194 (purified) O
Quenching of any N~
~--NH-NHZ remaining 191/192 N H~T" A
Scheme 37 illustrates the preparation of compounds wherein Q is Q-40. Readily available amine 200; wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with p-nitrophenyl chloroformate to give rise to carbamate 201.
Intennediate 201 is reacted with a substituted amino acid ester with a suitable base to afford urea 202. Further treatment with base results in cyclization to afford hydantoin 203. The protecting group P is removed to afford the key amine-containing intermediate 204.
Alternatively, if P is a nitro group, then 203 is converted to 204 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 204. is converted to 205A by reaction with an isocyanate; 204 is converted to amide 205B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 204 is converted to carbamate 205C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 37 H
p-Nitrophenyl 0 NOz ~N COZR3 D ~,)\ chloroformate P,p\ /(Y)\ ~
~O R<
P (E)Q NHz Base (E)Q H
Base 'K 0 Ro R4 Base p (Y)t O Deprotection or ~p\ (Y)\ Pi \(E)q NR4 reduction P (E)Q N N COzRa H ~
O
D (Y)~ 0 A-T,-N=C=O A-T, ~ /D\ /(Y)t O
H2N (E)4 ~~ R4 H H (E)Q ~~~ R4 O N R4 205A p N R4 204 R4 A-T-COCI 0 h4 -- /\ ip\ (Y)t O
Base A T H (E)q O~,N/Ra nR4 205B 205C j4 Scheme 38 illustrates the synthesis of key substituted hydrazine 210. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The nitrophenyl substituted amine 206 is reacted with p-nitrophenyl chloroformate to give rise to carbamate 207. Reaction of 207 with a suitable amino acid ester affords urea 208, which is cyclized under basic conditions to give hydantoin 209. Reduction of the nitro group of 209, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 210.
Scheme 38 H
p-Nitrophenyl OZN (Y)t 0 N02 R4/N~COzR3 Oz N ~-/~.)\ chloroformate ~N~O R4 R4 / NH H
z Base Base 206 207 0 Ro Ra Base OzN (Y)t O
OzN (Y)t 1) Pd/C, H2 N~NA C02R3 I ~~Ra H I N R4 2) NaNO2, HCI
Ra R4 3) SnCIZ
H
H N- N \/~~\ 0 z I j N~Ra O~ N Rn Scheme 39 illustrates the synthesis of key substituted hydrazines 213 and 216, utilized to prepare compounds of formula IB wherein Q is Q-42 and G is oxygen.
Nitrophenol 211 is reacted with an alpha-hydroxy acid, wherein R42 is H or alkyl and R43 is alkyl, under Mitsunobu reaction conditions to give 212; alternatively 211 is reacted under basic conditions with a carboxylic acid ester containing a displaceable Q, group to afford 212.
Conversion of 212 to the hydrazine 213 is accomplished by standard procedures as described above.
Scheme 39 HOI_t~ CO2R43 O2N O~/ COzR43 1) Pd/C, HZ HN
-- ~ I --= HZN~ \ O\~ C02Ra3 Mitsunobu R42 2) NaNO2, HCI I
O2N OH Reaction 212 3) SnC12 R'~
~ 213 211 Qx1~1 COZR43 Base OZI% R N \/O C02R43 Hydrolysis QZN /O CO H NH(R h 02N O O
v Y 2 _ \ \ N
R42 EDC, HOBT RT42 R
212 214 1) Pd/C, HZ
2) NaNOZ, HCI
3) SnCIZ
O
HZN' HN I \ O'T'NR4 I
Alternatively, the ester group of 212 is hydrolyzed to afford carboxylic acid 214, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 215. Conversion of 215 to the substituted hydrazine 216 is accomplished by standard procedures. Hydrazines 213 and 216 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 40 illustrates the synthesis of key substituted hydrazines 219 and 222, utilized to prepare compounds of formula I_B wherein Q is Q-42 and G is ]nethylene.
Nitrophenyl bromide 217 is reacted with an alpha-beta unsaturated ester using Pd(0) catalyzed Heck reaction conditions, . to afford ester 218. This intermediate is converted to the substituted hydrazine 219 by standard procedures involving concomitant reduction of the alpha-beta unsaturated bond. Alternatively, ester 218 is hydrolyzed to the carboxylic acid 220, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 221. Conversion of 221 to the substituted. hydrazine 222 is accomplished by standard procedures. Hydrazines 219 and 222 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 40 Raz C02R43 O2N \ COzR43 1) Pd/C, H2 -- I % /~/ -- H2N.HN C02~s Heck _IR42 2) NaNOZ, HCI
OzN \~Br Reaction 3) SnCI2 R'Z
OZN Hydrolysis OzN NH(R4)2 OZN O
I /\ /COZR~~ I ~ ~COzH - I \ \ NR4 \R4Z EDC, HOBT
Raz R4z R4 1) Pd/C, H2 2) NaNOZ, HCI
3) SnC12 O
HZN- HN I N.R4 Scheme 41 illustrates an alternative synthesis of key substituted hydrazines 225 and 228, utilized to prepare compounds of formula IB wherein Q is Q-42, G is methylene, and one or both of R42 are carbon-containing substituents. Nitrobenzyl acetate.223 is reacted with a substituted silylketene acetal to afford ester 224. This intermediate is converted to the substituted hydrazine 225 by standard procedures. Alternatively, ester 223 is hydrolyzed to the carboxylic acid 226, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 227. Conversion. of 227 to the substituted hydrazine 228 is accomplished by standard procedures. Hydrazines 225 and 228 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 41 OTMS
R4z -(~OEt 02R~z N \ COZEt 1) Pd/C, H2 HN
I % ~ HzN' \ COzEt Mg(ClO4h, DCM R+z R02 2) NaN02, HCl I/ ~z O N I\ 3) SnC12 Wz ~OAC
OzN CO Et Hydrolysis OzN NH(R4)2 OzN O R
z COZH . e ~z R42 R42R+2 R/'R4z EDC,HOBT
~
4z 1) Pd/C, HZ
2) NaNO2, HCI
3) SnClz HzN,HN I \ N.W
R4z ~z Ra Scheme 42 illustrates an alternative synthesis of key substituted hydrazines 231 and 234, utilized to prepare compounds of formula IB wherein Q is Q-42 and G is NH.
lodoaniline 229 is reacted with an alpha-keto ester under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford ester 230. This intermediate is converted to the substituted hydrazine 231 by Cu(I)-catalyzed reaction with N-BOC
hydrazine.
Alternatively, ester 231 is hydrolyzed to the carboxylic acid 232, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 233. Conversion of 233 to the substituted hydrazine 234 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazines 231 and 234 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCI-dioxane.
Scheme 42 A I H
~COzR~y NHZ-NHBOC ~N,N I\ N
R4Z C02R43 N \ /COzR43 T
~ Na BH(OAc)3 ~~ Cu(I) R4Z
I H Hydrolysis I H NH(R4)Z H O
~NyC02R43 N COZH NNW
R Y EDC,HOBT
R42 Rr2 Cu(I) BOC O
Ru R4 Scheme 43 illustrates an alternative synthesis of key substituted hydrazine 239, utilized to prepare compounds of formula IB wherein Q is Q-42, G is oxygen, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
lodophenol 235 is reacted with an alpha-hydroxy acid under Mitsunobu reaction conditions to give 236;
alternatively 235 is reacted under basic conditions with a carboxylic acid ester containing a displaceable Q,, group to afford 236. Ester_236 is hydrolyzed to the carboxylic acid 237, which is reacted with an amine X-H in the presence of a coupling reagent, preferably EDG/HOBT, -to give-amide -238. Conversion-of--238 to the substituted hydrazine 239 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazine 239 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCl-dioxane.
Scheme 43 HO'k COzRa3 ~ I \ /O\~CO2R43 --- T
Mitsunobu / R42 Reaction 236 Raz 235 OXI)__I CO2Ra3 Base O
~ /OyCO2R43 Hydrolysis I\/OyC02H X H O\ ~X
~ R42 Raz EDC, HOBT 7Raz IrLrv '~IV lfvv Cu(1) CNJ \S/ ~ BOC O
G ~
Ril 0 p R120 R13 H2N.N p\/\uX
Rlaz Scheme 44 illustrates an alternative synthesis of key substituted hydrazine 241, .5 utilized to prepare compounds of formula IB wherein Q is Q-42, G is NH, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
Carboxylic acid 237 is reacted with an amine X-H in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 240. Conversion of 240 to the substituted hydrazine 241 is accomplished by Cu(I)-catalyzed-reaction with N-BOC hydrazine.- Hydrazine 241 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting gr~oup, preferably with trifluoroacetic acid or HCI-dioxane.
Scheme 44 BOC
1 H X-H H p NH2-NHBOC 'N O
I/NYCp2H EDC,HOBT N Cu(I) H2N I/ NTKx .,.nr .rw llvv .rvv N N N N
x r 1 rN, rsl YOR13 'J Rip 0 Scheme 45 illustrates an alternative synthesis of key substituted hydrazine 246, utilized to prepare compounds of formula I.B wherein Q is Q-42, G is methylene, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
lodobenzyl acetate 242 is reacted with a substituted silylketene acetal to afford ester 243.
Ester 243 is hydrolyzed to the carboxylic acid 244, which is reacted with an amine X-H in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 245.
Conversion of 245 to the substituted hydrazine 246 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazine 246 can be converted into compounds of formula LB
using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCI-dioxane.
Schetne 45 OTMS
R42 _FOI__ OEt R42 ~ I \ ~ COZEt Hydrolysis COyH
Mg(CI04)2, DCM R42 R42 R42 Raz ~'~OAc BOC
O
X-H O
NH2-NHBOC ' N _r~ 244 - ~ - HzN \ X
\
EDC,HOBT ~ X Cu(I) I/
/ R42 R42 Ra2 R4z ,nnr .nnr .nnr ,nlv X N N
N I
~ N 'g~ ~
Ril 'O R7z0 R~~
O
Scheme 46 illustrates an alternative synthesis of key substituted hydrazines 248, 252, and 255, utilized to prepare compounds of formula I_B wherein Q is Q-47 or Q-48.
Nitrophenol 211 is reacted with a substituted alcohol under Mitsunobu reaction conditions to afford 247; alternatively 211 is alkylated with R4-Q,,, wherein Q,, is a suitable leaving group, under basic reaction conditions, to give rise to 247. Conversion of 247 to the substituted hydrazine 248 is accomplished under standard conditions.
The nitrobenzoic acid -249 is converted to the acid fluoride -250 by reaction with a fluorinating reagent, preferably trifluorotriazine. Treatment of acid fluoride 250 with a nucleophilic fluoride source, preferably cesium fluoride and tetra-n-butylammonium fluoride, affords the alpha-alpha-difluorosubstituted carbinol 251. Conversion of 251 to the substituted hydrazine 252 is accomplished under standard conditions.
Nitrobenzaldehyde 253 is reacted with trimethylsilyltrifluoromethane (TMS-CF3) and tetra-n-butylammonium fluoride to give rise to trifluoromethyl-substituted carbinol 254.
Conversion of 254 to the substituted hydrazine 255 is accomplished under standard conditions. Hydrazines 248, 252, and 255 can be converted into compounds of formula I_B
using the methods previously outlined in Schemes 35 and 36.
Scheme 46 HOIR4 OzN \ o' 1) Pd/C, Hy HzNHN O, R' Mitsunobu ~ 2) NaNOZ, HCI
OZN OH Reaction 247 3) SnCIZ
\ /
~ / 248 211 Ox , R' Base F
NN 0 OH 1) Pd/C, Hz H OH
J I\~ CsF, TBAF OzN I\~ HzN= N I\ F
OzN OzN
I\/C02H F~:N~F
F F F 2) NaNO2, HCI F
3) SnC12 OH
TMS-CF, OzN OH 1) Pd/C, H2 HZN- N CF
OzN \ CHO \ -~ \
" CF
3 I// TBAF ~/ " 2) NaNO2, HCI I/ ~
3) SnClz Scheme 47 illustrates the preparation of compounds of formula IB wherein Q is Q-5 59. p-Nitrophenylcarbamate 201 is reacted with a substituted alpha-hydroxy ester with a suitable base to afford carbamate 256. Further treatment with base results in cyclization to afford oxazolidinedione 257. The protecting group P is removed to afford the key amine-containing intermediate 258; alternatively, if P is a nitro group, then 257 is converted to 258 under reducing conditions such as iron/HC1, tin(II) chloride, or catalytic hydrogenation.
10 Amine -258 is converted to 259k by reaction with an isocyanate wherein TI
is alkylene or a direct bond connecting A and the carbonyl moiety; 258 is converted to amide 259B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 258 is converted to carbamate 259C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 47 H'O COzRaa O / NOZ ~/ ~ 0 R4 R4 ~D\ /(Y)~ ~O ~ I P~D(E)4 (Y)~N~OACOzR4s P (E)q H Base H
Base O Deprotection or D (Y)t O
PD(E)q (Y)N Ra reduction HzN/ \(E)4 ~N Ra - R
O~O Ra O O a O
A-T,-N=C=O A-T, ~ D /(1')t O
258 H N \(E)4 ~N~Ra H
259A O-~ O R4 258 \ 1-1 D\ (Y)~ O
Base A T ~H (E)4 NRa 259B O Ra Scheme 48 illustrates an alternative approach to the preparation of compounds of formula IB wherein Q is Q-59. Amine 260 is reacted with p-nitrophenylchloroformate under basic conditions to give rise to carbamate 261. This intermediate is reacted with an alpha-hydroxy ester in the presence of base to afford carbamate 262. Further treatment with base converts 262 into the oxazolidinedione 263. Conversion of 263 to the substituted hydrazine 264 is accomplished by standard procedures. Hydrazine 264 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 48 NOz H-0 CO2R43 p-Nitrophenyl OzN' \ t 0 ~
02N \ ~)t chloroformate N~O \ R4 R4 / , NHz Base / H
261 Base 0 R4 R4 Base OzN (Y)t O
~f~( /~ 1) Pd/C, H2 02N \ /(Y)\ /I / ~ --- I / N~R4 -~
CO
H O zRa3 O~0 R4 2) NaNO2, HCI
262 263 3) SnCIZ
H
H NiN /(Y) 0 z I / N~R4 O~O R4 Scheme 49 illustrates thee approach to the preparation of compounds of formula I_B
wherein Q is Q-57. Amine 265 is reacted with p-methoxybenzylisocyanate under standard conditions to give rise to urea 266. This intermediate is reacted with an oxalyl chloride in the presence of base to afford trione 267. Conversion of 267 to the substituted hydrazine 268 and removal of the p-methoxybenzyl protecting group is accomplished by standard procedures.
Hydrazine 264 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 49 I \ NCO O
Me0/~% OzN (Y 0 Ci CI
i\~J
OZN lY)\ )~ H H
\/ I j I\ 0 ~ NHp 266 OMe Base ozN (Y O 1) FeC13 HZNHN (y 0 / \NAN \ NA NH
\ ~ / 2) NaNOZ, HCI
O/f- OMe 3) SnCIZ 0 0 Scheme 50 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-56. Amine 269 is reacted with p-methoxybenzylsulfonylchloride under standard conditions to give rise to sulfonylurea 270. This intermediate is reacted with an oxalyl chloride in the presence of base to afford the cyclic sulfonyl urea 271. Conversion of 271 to the substituted hydrazine 272 and removal of the p-methoxybenzy]
protecting group is accomplished by standard procedures. Hydrazine 272 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 50 0 0 ~N i~
\\S%
I NHZ CICI I~ H CI
Me0 ~ -~ Me0 ~
Base O
Base OZN (Y)t 00 CICI
02N )\ I%/ \NN O
I NH y H f I I ~ ---270 OMe Base 02N ~ (Y)t O~ 1) FeC13 H2NHN ~ (Y 0 )t ~ /~
~/ \NSN a'zt:~ ~ \N-S.NH
2) NaNO2, HCI ~
OMe 3) SnC12 O// \\O
Scheme 51 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-58. Amine 273 is reacted with a cyclic anhydride e.g. succinic anhydride in the presence of base under standard conditions to give rise to imide 274.
Conversion of 274 to the substituted hydrazine 275 is accomplished by standard procedures.
Hydrazine 275 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 51 p 0 p ROZN (Ylt 0 1) FeCl3 ~2N \ j(Y)~ - ~ / ~N
~ j NHz ~ )X 2) NaNOz, HCI
0 R R4. 3) SnC12 H2NHN ~
(~~
N )X
0, R4 R4 Scheme 52 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-54 or Q-55. Carboxylic acid 276 is converted to protected amine 279 under standard conditions, which can be subsequently converted to hydrazine 280 by standard procedures. Hydrazine 280 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36 to yield protected amine 283 which is readily deprotected to yield amine 284. Reaction of amine 284 with CDI and amine (R4)2NH
.10 yields 285 (Q=Q-54). Reaction of amine 284 with the indicated sulfamoylchloride derivative yields 286 (Q=Q-55).
Scheme 52 O,N OH 02N mri NHR4 LAH OzN~ (y)t BocZO
p- 9N}12 ~ - I- ~ O ---~ ~ / ~ ~NHz EDC,HOBT
276_ 277 278 O
OpN
~/(Y)\ 1) Pd/C HzNHN ~/(y)~ + O N~T'A + O HN T A
NBoc--- ~ /~
Ra 2) NaNO2, HCI I j NBoc ~ R4o v ORõ
3) SnCIZ R4 Ra OR41 R40 Rao Rao O
CDI
N H~TA TFA N NTA R4NHR4 N~ N NTA
H H
O
/
/ ~
BocN~ H I R4, ~ (Ot Ra-N /~ N~N(y I
(~t R+o \ O
N/
O,,,O \N HT A
R4NHR4 SOyCIZ R4, N S'Ol O' "O
Base R4 R, N'S'N~(~1 ~
Scheme 53 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-49, Q-50 or Q-51. Protected amine 287 (available by several literature procedures) is converted to deprotected hydrazine 288 is accomplished by standard procedures. Hydrazine 288 (Q=Q-49) can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. Amine 287 can be deprotected by TFA to yield amine 289 which can be subsequently converted amide 290. Amide 290 is converted to hydrazine 291 (Q=Q-50) by standard procedures, which can be subsequently converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. Alternatively, amine 289 can be reacted with CDI and amine (R4)2NH
to yield urea 292 (Q=Q-51). Urea 292 is converted to hydrazine 293 (Q=Q-51) by standard procedures, which can be subsequently converted into compounds of formula LB
using the methods previously outlined in Schemes 35 and 36.
Scheme 53 NO2 NHNH2 1) Pd/C
\ -- \
2) NaNO2, HCI
Boc N 3) SnC12 HN
287 4) TFA 288 TFA NOz NHNH2 NOz O
/ I \
RB""kOH 1) Pd/C
O N O N
EDC; HOBT 2) NaNOZ, HCI
HN
Re 3) SnC12 R8.
1) Pd/C
CDI 2) NaN02, HCI
3) SnCIZ
Oy N Oy N
Ra"IN' R4~ N\ R
Rq 4 Scheme 54 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-52 and Q-53. Protected amine 294 (available by several literature procedures) is converted to protected hydrazine 295 is accomplished by standard procedures.
Hydrazine 295 (Q=Q-49) can be converted into compounds of formula IB to yield protected amine 298 which is readily deprotected to yield amine 299._ Reaction of amine 299 with chlorosulfonylisocyanate followed by amine (R4)2NH yields 300 (Q=Q-52).
Alternatively, reaction of chlorosulfonylisocyanate and amine (R4)2NH followed by amine 299 yields 301 (Q=Q-53).
Scheme 54 1) Pd/C ~ ~ T" A
\ - ~ \ + 0 N T~A 0 HN +
Boc N 2) NaN02, HCI /N J~~ ~/ OR41 3) SnCl2 Bx ~o OR<~
N~ A N~ A 1) CISOZNCO N~ ,A
N H T TFA N H T 2) R4NHR4 N H T
--- -~
Boc N HN O N
S,NH
R40 o~ N
~ ~ O R,~ 'w 1) C1S0 NCO N
R4NHR4 z .N H T,A
R
~
R4"N' O l 'N~ ~N 301 llf O S O
Scheme 55 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-36. Amine 302 is reacted with CDI and amine R4NH2 to yield 303, which is reacted with chlorocarbonyl sulfenylchloride to yield thiadiazolidinedione 304. Conversion of 304 to the substituted hydrazine 305 is accomplished by standard procedures.
Hydrazine 305 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 55 O
(Y)t OZN \ /~ )\ CDI O~N ~NR4 CI~8~cl OZN I ~-~Z,,(Y)ltN'kNIR4 j NH2 Base, R4NH2 Base ~-8 1) Pd/C, H2 HzNHN ~
(Y)~ Ra 2) NaNO2, HCI N N
3) SnCIZ OIl-S
Scheme 56 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-37, Q-38 or Q-39. Imides 309a, 309b, and 312 are all available via several literature methods, and are-each able to be alkylated with chloride 306 to yields intermediates 307, 310 and 313 respectively. Intermediates 307, 310 and 313 are respectively converted to hydrazines 308 (Q=Q-37), 311 (Q=Q-38), and 314 (Q=Q-39) by standard procedures.
H
Scheme 56 Oy( N111~ O
N-N
02N \ (~)t R/309a~ 02N \~(Y)t-N ~NR+ 1)Pd/C,H2 HZNHN \ (Y)t~N ~NR+
I " \C1 \'N. --- --- - I / ~N.
DMF, KZC03 0/f R+ 2) NaNO2, HCI 0 R+
3) SnC)Z
H
O__-(N'O
i-0 / NN
0'~0 R ~0 ~~ R
R+ 309bR+ OZN +\/(Y)t~N - N + 1) Pd/C, H2 H2NHN (Y)t,N S,N' +
=-- f / N~ N
DMF, K2CO3 R+ 2) NaNO2, HCI R+
310 3) SnC12 311 H
O
RN ~O
R+ OR+ ~0 ~~ R+
3 2 OZN I\/(Y)t\N~S,N R+ 1) Pd/C, H2 HZNHN (Y)tN S,N R+
O~R+ 2) NaNOZ, HCl +
DMF, K2C03 3) SnC12 Scheme 57 illustrates an alternative preparation of compounds.wherein Q is Q-37.
Readily available amine 315, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with S02C12 to give rise to sulfonyl chloride 316.
Intermediate 316 is reacted with a substituted amino acid ester with a suitable base to afford sulfonylurea 317. Further treatment with base results in cyclization to afford sulfohydantoin 318_ The protecting group P is removed to afford the key amine-containing intermediate 319.
Alternatively, if P is a nitro group, then 318 is converted to 319 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 319 is converted to 320A by reaction with an isocyanate; 319 is converted to amide 320B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 319 is converted to carbamate 320C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
H
Scheme 57 R 1-1 N \ /COZR3 SOZCIs D (Y)t ~ SO 4 R4xR' pp(E)Q ~)\NHZ Base pi \(E)q ~H CI Base p Deprotection or 00 R4 R4 Base /D\ (Y)~ ~ S~ reduction p /(Y)t p (E)4 N R4 p~ (E)y ~N~ N C0ZR3 - ~
H 1 p-1- N Ra %
K4 318 Ra O~I
p (Y)t 0~ A-T~ N=C=O A-TI, /\ iD\ (~')~ ~SOO
H2N~ (E)q O~N' R4 H H (E)q ~ Ra /Y'R4 320A p N~I
-~ II p / (Y)t Base A-TH \(E)q ~N~S R4 O_ N~R
Scheme 58 illustrates an alternative synthesis of key substituted hydrazine 325 of compounds wherein Q is Q-37. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The amine 321 is reacted with SO2C12 to give rise to sulfonyl chloride 322. Reaction of 322 with a suitable amino acid ester affords sulfonylurea 323, which is cyclized under basic conditions to give sulfohydantoin 324. Reduction of the nitro group of 324, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 325.
Scheme 58 H
' /COZR3 R,N x a SOZC12 0ZN ~)t ~"~ Ra Ra 02N \(Y)t - - I _ " \N~S~CI.._ - ~ j NHz Base - /-----H JBase 0 0 Ra Ra Base OzN~/(Y ~S~ 1)Pd/C,H2 O
zN I\~(~'~NgN~COZR3 )\N Ra ~ H I O_ N~Ra 2) NaNO2, HCI
323 Ra 324 R4 3) SnClz N ) H N' \ /\ 'C
z N~S Ra NXRa Ra Scheme 59 illustrates an alternative preparation of compounds wherein Q is Q-38.
Readily available amine 326, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with SOZCIz to give rise to sulfonyl chloride 327.
Intermediate 327 is reacted with a substituted hydrazide ester with a suitable base to afford sulfonylurea 328. Further treatment with base results in cyclization to afford sulfotriazaolinedione 329. The protecting group P is removed to afford the key amine-containing intermediate 330. Alternatively, if P is a nitro group, then 329 is converted to 330 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation.
Amine 330 is converted to 331A by reaction with an isocyanate; 330 is converted to amide 331B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 330 is converted to carbamate 331C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
H
Scheme 59 R ~N~N~CO2R3 SO Cl O p 4 i z 2 D (Y)t\/S, CI R4 PD(E)q ~) 'NHz Base P/ (E)q H Base Deprotection or ~' ~O R4 Base /D\ ~)~ O 8 reduction p /(~')t s N p (E)q N , P, \(E)q ~N, N C02R3 -~ O~N N,R4 H I -~
. R4 I
p\ (Y)~ ~~ A-T,-N=C=O A-T,~ ~ D\ /(Y)~ ~S ~
H2N (E)q N' N H (E)q N \
~ N_Ra N-R4 O N 331A p N.
D / (Y)t ~\ 9 0 Base A-TH~ \(E)q \N~S\
O N i 331B 331C ~
Scheme 60 illustrates an alternative synthesis of key substituted hydrazine 336 of compounds wherein Q is Q-38. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The amine 332 is reacted with SO2Clz to give rise to sulfonyl chloride 333. Reaction of 333 with a ubstituted hydrazide ester affords sulfonylurea 334, which is cyclized under basic conditions to give sulfotriazaolinedione 335. Reduction of the nitro group of 335, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 336.
Scheme 60 H
Ra N1~ N'ICOZR3 i SO2C12 CZN ~ (Y)t ~"~ R4 02N ~(Y)t \N'S" CI llw NH2 Base H Base 02N 0~.0 R4 Base OzN/(Y)t ~S~ 1) Pd/C, HZ
~)~ S~ ~N~CO -~ I ~ N
H
O~ N R4 2) NaNO2, HCl R4 R4 3) SnCIZ
H
HzN-N (Y)t Og N~
O"L-N
336 Ra Scheme 61 illustrates the preparation of compounds wherein Q is Q-39. Readily available amine 337, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with p-nitrophenyl chloroformate to give rise to carbamate 338.
Intermediate 338 is reacted with a substituted amino acid ester with a suitable base to afford urea 339. Further treatment with base results in cyclization to afford triazolinedione 340.
The protecting group P is removed to afford the key amine-containing intermediate 341.
Alternatively, if P is a nitro group, then 340 is converted to 341 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 341 is converted to 342A by reaction with an isocyanate; 341 is converted to amide 342B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 341 is converted to carbamate 342C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 61 H
p-Nitrophenyl 0 ~NOZ R4i N" NC02R3 chloroformate D ,(Y)t PD(E)q (Y)\NH2 Base Pi \(E)q ~H 0 Base O Deprotection or /D\ /(Y)\ 0 / Na Base PD(E)q (Y)N reduction P (E)q HN COsR3 ~ O~N N1R4 _-~
B4 ' 339 340 R4.
O O
D /(Y)t O A-T,-N=C=O A-T,, /~'I /O\(E)q (Y)\N~( H2N ~ (E)q ~ ~ \
N-R4 H H N'~
341 ~4 R4 'k, /p\ /(Y)\ 0 Base A-T H N (E)q N- \
~ N' R4 O N
342B 342C ~4 Scheme 62 illustrates an alternative synthesis of key substituted hydrazine 347 of compounds wherein Q is Q-39. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The nitrophenyl substituted amine 343 is reacted with p-nitrophenyl chloroformate to give rise to carbamate 344.
Reaction of 344 with a suitable amino acid ester affords urea 345, which is cyclized under basic conditions to give triazolinedione 346. Reduction of the nitro group of 346, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 347.
Scheme 62 H
p-Nitrophenyl OZN mt ~ ~ I NOz ~~N~N,COzR3 OZN ~.)t chloroformate N
~
~ H
NHz Base Base OZN ~ -?a Base OZN/-(~')t O 1) Pd/C, H2 (Y)t H iNCO2R3 O~
345 N R4 2) NaNOZ HCI
R4 346 R4 3) SnC12 H
H N-N ~)~ " \
z N
j O N
Scheme 63 illustrates the synthesis of compounds wherein Q is Q-43. Morphiline is alkylated with protected bromohydrine. Removal of the alcohol protecting group yields intermediate 349, which can be oxidized to aldehyde 350. When G NH, iodoaniline 351 is reacted with 350 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 352. This intermediate. is converted to the substituted hydrazine 353 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 355 is either alkylated with 354 or reacted under Mitsunobu conditions with alcohol 349 to yield intermediate 356. This intermediate is converted to the substituted hydrazine 353 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 63 BOC
i ~ NH2 Na BH(OAc)3 _N~~ NH2-NHBOC ~ N N~
~/ o '' v 0 Cu(1) H?N I/ 1 I y N~ IC
H
351 0N v 352 353 lEo]
H
CN~ I) TBSO -1~4 Br /--\ OH
2 TBAF v O ) Mitsunobu 348 349 Reaction j~ Ox lN
~~ Bi oc /OH 354 /O\/N~ NHZ-NHBoc HsNN ~
Base / 1110 Cu(I) ~/ 1 I v 355 356 35'7 \~
Scheme 64 illustrates the synthesis of compounds wherein Q is Q-43, G=CH2.
Nitroacid 358 (readily available by anyone with normal skills in the art) is reacted with morphiline to yield amide 359, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 360. This hydrazine can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 64 O
O 1) LAH O
OzN~ ~ Il OH EDC, HOBT OzN ~ L) ]l 2) Pd/C HZNHN ~
~ N
I/ N I v 3) NaNO2, HCI ~/ v ~ I~
4) SnC1Z
358 Co 359 360 Scheme 65 illustrates the synthesis of compounds wherein Q is Q-44. N-methyl piperazine 361 is alkylated with protected bromohydrine. Removal of the alcohol protecting ] 5 group yields intermediate 362, which can be oxidized to aldehyde 363. When G=NH, iodoaniline 364 is reacted with 363 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 365. This intermediate is converted to the substituted hydrazine 366 by Cu(1)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 368 is either alkylated with 367 or reacted under Mitsunobu conditions with alcohol 362 to yield intermediate 369. This intermediate is converted to the substituted hydrazine 370 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 65 BOC
i I~ ryHZ Na BH(OAc)3 ' I ' v ON,R4 z NHi-NHBOH N'N I~ jN~~H Cu(I) / v N'~
364 R~- ~N () v 365 366 H /~ If01 N 1) TBSO/_~B~ ,~ OH
C / V Rq-N~\N-(')v ~J
N 2) TB~ ~ Mitsunobu R4 ~ L62 Reaction /-Ox Ra- N-() v Boc jOH 367 NH2-NHBoc HzNN I~ jO N~
I / Base v ~N.~ Cu(I) ~v ~N'~
368 %' 369 I\%' 370 Scheme 66 illustrates the synthesis of compounds wherein Q is Q-44, G=CH2.
Nitroacid 371 (readily available by anyone with normal skills in the art) is reacted with N-methyl piperazine to yield amide 372, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 373. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 66 0 0 1) LAH 0 OiN ~ EDC, HOBT 02N 2) Pd/C HyNHN
I ( OH --- I~ N~ ~ N
/ v N) 372 v N 3) NaNO2, HCI N, 371 (R44) SnCIz 373 R4 N
Rr Scheme 67 illustrates the synthesis of compounds wherein Q is Q-45.
Thiomorpholine sulphone 374 is alkylated with protected bromohydrine. Removal of the alcohol protecting group yields intermediate 375, which can be oxidized to aldehyde 376.
When G=NH, iodoaniline 377 is reacted with 376 under reductive amination conditions, preferably sodium triacetoxvborohydride, to afford intermediate 378. This intermediate is converted to the substituted hydrazine 379 by Cu(I)-catalyzed reaction with N-BOC
hydrazine. When G=O, iodophenol 380 is either alkylated with 381 or reacted under Mitsunobu conditions with alcohol 375 to yield intermediate 382: This intermediate is converted to the substituted hydrazine 383 by Cu(I)-catalyzed reaction with N-BOC
hydrazine.
Scheme 67 BOC
i I~ NH2 Na BH(OAc)3 NõM, N ~ NHZ-NHBOC H,N' N I~ N~os-0 v 0 H o Ca(I) / 377 vv 1[0]
N 1) TBSO-~4Br 0' OH
v C J 2 TBAF N v OSO ) Mitsunobu 375 Readion O~S/_~N~Ox Boc I \/OH ' 381 y i I\~O~c ~N~ NHZ-NHBOC H2NN I\ O"c ~OS=O
I / Base S=O Cu(I) l 1 O
Scheme 68 illustrates the synthesis of compounds wherein Q is Q-44, G=CH2.
Nitroacid 384 (readily available by anyone with normal skills in the art) is reacted with thiomorpholine sulphone to yield amide 385, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 386. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 68 0 0 I) LAH 0 02N' ~l x EDC, HOBT 02N \ L\ jj 2) Pd/C H2NHN I
/, N /~7/~N
O H --~ I N~
v N / v SnO 3) NaNOZ, HCI v ~S~O
~
384 C) 385 0 4) SnCIZ 386 O
O~S~O
Scheme. 69 illustrates the synthesis of compounds wherein Q is Q-46.
Piperadine derivative 387 is alkylated with protected bromohydrine. Removal of the alcohol protecting group_yields_intermediate_ 388, which can__be-oxidized_to- aldehy.de _389.__ When_ G=NH, iodoaniline 390-is reacted with 389 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 391. This intermediate is converted to the substituted hydrazine 392 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 393 is either alkylated with 396 or reacted under Mitsunobu conditions with alcohol 388 to yield intermediate 394. This intermediate is converted to the substituted hydrazine 395 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 69 H BOC
i I jNH Ne BH(OAC)3 i I\ N CkRi NHyNHBOC HN N jN
2 ' ' ' ~-~ Z ' I
~ ~\ O H oCu(I) ~ I.t Rio 390 R O>( N 391 OR" 392 OR44 ar ~/ II
Br 1) TBSO~ OH
v Rlo N
2) TBAF R440 v Miisunobu R440 RIo ~ 398 Reaction R~o RaO/N ~Ox Boc i /OH 396 j v ON NHZ-NHBOC HzNN I\ 0 N
/ Base v Rio CU(I) ~j Rio 393 394 ORM 395 OR,u Scheme 70 illustrates the synthesis of compounds wherein Q is Q-44, G=CHZ.
Nitroacid 397 (readily available by anyone with normal skills in the art) is reacted with thiomorpholine sulphone to yield amide 398, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 399. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 70 0 0 1) LAH 0 p2N EDC,HOBT 02N 2) Pd/C HzNHN
~ OH N
/ v H
R~o) NaNOq, HC Rio pR44) SnC12 399 pa4a R44p Rio AFFINITY AND BIOLOGICAL ASSESSMENT
A fluorescence binding assay is used to detect binding of inhibitors of Formula I with unphosphorylated p38-alpha kinase as previously described: see J. Regan et al, Journal of Medicinal Chemistry (2002) 45:2994.
1. P38 MAP kinase binding assay The binding affinities of small molecule modulators for p38 MAP kinase were determined using a competition assay with SKF 86002 as a fluorescent probe, modified based on published methods (C. Pargellis, et al Nature Structural Biology (2002) 9, 268-272. J..
Regan, et al J. Med. Chem. (2002) 45, 2994-3008). Briefly, SKF 86002, a potent inhibitor of p38 kinase (Kd = 180 nM), displays an emission fluorescence around 420 nm when excitated at 340 nm upon its binding to the kinase. Thus, the binding affinity of an inhibitor for p38 kinase can be measured by its ability to decrease the fluorescence from SKF
86002. The assay was performed in a 384 plate (Greiner uclear 384 plate) on a Polarstar Optima plate reader (BMG). Typically, the reaction mixture contained I M SKF 86002, 80 nM
p38 kinase and various concentrations of an inhibitor in 20 mM Bis-Tris Propane buffer, pH 7, containing 0.15 %(w/v) n-octylglucoside and 2 mM EDTA in a final volume of 65 l. The reaction was initiated by addition of the enzyme. The plate was incubated at room temperature (- 25 C) for 2 hours before reading at emission of 420 nm and excitation at 340 nm. By comparison of rfu (relative fluorescence unit) values with that of a control (in the absence of an inhibitor), the percentage of inhibition at each concentration of the inhibitor was calculated. IC50 value for the inhibitor was calculated from the %
inhibition values obtained at a range of concentrations of the inhibitor using Prism. When time-dependent inhibition was assessed, the plate was read at multiple reaction times such as 0.5, 1, 2, 3, 4 and 6 hours. The IC50 values were calculated at the each time point. An inhibition was assigned as time-dependent if the IC5o values decrease with the reaction time (more than two-fold in four hours). This is illustrated below in Table 1.
Table 1 Example # IC50, nM Time-dependent 1 292 Yes 2 997 No 2 317 No 3 231 Yes 4 57 Yes 1107 No 6 238 Yes 7 80 Yes 8 66 Yes 9 859 No 2800 No 11 2153 No 12 -10000 No 13 384 Yes 949 No 19 -10000 No 21 48 Yes 22 666 No 151 Yes 26 68 Yes 29 45 Yes 87 Yes 31 50 Yes 32 113 Yes 37 497 No 38 508 No 41 75 Yes 42 373 No 43 642 No 45 1855 No 46 1741 No 47 2458 No 48 3300 No 57 239 Yes IC50 values obtained at 2 hours reaction time P-38 alpha kinase assay (spectrophometric assay) Activity of phosphorylated p-38 kinase was determined by following the production of ADP -from- the kinase-.-reaction _through._coupling_with-_the_pyruvate-_kinase/lactate dehydrogenase system-(e.g., Schindleri et- al.--Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH was continuously measured spectrophometrically. The reaction mixture (100 l) contained phospho p-38 alpha kinase (3.3 nM. Panvera), peptide substrate (IPTSPITTTYFFFKKK-OH, 0.2 mM), ATP (0.3 mM), 1VIgC12 (10 mM), pyruvate kinase (8 units. Sigma), lactate dehydrogenase (13 units. Sigma), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 65 mM Tr_is buffer,_.pH 7.5, containing 3.5 % DMSO and 150 uM n-Dodecyl-B-D-maltopyranoside. The reaction was initiated by adding ATP. The absorption at 340 nm was monitored continuously for up to 4 hours at 30 C on Polarstar Optima plate reader (BMG). The kinase activity (reaction rate) was calculated from the slope at the time frame from 1.5 h to 2 h. Under these conditions, a turn over number (kat) of -1 s"1 was obtained. The reaction rates calculated from different time frames such as 0.5 min to 0.5 h, 0.5 h to I h, 1.5 h to 2 h or 2.5 h to 3 h were generally constant.
For inhibition detenninations, test compounds were incubated with the reaction mixture for - 5 min before adding ATP to start the reaction. Percentage of inhibition was obtained by comparison of reaction rate with that of a control well containing no test compound. IC50 values were calculated from a series of % inhibition values determined at a range of concentrations of each inhibitor using Prism to process the data and fit inhibition curves. Generally, the rates obtained at the time frame of 1.5 h to 2 h were used for these calculations. In assessing whether inhibition of a test compound was time-dependent (i.e., greater inhibition with a longer incubation time), the values of % inhibition and/or IC50 values obtained from other time frames were also calculated for the inhibitor.
The biological activity for compounds of the present invention in the spectrophotometric assay are illustrated in Tables 2 and 3.
Example # IC50, uM % inhibition concentration, uM
1 0.067 2 0.29 3 0.019 4 0.609 0.514 6 0.155 7 0.165 9 0.355 83% 10 11 0.953 12 70% 10 13 0.269 14 0.096 0.53 17 40% 10 18 60% 10 21 0.171 22 0.445 0.055 26 0.19 29 0.011 0.251 31 . 0.056 32 0.307 38 0.51 39 0.012 0.055 41 0.013 42 0.425 43 7.5 0.48 47 0.295 49 0.071 51 0.033 52 0.416 53 0.109 54 68% 1.0 0.74 57 0.782 58 0.172 59 0.709 0.264 D 0.179 F 0.437 Example # IC50, uM % Inhibition concentration, uM
146 9% 10 147 27% 10 150 5 3 % CM- 10 154 21% 10 155 58% 10 160 0.044 161 0.1 162 0.65 163 0.464 196 0.028 197 0.243 198 0.137 199 0.684 200 73% 1.0 201 0.029 202 1.9 203 0.328 204 0.008 206 0.013 207 0.033 209 0.354 284 1.95 285 0.102 286 0.079 287 0.041 288 0.104 289 1.3 291 5.1 294 2.1 295 1.2 296 0.284 297 0.34 298 0.025 299 2.3 300 0.251 301 0.63 302 0.077 Human peripheral blood mononuclear leukocyte cell assay.
Human peripheral blood mononuclear leukocytes are challenged with 25ng/mL
lipopolysaccharide (LPS) in the absence or presence of Test Compound and incubated for 16 hours as descr.ibed by. Welker P. et al, International Archives Allergy and Immunology (1996) 109: 110. The quantity of LPS-induced tumor necrosis factor-alpha (TNF-alpha) cytokine release is measured by a commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit. Test compounds are evaluated for their ability to inhibit TNF-alpha release.
Table 2 records IC50 values for inhibition of TNF-alpha release by Test Compounds of the present invention, wherein the IC50 value, in micromolar concentration, represents the concentration of Test Compound resulting in a 50% inhibition of TNF-alpha release from human peripheral blood mononuclear leukocytes as compared to control experiments containing no Test Compound. Test compounds evaluated are illustrated in Table 4.
Example Number IC50, uM
3 6.1 13 6.32 21 3.4 29 2.68 31 4.52 60 2.34 296 3.49 300 4.78 302 5.45 EXAMPLES
The following examples set forth preferred methods in accordance with the invention.
It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.
[Boc-sulfamide] aminoester (Reagent AA), 1,5,7,-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid (Reagent BB), and Kemp acid anhydride (Reagent CC) was prepared according to literature procedures. See Askew et. al J. Am. Chem.
Soc. 1989, 111, 1082 for further details.
EXAMPLE A
N~ N NH2 Et02C b To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) in concentrated HC1 was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mol) at 0 C. The reaction mixture was stirred for I h and a solution of SnCl2=2H20 (662 g, 2.92 mol) in concentrated HCI
(2 L) was then added at 0 C, and the reaction stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-hydrazino-benzoic acid hydrochloride as a white solid.
The crude material from the previous reaction (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) were heated to reflux overnight. The reaction solution was evaporated in vacuo and the residue purified by column chromatography to yield ethyl 3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)benzoate (Example A, 116 g, 40%) as a white solid together with 3-(5-amino-3-tert-butyl-1 H-pyrazol-l-yl)benzoic acid (93 g, 36%). 'H NMR
(DMSO-d6): 8.09 (s, 1 H), 8.05 (brd, J= 8.0 Hz, 1 H), 7.87 (brd, J= 8.0 Hz, 1 H), 7.71 (t, J= 8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H), 1.28 (s, 9H).
EXAMPLE B
N/ 1 J~ \ I
'N H H \ ~
EtO2C
To a solution of 1-naphthyl isocyanate (9.42 g, 55.7 mmol) and pyridine (44 mL) in THF
(100 mL) was added a solution of Example A (8.0 g, 27.9 mmol) in THF (200 mL) at 0 C. The mixture was stirred at RT for lh, heated until all solids were dissolved, stirred at RT for an additional 3h and quenched with H20 (200 mL). The precipitate was filtered, washed with dilute HCl and H20, and dried in vacuo to yield ethyl3-[3-t-butyl-5-(3-naphthalen-1-yl)ureido)-1H-pyrazol-l-yl]benzoate(12.0 g, 95%) as a white power. 'H NMR (DMSO-d6): 9.00 (s, 1 H), 8.83 (s, 1 H), 8.25 7.42 (m, 11 H), 6.42 (s, 1 H), 4.30 (q, J 7.2 Hz, 2 H), 1.26 (s, 9 H), 1.06 (t, J
7.2 Hz, 3 H); MS (ESI) m/z: 457.10 (M+H+).
EXAMPLE C
CI
N/ \
, N N N
H H
EtO2C
To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine (56 mL) and THF (30 mL) was added a solution of 4-nitrophenyl 4-chlorophenylcarbamate (10 g, 34.8 mmol) in THF (150 mL) at 0 C. The mixture was stirred at RT for 1 h and heated until all solids were dissolved, and stirred at RT for an additional 3 h. HZO (200 mL) and CHZCIZ
(200 mL) were added, the aqueous phase separated and extracted with CHZC12 (2 x 100 mL). The combined organic layers were washed with 1N NaOH, and 0.1N HCI, saturated brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield ethyl 3-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-l-yl}benzoate (8.0 g, 52%). 'H NMR (DMSO- d6):
S 9.11 (s, 1 H), 8.47 (s, 1 H), 8.06 (m, 1 H), 7.93 (d, J= 7.6 Hz, 1 H), 7.81 (d, J= 8.0 Hz, 1 H), 7..65 (dd, J
= 8.0, 7.6 Hz, 1 H), 7.43 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, IH), 4.30 (q, J=
6.8 Hz, 2H), 1.27 (s, 9H), 1.25 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 441 (M++H).
EXAMPLE D
N/ J' 'N H H
b HO To a stirred solution of Example B(8.20 g, 18.0 mmol) in THF (500 mL) was added LiA1H4 powder (2.66 g, 70.0 mmol) at -10 C under N2. The mixture was stirred for 2 h at RT
and excess LiA1H4 destroyed by slow addition of ice. The reaction mixture was acidified to pH
= 7 with dilute HCI, concentrated in vacuo and the residue extracted with EtOAc. The combined organic layers were concentrated in vacuo to yield 1- { 3-tert-butyl-l-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (7.40 g, 99%) as a white powder. 'H
NMR (DMSO-d6): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, 11 H), 6.41 (s, 1 H), 4.60 (s, 2 H), 1.28 (s, 9 H); MS (ESI) m/z: 415 (M+H+).
EXAMPLE E
N/ \ ~ \ I
, N
H H
Cl \
A solution of Example C (1.66 g, 4.0 mmol) and SOCIZ (0.60 mL, 8.0 mmol) in (100 mL) was refluxed for 3 h and concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (1.68 g, 97%) was obtained as white powder. 'H NMR (DMSO-d6): S 9.26 (s, 1 H), 9.15 (s, 1 H), 8.42 - 7.41 (m, 11 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H). MS (ESI) m/z: 433 (M+H+).
EXAMPLE F
CI
N
, N N i N \ I
H H
/ ~
HO \
To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added LiA1H4 powder (413 mg, 10.9 mmol) at -10 C under N2. The mixture was stirred for 2h and excess LiAlH4 was quenched by adding ice. The solution was acidified to pH = 7 with dilute HCI. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200 +
100 mL). The filtrate was concentrated to yield 1-{3-tert-butyl-l-[3-hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.40 g, 97%).'H NMR (DMSO- d6): S
9.11 (s, 1H), 8.47 (s, IH), 7.47-7.27 (m, 8H), 6.35 (s, IH), 5.30 (t, J 5.6 Hz, 1 H), 4.55 (d, J 5.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 399 (M+H+).
EXAMPLE G
0 / ~~
N~ N ' N J~. N\ I
H H
Cl A solution of Example F (800 mg,.2.0 mmol) and SOC12 (0.30 mL, 4 mmol) in (30 mL) was refluxed gently for 3h. The solvent was evaporated in vacuo and the residue was taken up to in CH2C12 (2 x 20 mL). After removal of the solvent, 1-{3-tert-butyl-l-[3-(chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (812 mg, 97%) was obtained as white powder.'H NMR (DMSO- d6): S 9.57 (s, 1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.50 - 7.26 (m, 7H), 6.35 (s, 1H), 4.83 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 417 (M+H+).
EXAMPLE H
To a suspension of LiAlH4 (5.28 g, 139.2 mmol) in THF (1000 mL) was added Example A (20.0 g, 69.6 mmol) in portions at 0 C under N2. The reaction mixture was stirred for 5 h, quenched with I N HC1 at 0 C and the precipitate was filtered, washed by EtOAc and the filtrate evaporated to yield [3-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)phenyl]methanol (15.2 g, 89%).
'H NMR (DMSO-d6): 7.49 (s, 111), 7.37 (m, 2H), 7.19 (d, J = 7.2 Hz, IH), 5.35 (s, 1H), 5.25 (t, J=5.6 Hz, 1 H), 5.14 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 1.19 (s, 9H); MS
(ESI) m/z: 246.19 (h'1+H+)=
The crude material from the previous reaction (5.0 g, 20.4 mmol) was dissolved in dry THF (50 mL) and SOC12 (4.85 g, 40.8 mmol), stirred for 2h at RT, concentrated in vacuo to yield 3-tert-butyl-l-(3-chloromethylphenyl)-1 H-pyrazol-5-amine (5.4 g), which was added to N3 (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixture was heated at 30 C for 2 h, poured into H20 (50 mL), and extracted with CHZCIZ. The organic layers were combined, dried over MgSO4, and concentrated in vacuo to yield crude 3-tert-butyl-l-[3-(azidomethyl)phenyl]-1H-pyrazol-5-amine (1.50 g, 5.55 mmol).
EXAMPLE I
\ 0 N~ ~
NN
N
H H
~ I
H2N ~
Example H was dissolved in dry THF (10 mL) and added a THF solution (10 mL) of isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3h, quenched with H20 (30 mL), the resulting precipitate filtered and washed with 1 N HCI and ether to yield 1-[2-(3-azidomethyl-phenyl)-5-t-butyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (2.4 g, 98%) as a white solid.
The crude material from the previous reaction and Pd/C (0.4 g) in THF (30 mL) was hydrogenated under 1 atm at RT for 2 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-(amonomethyl)phenyl}-1H-pyrazol-5y1)-3-(naphthalene-l-yl)urea (2.2 g, 96%) as a yellow solid. 'H NMR (DMSO-d6): 9.02 (s, 1H), 7.91 (d, J= 7.2 Hz,1H), 7.89 (d, J= 7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, 1H), 3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H+) EXAMPLE J
/ ci I
N% N NN \
H H
H2N \
To a solution of Example H(1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF
solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H20 (30 mL) was added. The precipitate was filtered and washed with 1N HCI and ether to give 1-{3-tert-butyl-l-[3-(amonomethyl)phenyl}-1H-pyrazol-5y1)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for next step without further purification. MS (ESI) m/z: 424 (M+H+).
EXAMPLE K
H
N~
N . N
H H
To a solution of benzyl amine (16.5g, 154 mmol) and ethyl bromoacetate (51.5g, mmol) in ethanol (500 mL) was added KZC03 (127.5g, 924 mmol). The mixture was stirred at RT for 3h, was filtered, washed with EtOH, concentrated in vacuo and chromatographed to yield N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (29g, 67%). 'H
NMR (CDC13):
8 7.39-7.23 (m, 514), 4.16 (q, J= 7.2 Hz, 4H);-3-:9T(s,-2H),-3.-54"(s; 4H);-T:26'(t; J="7:2 Hz, 6H);
MS (ESI): m/e: 280 (M++H).
A solution ofN-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (7.70g, 27.6 mmol) in methylamine alcohol solution (25-30%, 50 mL) was heated to 50 C in a sealed tube for 3h, cooled to RT and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide in quantitative yield (7.63g). 'H NMR
(CDC13): S 7.35-7.28 (m, 5H), 6.75 (br s, 2H), 3.71(s, 2H), 3.20 (s, 4H), 2.81 (d, J= 5.6 Hz, 6H); MS (ESI) m/e 250(M+H+).
The mixture ofN-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40 C under 40 psi H2 for lOh, filtered and concentrated in vacuo to yield. N-(2-methylamino-2-oxoethyl)-glycinemethylamide in quantitative yield (1.76g). 'H
NMR (CDC13):
S 6.95(br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25(br s 1H); MS
(ESI) m/e 160(M+H+) fI
N NJ~N \
N H H I
N /O /
HN IN ~ I
O
To a solution of 1-methyl-[1,2,4]triazolidine-3, 5-dione (188 mg, 16.4 mmol) and sodium hydride (20 mg, 0.52 mmol) in DMSO (I mL) was added Example E (86 mg, 0.2 mmol). The reaction was stirred at RT overnight, quenched with H20 (10 mL), extracted with CH2C12, and the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to yield 1-(3-tert-butyl-l-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]phenyl } -1 H-pyrazol-5-yl)-3-(naphthalene-l-yl)urea (Example 1, 14 mg). 'H NMR (CD3OD): 57.88-7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s, 6H); MS
(ESI) m/z: 525 (M+H+).
cl N/ \ ~ \ I
, N N N
O H H
N~ /
H N N \ ~
)r O
The title compound was synthesized in a manner analogous to Example 1, utilizing Example G to yield 1-(3-tert-butyl-l-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea'H NMR (CD3OD): 8 7.2-7.5 (m, 7H), 6.40 (s 1 H), 4.70 (s, 2H), 2.60 (d, J=14 Hz, 2H), 1.90 (m, l H), 1.50 (m, 1 H),1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H+).
OI
N N ' NJI~N
r--f O H H
HN~, ~N
OSO
A mixture of compound 1,1-Dioxo-[ 1,2,5]thiadiazolidin-3-one (94 mg, 0.69 mmol) and NaH (5.5 mg, 0.23 mmol) in THF (2 mL) was stirred at -10 C under NZ for 1 h until all NaH was --dissolved. Example E(100 mg, 0--23 mmol) was added- and the reaction was allowed to stir at RT
overnight, quenched with H20, and extracted with CHZC12. The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC to yield 1-(3-tert-butyl-1-{ [3-(1,1,3-trioxo-[ 1,2,5]thiadiazolidin-2-yl)methyl]phenyl } -1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea (18 mg) as a white powder. 'H NMR (CD3OD): 6 7.71 - 7.44 (m, 11 H), 6.45 (s, I H), 4.83 (s, 2 H), 4.00 (s, 2 H), 1.30 (s, 9 H). MS (ESI) m/z: 533.40'(M+H+).
NN N N\ I
O H H
HN" 'IN
OS\\O
The title compound was obtained in a manner analogous to Example 3 utilizing Example G. to yield 1-(3-tert-butyl-l-{[3-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'H NMR (CD3OD): S 7.38 - 7.24 (m, 8 H), 6.42 (s, 1 H), 4.83 (s, 2 H), 4.02 (s, 2 H), 1.34 (s, 9 H); MS (ESI) m/z: 517 (M+H+).
~ ci N NN ~ I
H H
H H ~ I
ONN, N ~
0 O S~O
-To a stirred solution of chlorosulfonyl isocyanate (19.8 L, 0.227 mmol) in CH2C12 (0.5 mL) at 0 C was added pyrrolidine (18.8 L, 0.227 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After stirring for 1.5 h, a solution of Example J (97.3 mg, 0.25 mmol) and Et3N (95 L, 0.678 mmol) in CHZC12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 C. When the addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10%
HCI, extracted with CH2Cl2, the organic layer washed with saturated NaC1, dried over MgSO4, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC
t o y i e 1 d 1-( 3 t e r t- b u t y 1- l -[[ 3- N-[[( 1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'H NMR(CD3OD): S 7.61 (s, 1 H), 7.43 -7.47 (m, 3 H), 7.23 -7.25 (dd, J
=6.8 Hz, 2 H), 7.44 (dd, J=6.8 Hz, 2 H), 6.52 (s, 1 H), 4.05 (s, 2 H), 3.02 (m, 4 H), 1.75 (m, 4 H), 1.34 (s, 9 H); MS (ESI) m/z: 574.00 (M+H+).
NI NJ~N
N H
a H
~ \ I
N~ N
O 0 i~0 The title compound was made in a manner analogous to Example 5 utilizing Example I
to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]-phenyl]-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.'HNMR (CDC13): S 7.88 (m, 2 H), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, 1 H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H+).
CI
O
/ II
N
H H
/
H H
N'S'N N ,~ ~
O~ ~O ~
O
To a stin=ed solution of chlorosulfonyl isocyanate (19.8 A, 0.227 ok) tv XHiXxo (0.5 A) aT 0 C, was added Example J (97.3 mg, 0.25 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of pyrrolidine (18.8 L, 0.227 mmol) and Et3N (95 L, 0.678 mmol) in CH2C12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 C. When addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10%
HCI, extracted with CH2C121 the organic layer was washed with saturated.NaCl, dried over MgZSO4, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'HNMR (CDC13): S 7.38 (m, 1 H), 7.36 - 7.42 (m, 3 H), 7.23 (d, J= 8.8 Hz, 2 H), 7.40 (d, J= 8.8 Hz, 2 H), 6.43 (s, 1 H), 4.59 (s, 1 H), 4.43 (s, 2 H), 1.81 (s, 2 H), 1.33 (s, 9 H); MS (ESI) m/z: 574.10 (M+H+).
oII
N/ NN
N H H
OtN N N \ I
OOy O
The title compound was made in a manner analogous to Example 7 utilizing Example I
to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]-phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.'HNMR (CDC13): S 7.88 (m, 2 H), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, I H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77-1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H+).
N,N H H
p' NH
H~IY
N
To a solution of Reagent BB (36 mg, 0.15 mmol), Example I(62 mg, 0.15 mmol), HOBt (40 mg, 0.4 mmol) and NMM (0.1 mL, 0.9 mmol) in DMF (10 mL) was added EDCI (58 mg, 0.3 mmol). After being stirred overnight, the mixture was poured into water (15 mL) and extracted with EtOAc (3 5 mL). The organic layers were combined, washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to yield 1,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1 ]nonane-7-carboxylic acid 3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]benzylamide (22 mg). 'H NMR (CDC13): S
8.40 (s, 1H), 8.14 (d, J= 8.0 Hz, 2H), 7.91 (s, 1 H), 7.87 (s, 1 H), 7.86 (d, J= 7.2 Hz, 1 H), 7.78 (d, J= 7.6 Hz, 1 H), 7.73 (d, J= 8.4 Hz, 1 H), 7.69 (d, J= 8.4 Hz, 1 H), 7.57-7.40 (m, 4H), 7.34 (d, J= 7.6 Hz, 1 H), 6.69 (s, 1 H), 6.32 (t, J= 5.6 Hz, 1 H), 5.92 (brs, 1 H), 4.31 (d, J=
5.6 Hz, 2H), 2.37 (d, J=
14.8 Hz, 2H), 1. 80 (d, J= 13.2 Hz, 1 H), 1.35 (s, 9H), 1.21 (d, J= 13.2 Hz, 1 H), 1.15 (s, 3H), 1.12 (d, J= 12.8 Hz, 2H), 1.04 (s, 6H); MS (ESI) m/z: 635 (M+H+).
iO(d1 H H
O IpY,NH
The title compound, was synthesized in a manner analogous to Example 9 utilizing Example J to yield 1,5,7-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid 3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-l-yl}benzylamide.'H NMR
(CDC13): 8 8.48 (s, 1H), 7.78 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.69 (s, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.48 (d, J= 8.8 Hz, 2H), 7.26 (m, 3H), 6.62 (s, 1 H), 6.35(t, J= 6.0 Hz, 1 H), 5.69 (brs, 1H), 4.26 (d, J= 6.0 Hz, 2H), 2.48 (d, J=14.0 Hz, 2H), 1.87 (d, J=13.6 Hz,1H),1.35 (s, 9H), 1.25 (m, 6H), 1.15 (s, 6H);
MS (ESI) m/z: 619 (M+H+).
o N'\ N~N
H
/
O N O
A mixture of Example I(41 mg, 0.1 mmol), Kemp acid anhydride (24 mg, 0.1 mmol) and Et3N (100 mg, 1 mmol) in anhydrous CH2C12 (2 mL) were stirred overnight at RT, and concentrated in vacuo. Anhydrous benzene (20 mL) was added to the residue, the mixture was refluxed for 3h, concentrated in vacuo and purified by preparative HPLC to yield 3-{3-[3-t-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-l-yl]-benzyl } -1,5-di-methyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid (8.8 mg, 14%). 'H NMR (CD3OD): S 7.3 -7.4 (m, 2H), 7.20 (m, 2H), 7.4 - 7.6 (m, 7H), 6.50 (m, 1 H), 4.80 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1H), 1.40 (m, 1H), 1.30 (m, 2H), 1.20 (s, 3H), 1.15 (s, 6H); MS (ESI) m/z: 636 (M+H+).
0 / C' ~N
NN N ~
H
CO,H
The title compound, was synthesized in a manner analogous to Example 11 utilizing Example J to yield 3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-l-yl]-benzyl}-1,5-dimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid. 'H NMR
(CD3OD): S 7.2 -7.5 (m, 7H), 6.40 (s 1 H), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1 H), 1.50 (m, 1 H), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H').
N/ \ ~ \ I
\N H H
/
HN" N O
O
The title compound was synthesized in a manner analogous to Example I
utilizing Example E and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-l-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-1-yl)methyl]phenyl} -1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea. 'H NMR
(CD3OD): S 7.88 - 7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s, 6H);MS (ESI) m/z: 525 (M+H+).
- - -/ CI
N/ \ ' N N N N
H H
HN' N O
O
The title compound was synthesized in a manner analogous to Example 1 utilizing Example G and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-l-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-l-yl)methyl]phenyl } -11Y-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
'H NMR (CD3OD): 6 7.60 - 7.20 (m, 8H), 6.43 (s, 111), 4.70 (s, 1 H), 1.34 (s, 9H), 1.26 (s, 6H);
MS (ESI) m/z: 509, 511 (M+H+).
HN N, N
O1:1) H H
N
' N O
H
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (64.2 mg, 0.15 mmol) were added HOBt (30 mg, 0.225 mmol), Example K (24 mg, 0.15 mmol) and 4-methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF (3 mL) and EDCI (43 mg, 0.225 mmol).
The reaction mixture was stirred at RT overnight and poured into HZO (3mL), and a white precipitate collected and further purified by preparative HPLC to yield 1-[1-(3-{bis [(methylcarbamoyl)methyl]carbamoyl } phenyl)-3-tert-butyl-1 H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (40 mg). 'H NMR (CDC13): S 8.45 (brs, 1 H), 8.10 (d, J 7.6 Hz; 1 H), 7.86-7.80 (m, 2H), 7.63-7.56 (m, 2H), 7.52 (s, IH), 7.47-7.38 (m, 3H), 7.36-7.34 (m, IH), 7.26 (s, IH), 7.19-7.17 (m, 2H), 6.60 (s, 1H), 3.98 (s, 2H), 3.81 (s, 3H), 2.87 (s, 3H), 2.63 (s, 3H),1.34 (s, 9H); MS
(ESI) m/z: 570 (M+H+).
/ \ ~ ~ I
HN NN N N
N I / H H
O-:--~ ~
N -~O C
H
The title compound was synthesized in a manner analogous to Example 15 utilizing Example C ( 3 7 mg) and Example K to y i e l d 1-[ 1-(3-{bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-tert-butyl-1 H-pyrazol-5-yl]-3-(4-chlorophenyl)urea. 'H NMR (CD3OD): 6 8.58 (brs, 1'H), 8.39 (brs, IH), 7.64 -7.62 (m, 3H), 7.53-7.51 (m, l H), 7.3 8(d, J= 9.2 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.44 (s, 1 H), 4.17 (s, 2H), 4.11 (s, 2H), 2.79 (s, 3H), 2.69 (s, 3H), 1.34-1.28 (m, 12H); MS (ESI) m/z:
554 (M+H+).
O
\
N,N NN
H H
O I /
p O
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (0.642 g, 1.5 mmol) in dry THF (25 mL) at -78 C were added freshly distilled triethylamine (0.202 g, 2.0 mmol) and pivaloyl chloride (0.216 g,1.80 mmol) with vigorous stirring. After stirring at -78 C for 15 min and at 0 C for 45 min, the mixture was again cooled to -78 C and then transferred into the THF solution of lithium salt of D-4-phenyl-oxazolidin-2-one [*: The lithium salt of the oxazolidinone regeant was previously prepared by the slow addition of n-BuLi (2.50M in hexane, 1.20 mL, 3.0 mmol) into THF solution of D- 4-phenyl-oxazoldin-2-one at -78 C]. The reaction solution was stirred at -78 C for 2 h and RT overnight, and then quenched with aq.
ammonium chloride and extracted with dichloromethane (100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl} -3-(naphthalen-l-yl)urea (207 mg, 24%). 'H NMR (CDC13): S 8.14 -8.09 (m, 2H), 8.06 (s, l H), 7.86 - 7.81 (m, 4H), 7.79 (s, 1 H), 7.68 - 7.61 (m, 2H), 7.51 -7.40 (m, 9H), 6.75 (s, 1 H), 5.80 (t, J=9.2, 7.6 Hz, 1 H), 4.89 (t, J= 9.2 Hz, 1 H), 4.42 (dd, J=9.2, 7.6 Hz, 1 H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H+).
N X ~ \ ( 'N H H
\
O I /
QFI.Co The title compound was synthesized in a manner analogous to Example 17 utilizing Example B and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-l-yl)urea'H NMR
(CDC13):
S 8.14 - 8.09 (m, 2H), 8.06 (s, l H),.7.86 - 7.81 (m, 4H), 7.79 (s, 1H), 7.68 -7.61 (m, 2H), 7.51 -7.40 (m, 9H), 6.75 (s, 1 H), 5.80 (t, J=9.2, 7.6 Hz, 1 H), 4.89 (t, J 9.2 Hz, 1 H), 4.42 (dd, J=9.2, 7.6 Hz, IH), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H+) O C
J ) NN N N
H H
_ --- - ~ \
O
N
IrO
O
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-(4-chlorophenyl)urea. 'H
NMR (CDC13):
6 7.91 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.79 (d, J 7.6 Hz, 1 H), 7.71 (m, 1 H), 7.65 (m, 1 H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1 H), 5.77 (dd, J= 8.8, 8.0 Hz, 1 H), 4.96 (t, 8.8 Hz, 1H), 4.44 (dd, J= 8.8, 8.0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H+) CI
~I
N N N
H H
~ \
O /
/
N
O
O
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(4-chlorophenyl)urea.'H NMR
(CDC13):
S 7.91 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.79 (d, J= 7.6 Hz, 1 H), 7.71 (m, 1 H), 7.65 (m, 1 H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1 H), 5.77 (dd, J= 8.8, 8.0 Hz, 1 H), 4.96 (t, 8.8 Hz, 1 H), 4.44 (dd, J= 8.8, 8.0 Hz, 1 H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H+) EXAMPLE L
N-N
.. ~N
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CHZC12 (40 ml, with a catalytic amount of DMF) at 0 C under NZ was added oxalyl chloride (1:1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1 -morpholin-4-yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-y1-2-(3-nitro-pheny)-ethanone (2 g) and 10 % Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCI (15 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-l-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N
HCI (I ml) were refluxed for I h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
N!
N
/
\ I HNO
H N
N
O
A mixture of Example L(0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2C12 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-l-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-l-yl)urea. mp: 194 - 196 ; 'H
NMR
(200MHz, DMSO-d6): 5 9.07 (IH, s), 8.45 (s, IH), 8.06 - 7.93 (m, 3H), 7.69 -7.44 (m, 7H), 7.33 - 7.29 (d, 6.9 Hz, 1H), 6.44 (s, IH), 3.85 (m, 2H), 3.54 - 3.45 (m, 8H), 1.31 (s, 9H); MS:
N
N
HN O
ogcl The title compound was synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-tert-butyl-l-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl} -3-(4-chlorophenyl)urea.
mp: 100 104 ;'H NMR (200MHz, DMSO-d6): S 9.16 (s, 1H), 8.45 (s, 1H), 7.52-7.30 (m, 8H), 6.38 (s, IH), 3.83 (m, IH), 3.53 - 3.46 (m, 8H), 1.30 (s; 9H); MS:
N-N
HN
N HN O
O
The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and phenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl } -3-phenylurea.
N
N
HNHN :&Ome OF
O
The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 1-isocyanato-4-methoxy-naphthalene to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl } -3-(1-methoxynaphthalen-4-yl)urea.
EXAMPLE M
O ~
N N~N ~ ~
H H
O I /
OEt The title compound is synthesized in a manner analogous to Example C utilizing Example A and phenylisocyanate to yield ethyl3-(3-tert-butyl-5-(3-phenylureido)-1 H-pyrazol-l-yl)benzoate.
EXAMPLE N
N-N
A solution of (3-nitrophenyl)acetic acid (23 g, 127 mmol) in methanol (250 ml) and a catalytic amount of concentrated in vacuo H2SO4 was heated to reflux for 18 h.
The reaction mixture was concentrated in vacuo to a yellow oil. This was dissolved in methanol (250 ml) and stirred for 18 h in an ice bath, whereupon a slow flow of ammonia was charged into the solution.
The volatiles were removed in vacuo. The residue was washed with diethyl ether and dried to afford 2-(3-nitrophenyl)acetamide (14 g, off-white solid). 'H NMR (CDC13): S
8.1 (s, 1H), 8.0 (d, 1 H), 7.7 (d, IH), 7. 5(m, 1 H), 7.1 (bd s, IH), 6.2 (brs, IH), 3.6 (s, 2H).
The crude material from the previous reaction (8 g) and 10 % Pd on activated carbon (1 g) in ethanol (100 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-aminophenyl)acetamide (5.7 g). A solution of this material (7 g, 46.7 mmol) was dissolved in 6 N HCl (100 ml), cooled to 0 C, and vigorously stirred.
Sodium nitrite (3.22 g, 46.7 mmol) in water (50 ml) was added. After 30 min, tin (II) chloride dihydrate (26 g) in 6 N HCI (100 ml) was added. The reaction mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazinophenyl)acetamide.
The crude material from the previous reaction (ca. 15 mmol) and 4,4-dimethyl-3-oxopentanenitrile ( 1.85 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1.5 ml) was refluxed for.
1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue, which was extracted with ethyl acetate. The solvent was removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)phenyl]acetamide as a white solid (3.2 g), which was used without further purification.
N-N
F HN~/O
HN
O
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2ClZ (4 ml) was stirred at RT under NZ for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-l-yl)urea as a white solid (0.22 g). mp: 230 (dec.); 'H NMR (200MHz, DMSO- d6): S 9.12 (s, 1H), 8.92 (s, 1 H), 8.32 - 8.08 (m, 3H), 7.94 - 7.44 (m, 8H), 6.44 (s, IH), 3.51 (s, 211), 1.31 (s, 9H); MS:
N--N
HN O
HzN HN 0 c, The title compound was synthesized in a manner analogous to Example 23 utilizing Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate (0.112 g, 0.73 mmol) to yield 1-{3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as a white solid (0.28 g). mp: 222 224 .(dec.);'H NMR (200MHz, DMSO- d6); S 9.15 (s,1H), 8.46 (s, IH), 7.55 - 7.31 (m, 8H), 6.39 (s, 1H), 3.48 (s, 2H), 1.30 (s, 9H); MS:
O
SNJLN
I H H
OEt The title compound is synthesized in a manner analogous to Example C utilizing Example A and 1-isocyanato-4-methoxy-naphthaleneto yield ethyl 3-(3-tert-butyl-5-(3-(1-methoxynaphthalen-4-yl)ureido)-1 H-pyrazol-l-yl)benzoate.
"+ H H
o The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and D-4-phenyl-oxazolidin-2-one to yield D-1-{ 5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-phenylurea.
N/ N N ~ . ~
H H
\
O I /
/
N O
i .. ~ \ ~
C O
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-phenylurea.
EXAMPLE P
N
N
/ I
~ I NH2 O
MeO
A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10 % Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal of the volatiles in vacuo provided 3-(3-amino-phenyl)propionic acid methyl ester (6 g).
A vigorously stirred solution of the crude material from the previous reaction (5.7 g, 31.8 mmol) dissolved in 6 N HCl (35 ml) was cooled to 0 C, and sodium nitrite (2.2 g) in water (20 ml) was added. After lh, tin (II) chloride dihydrate (18 g) in 6 N HCI (35 ml) was added. And the mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided methyl 3-(3-hydrazino-phenyl)propionate (1.7 g).
A stirred solution of the crude material from the previous reaction (1.7 g, 8.8 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.2 g, 9.7 mmol) in ethanol (30 ml) and 6 N
HC1(2 ml) was refluxed for 18 h and cooled to RT. The volatiles were removed in vacuo and the residue dissolved in EtOAc and washed with I N aqueous NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo and the residue was purified by column chromatography using 30 %
ethyl acetate in hexane as the eluent to provide methyl 3-[3-(3-tert-butyl-5-amino-lH-pyrazol -1-yl)phenyl]propionate (3.2 g), which was used without further purification N
N
HNO
O HN
HO
A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19 g, 1.05 mmol) in dry CHZC12 (5 ml) was stirred at RT under N2 for 20 h. The solvent was removed. in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc and dilute citric acid solution. The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column chromatography using 3 % methanol in CH2C12 as the eluent to yield 3-(3-{3-tert-butyl-5-[3-(naphthalen-l-yl)ureido]-1H-pyrazol-l-yl)phenylpropionic acid (0.22 g, brownish solid). mp: 105-107 ;'H NMR (200MHz, CDC13):
S 7.87 - 7.36 (m, l OH), 7.18 - 7.16 (m, 1 H), 6.52 (s, 1 H), 2.93 (t, J= 6.9 Hz, 2H), 2.65 (t, J=
7.1 Hz, 2H), 1.37 (s, 9H); MS
Nf N
HN O
O HN
HO \ / CI
The title compound was synthesized in a manner analogous to Example 29 utilizing Example P(0.30g, 0.95 mmol) and 4-chlorophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3-{ 3-tert-butyl-5-[3-(4-chloropnehyl)ureido]-1 H-pyrazol-1-yl)phenyl)propionic acid (0.05 g, white solid). mp:85 87 ;'H NMR (200MHz, CDC13): S 8.21 (s, lH), 7.44 - 7.14 (m, 7H), 6.98 (s,1H), 6.55 (s, 1 H), 2.98 (t, J 5.2 Hz, 2H), 2.66 (t, J= 5.6 Hz, 2H), 1.40 (s, 9H);
MS
EXAMPLE Q
N
N /
Et0 HN-.~O
HN ~
O
A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for l 8h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
A solution of the crude material from the previous reaction (1.5 g, 8.4 mmol) was dissolved in 6 N HCl (9 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After lh, tin (II) chloride dihydrate (5 g) in 6 N HCl (10 ml) was added.
The reaction mixture was stirred at 0 C for 3h. The pH was adjusted to pH 14 with solid KOH
and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided ethyl3-(4-hydrazino-phenyl)-propionate(1 g).
The crude material from the previous reaction (1 g, 8.8 mmol) and 4,4-dimethyl-oxopentanenitrile ( 0.7 g) in ethanol (8 ml) and 6 N HCl (1 ml) was refluxed for 18h and cooled to RT. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with I N aqueous sodium hydroxide solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography using 0.7 %
methanol in CH2C12 as the eluent to provide ethyl 3-{4-[3-tert-butyl-5-(3-(naphthalene-l-yl)ureido]-1 H-pyrazol-1-yl } phenyl)prpanoate (0.57 g).
N
N /
O
HO HN
HN
O
A mixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13 g, 0.8 mmol) in dry CH2C12 (5 ml) was stirred at RT under NZ for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3h at RT and diluted with EtOAc and diluted citric acid solution.
The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column chromatography using 4 % methanol in CH2C12as the eluent to yield 3- {4-[3-tert-butyl-5-(3-(naphthalene-l-yl)ureido]-1 H-pyrazol-l-yl } phenyl)propanonic acid (0.18 g, off-white solid). mp: 120 122 ;'H NMR (200MHz, CDC13): S 7.89 - 7.06 (m, 11 H), 6.5 (s, 1 H), 2.89 (m, 2H), 2.61 (m, 2H), 1.37 (s, 9H); MS
Nr N
HO HN~O
HN ~
O CI
The title compound was synthesized in a manner analogous to Example 31 utilizing Example Q(0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate (0.077 g, 0.5 mmol) to yield 3-{4-[3-tert-butyl-5-(3-(4-chlorphenyl)ureido]-1H-pyrazol-1-yl}phenyl)propanonic acid acid (0.16 g, off-white solid). mp: 112 - 114 ; 'H NMR (200MHz, CDC13): S 8.16 (s, 1 H), 7.56 (s, 1 H), 7.21 (s, 2H), 7.09 (s, 2H), 6.42 (s, 1H), 2.80 (m, 2H), 2.56 (m, 2H), 1.32 (s, 9H); MS
EXAMPLE R
N
N
A 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with 3-nitrobiphenyl (20 g, 0.10 mol) dissolved in THF (-100 mL) and 10% Pd/C (3 g).
The reaction vessel was charged with H2 (g) and purged three times. The reaction was charged with 40 psi H2 (g) and placed on a Parr shaker hydrogenation apparatus and allowed to shake overnight at RT.
HPLC showed that the reaction was complete thus the reaction mixture was filtered through a bed of Celite and evaporated to yield the amine: 16.7g (98% yield) In a 250 mL Erlenmeyer flask with a magnetic stir bar, the crude material from the previous reaction (4.40 g, 0.026 mol) was added to 6 N HCI (40 mL) and cooled with an ice bath to - 0 C. A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop wise. After 30 min, SnC12-2HZ0 (52.0 g, 0.23 mol, 8.86 eq.) in 6N HCI (100 rnL) was added and the reaction mixture was allowed to stir for 3h, then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for.4h, concentrated in vacuo and the residue extracted with EtOAc (2x100 mL). The residue was purified by column chromatograph using hexane/
EtOAc/Et3N (8:2:0.2) to yield 0.53g of Example R. 'H NMR (CDC13): S 7.5 (m, 18H), 5.8 (s, 1H), 1.3 (s, 9H).
O /
~ I
HN' N
N H
N
In a dry vial with a magnetic stir bar, Example R(0.145 g; 0.50 mmol) was dissolved in 2 mL CHZC12 (anhydrous) followed by the addition ofphenylisocyanate (0.0544 mL; 0.50 mmol;
I eq.). The reaction was kept under argon and stirred for 17h. Evaporation of solvent gave a crystalline mass that was triturated with hexane/EtOAc (4:1) and filtered to yield 1-(3-tert-butyl-1-(3-phenylphenyl)-11Y-pyrazol-5-yl)-3-phenylurea (0.185 g, 90%). HPLC purity:
96%; mp: 80 84 ;'H NMR (CDCI,): 8 7.3 (m, 16 H), 6.3 (s, IH), 1.4 (s, 9H).
\
~ o ~ ci I . HN~N
~
H
N N
N
The title compound was synthesized in a manner analogous to Example 33 utilizing Example R(0.145 g; 0.50 mmol) andp-chlorophenylisocyanate (0.0768 g, 0.50 mmol, I eq.) to yield 1-(3-tert-butyl-l-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea (0.205 g, 92%). HPLC purity: 96.5%; mp: 134 136 ; 'H NMR (CDC13): 8 7.5 (m, 14H), 7.0 (s, 1H), 6.6 (s, 1 H), 6.4 (s, 1 H), 1.4 (s, 9H).
EXAMPLE S
F
/
N N N
\ Fi H
O I /
O Et The title compound is synthesized in a manner analogous to Example C utilizing Example A and. 4-fluorophenyl isocyanate yield ethyl 3-(3-tert-butyl-5-(3-(4-flurophenyl)ureido)-1 H-pyrazol-l-yl)benzoate.
OMe _ I
N\
O I /
~ \ N
~-O
O
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3--(naphthalen-l-yl)urea.
N
N
HN
HN
S O
HO F
The title compound is synthesized in a manner analogous to Example 29 utilizing Example P(0.30g, 0.95 mmol) and 4-fluOrophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3-(3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol-l-yl)phenyl)propanoic acid.
EXAMPLE T
N-N
NHZ
NHBoc To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane-methylsulfide (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCl was added and heated to reflux for.10 min. The mixture was basified with NaOH
and extracted with EtOAc. The organic layer was dried (NazSO4) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5 amine (0.9 g).
A mixture of the crude material from the previous reaction (0.8 g, 3.1 mmol) and di-tert-butylcarbonate (0.7 g, 3.5 mmol) and catalytically amount of DMAP in dry CHZCIZ (5 ml) was stirred at RT under N2 for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using 1% methanol in CH2C12 as the eluent to yield tert-butyl 3-(3-tert-butyl-5-amino-lH-pyrazol-1-yl)phenylcarbamate (0.5 g).
N-N
HN/O
HN
A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate (0.123 g, 0.73 mmol) in dry CH2C12 (5 ml) was stirred at RT under N2 for 48 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 1% methanol in CH2C12as the eluent (0.15 g, off-white solid). The solid was then treated with TFA
(0.2ml) for 5 min and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-(2-Aminoethyl)phenyl]-1 H-pyrazol-5-yl} -3-(naphthalen-l-yl)urea as a solid (80 mg). mp: 110-112 ;'H NMR (200MHz, DMSO-d6): S 9.09 (s, 1 H), 8.90 (s, l H), 8.01 - 7.34 (m, 11 H), 6.43 (s; 1 H), 3.11 (m, 2H), 2.96 (m, 2H), 1.29 (s, 9H); MS
N-N
UHNI
The title compound was synthesized in a manner analogous to Example 37 utilizing Example T(0.15 g, 0.42 mmol) and 4-chlorophenylisocyanate (0.065 g, 0.42 mmol) to yield 1-{3-tert-butyl-l-[3-(2-Aminoethyl)phenyl]-IH-pyrazol-5-yl}-3-(4-chlorophenyl)urea as an off-white solid (20 mg). mp:125-127 ; 'H NMR (200MHz, CDC13): S 8.81 (s, IH), 8.66 (s, 1H), 7.36 - 7.13 (m, 8H), 6.54 (s, IH), 3.15 (brs, 2H), 2.97 (brs, 2H), 1.32 (s, 9H); MS
EXAMPLE U
N'N NHz 6"OCH3 In a 250 mL Erlenmeyer flask with a magnetic stir bar, m-anisidine (9.84 g, 0.052 mol) was added to 6 N HC1 (80 mL) and cooled with an ice bath to 0 C. A solution of NaNO2 (4.22 g, 0.0612 mo1,1.18 eq.) in water (10 mL) was added drop wise. After 30 min, SnC12-2HZ0 (104.0 g, 0.46 mol, 8.86 eq.) in 6 N HCl (200 mL) was added and the reaction mixture was allowed to stir for 3 h., and then subsequently transferred to a 1000 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (8.00 g, 0.064 mol) and EtOH (200 mL) were added and the mixture refluxed for 4 h, concentrated in vacuo and the residue recrystallized from CHZC12 to yield 3-tert-butyl-l-(3-methoxyphenyl)-1H-pyrazol-5-amine as the HCl salt (13.9 g).
The crude material from the previous reaction (4.65 g, 0.165 mol) was dissolved in 30 mL of CHZCIZ with Et3N (2.30 mL, 0.0165 mol, I eq.) and stirred for 30 min Extraction with water followed by drying of the organic phase with NaZSO4 and concentration in vacuo yielded a brown syrup that was the free base, 3-tert-butyl-l-(3-methoxyphenyl)-IH-pyrazol-5-amine (3.82 g, 94.5%), which was used without further purification.
N/ \ ~ \ I
'N H H
MeO b In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0 107 mol) was dissolved in CH2CIZ (5 mL, anhydrous) followed by the addition of 1-naphthylisocyanate (1.53 mL, 0.0107 mol, I eq.). The reaction was kept under Ar and stirred for 18 h. Evaporation of solvent followed by column chromatography with EtOAc/hexane/Et3N (7:2:0.5) as the eluent yielded 1-[3-tert-butyl-l-(3-methoxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (3.4g, 77%). HPLC: 97%;
mp: 78 - 80; 'H NMR (CDC13): S 7.9 - 6.8 (m, 15H), 6.4 (s, 1 H), 3.7 (s, 3H), 1.4 (s, 9H).
CI
N, N J~ N\ I N
H H
MeO \
The title compound was synthesized in a manner analogous to Example 39 utilizing Example U (3.82 g; 0.0156 mol) and p-chlorophenylisocyanate (2.39 g, 0.0156 mol, 1 eq.), purified by trituration with hexane/EtOAc (4:1) and filtered to yield 1-[3-tert-butyl-l-(3-methoxyphenyl)-1 H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (6.1 g, 98%). HPLC
purity: 95%; mp:
158 - 160 ;'H NMR (CDC13): S 7.7 (s, 1H); S 7.2 6.8 (m, 8H), 6.4 (s, 1H), 3.7 (s; 3H), 1.3 (s, 9H).
r N
N~
N H H
HO b In a 100 ml round bottom flask equipped with a magnetic stir bar, Example 39 (2.07 g) was dissolved in CHZC12 (20 mL) and cooled to 0 C with an ice bath. BBr3 (1 M
in CHZC12; 7.5 mL) was added slowly. The reaction mixture was allowed to warm warm to RT
overnight.
Additional BBr3 (1 M in CH2C12, 2 X I mL, 9.5 mmol total added) was added and the reaction was quenched by the addition of MeOH. Evaporation of solvent led to a crystalline material that was chromatographed on silica gel (30 g) using CH2C12/MeOH (9.6:0.4) as the eluent to yield 1-[3-tert-butyl-l-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalene-l-yl)urea (0.40g, 20%).
'H NMR (DMSO-d6): S 9.0 (s, IH), 8.8 (s, 1H), 8.1 - 6.8 (m, 11H), 6.4 (s, 1H), 1.3 (s, 9H). MS
(ESI) m/z: 401 (M+H+).
O CI
N, N N 'k N
H H
/
HO \
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 40 (2.00 g, 5 mmol) that resulted in a crystalline material that was filtered and washed with MeOH to yield 1-[3-tert-butyl-l-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (1.14 g, 60%). HPLC purity: 96%; mp: 214 - 216 ;'H NMR
(CDC13): S 8.4 (s, IH), 7.7 (s, 1 H), 7.4 - 6.6 (m, 9H), 1.3 (s, 9H).
EXAMPLE V
N, N NHZ
NH
The starting material, 1-[4-(aminomethyl)phenyl]-3-tert-butyl-N-nitroso-lH-pyrazol-5-amine, was synthesized in a manner analogous to Example A utilizing 4-aminobenzamide and 4,4-dimethyl-3-oxopentanenitrile.
A 1 L four-necked round bottom flask was equipped with a stir bar, a source of dry Ar, a heating mantle, and a reflux condenser. The flask was flushed with Ar and charged with the crude material from the previous reaction (12 g, 46.5 mmol; 258.1 g/mol) and anhydrous THF
(500 ml). This solution was treated cautiously with LiAlH4 (2.65 g, 69.8 mmol) and the reaction was stirred overnight. The reaction was heated to reflux and additional LiA1H4 was added complete (a total of 8.35 g added). The reaction was cooled to 0 and H20 (8.4 ml), 15% NaOH
(8.4 ml) and H20 (24 ml) were added sequentially; The mixture was stirred for 2h, the solids filtered through Celite, and washed extensively with THF, the solution was concentrated in vacuo to yield 1-(4-(aminomethyl-3-methoxy)phenyl)-3-tert-buty]-1H-pyrazol-5-amine (6.8 g) as an oil.
A 40 mL vial was equipped with a stir bar, a septum, and a source of Ar. The vial was charged with the crude material from the previous reaction (2 g, 8.2 mmol, 244.17 g/mol) and CHC13 (15 mL) were cooled to 0 under Ar and di-tert-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHC13 (5 mL) was added drop wise over a 2 min period. The mixture was treated with IN KOH (2 mL), added over a 2h period. The resulting emulsion was broken with the addition of saturated NaCI solution, the layers were separated and the aqueous phase extracted with CHZCIZ (2 x 1.5 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated in vacuo to yield tert-butyl (4-(3-tert-butyl-5-amino-1hT pyrazol-l-yl)-2-methoxybenzylcarbamate (2.23 g, 79%) as a light yellow solid. 'H NMR (CDC13):
S 7.4 (m, 5H), 5.6 (s, 114), 4.4 (d, 2H), 1.5 (s, 9H), 1.3 (s, 9H).
N/ /\
N H H
NH
A 40 mL vial was equipped with a septum, a stir bar and a source of Ar, and charged with Example V (2 g, 5.81 mmol), flushed with Ar and dissolved in CHC13 (20 mL).
The solution was treated with 2-naphthylisocyanate (984 mg, 5.81 mmol) in CHC13 (5 mL) and added over I min The reaction was stirred for 8h, and additional 1-naphthylisocyanate (81 mg) was added and the reaction stirred overnight. The solid was filtered and washed with CH2C12to yield tert-butyl4-(3-tert-butyl-5-(3-naphthalen-l-yl)ureido)-1H-pyrazol-l-yl]benzylcarbamate (1.2 g). HPLCpurity:
94.4 %; 'H NMR (DMSO-d6): S 9.1 (s, IH), 8.8 (s, 1 H), 8.0 (m, 3H), 7.6 (m, 9H), 6.4 (s, 1 H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
p ~ ci N~ \ I
H H
NH
O--,\O-<-The title compound was synthesized in a manner analogous to Example 43 utilizing Example V(2.0 g, 5.81 mmol) and p-chlorophenylisocyanate (892 mg) to yield tert-butyl 4-[3-tert-butyl-5-(3-(4-chloropnehyl)ureido)-1 H-pyrazol-l-ylJbenzylcarbamate (1.5 g). I-IPLC purity:
97%; 'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.4 (s, 1 H), 7.4 (m, 8H), 6.4 (s, 1 H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
/ CI
N
~ N~ N N\ ~
H H
NH
0-1\04 A 10 mL flask equipped with a stir bar was flushed with Ar and charged with Example 43 (770 mg, 1.5 mmol) and CH2C12 (1 ml) and 1:1 CH2C12:TFA (2.5 mL). After 1.5 h, reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (15 mL), washed with saturated NaHC03 (10 mL) and saturated NaCI (10 mL). The organic layers was dried, filtered and concentrated in vacuo to yield 1- { 3-tert-butyl-l-[4-(aminomethyl)phenyl]-1 H-pyrazol-5-yl }-3-(naphthalen-l-yl)urea (710 mg). 'H NMR (DMSO-d6): S 7.4 (m, l l H), 6.4 (s, l H), 3.7 (s, 2H), 1.3 (s, 9H).
/ CI
N~ ~ ~ \ ~
~N N N
H H
The title compound was synthesized in a manner analogous to Example 45 utilizing Example44 (1.5g, 1.5mmol)toyield 1-{3-tert-butyl-l-[4-(aminomethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.0 g). HPLC purity: 93.6%; mp: 100 - 102 ;'HNMR
(CDC13): S
8.6 (s, 1 H), 7.3 (m, 8H), 6.3 (s, IH), 3.7 (brs, 2H), 1.3 (s, 9H).
N -~
\N H H
N
~SOZ
A 10 ml vial was charged with Example 45 (260 mg, 63 mmol) and absolute EtOH
(3 mL) under Ar. Divinylsulfone (63 uL, 74 mg, .63 mmol) was added drop wise over 3 min and the reaction was stirred at RT for 1.5 h. and concentrated in vacuo to yield a yellow solid, which was purified via preparative TLC, developed in 5% MeOH:CHZCIZ. The predominant band was cut and eluted off the silica with 1:1 EtOAc:MeOH, filtered and concentrated in vacuo to yield 1-{3-tert-butyl-l-[4-(1,1-dioxothiomorpholin-4-yl)methylphenyl]-1H-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (150 mg). HPLC purity: 96%; 'H NMR (DMSO-d6): S 9.1 (s, IH), 9.0 (s, 111), 7.9 (m, 3H), 7.5 (m, 8H), 6.4 (s, 1 H), 3.1 (brs, 4H), 2.9 (brs, 4H), 1.3 (s, 9H).
~ ci I
N'N N N \
H H
N"') ~~S02 The title compound was synthesized in a manner analogous to Example 47 utilizing Example 46 (260mg, 0.66 mmol) to yield 1-{3-tert-butyl-l-[4-(1,1-dioxothiomorpholin-4-yi)methylphenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (180 mg). HPLC
purity: 93%; mp:
136 - 138 ;'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.5 (s, 1H), 7.4 (m, 9H), 6.4 (s, 1H), 3.1 (brs, 4H), 3.0 (brs, 4H), 1.3 (s, 9H).
O
N/ NN
N H H
O ~ I
II O~ ,O
NxNs, O \
G H
To a stirring solution of chlorosulfonyl isocyanate (0.35g, 5 mmol) in CH2C12 (20 mL) at 0 C was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5 C. After stirring for 2h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylmine (0.46 g, 9 mmol) in CHZC12 (20 mL) was added. When the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCI (10 mL) saturated with NaC1 , the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (IVTa2SO4) and concentrated in vacuo, purified by preparative HPLC to yield (pyrrolidine-l-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-1-yl]phenyl ester (40 mg). 'H NMR
(CDC13): S 9.12 (brs, 1H), 8.61 (brs, IH), 7.85 - 7.80 (m, 3H), 7.65 (d, J =
8.0 Hz, 2H), 7.53 -7.51 (m, 1H), 7.45 - 7.25 (m, 5H), 6.89 (s, 4H), 3.36 - 3.34 (brs, 1H), 3.14 -3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H+).
O / CI
/\ ~ I
N~N N N \
H H
~ O\ O '~ I
~N N'S' O ~
H
The title compound was synthesized in a manner analogous to Example 49 utilizing Example 42 to yield (pyrrolidine- I-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(4-chlorophenyl-l-yl-ureido)pyrazol-l-yl]phenyl ester. MS (ESI) m/z: 561 (M+H').
EXAMPLE W
N,N NH2 OMe Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight.
The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 'H NMR (DMSO-d6): S
7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, IH), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
O OMe N, N
H H
OMe To a solution of 1-isocyanato-4-methoxy-naphthalene (996 mg) in anhydrous CHZC12 (20 mL) of was added Example W (1.23 g). The reaction solution was stirred for 3 h, the resulting white precipitate filtered, treated with 10% HCI and recrystallized from MeOH, and dried in vacuo toyield 1-[3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl]-3-(1-methoxynaphthalen-4-yl-urea as white crystals (900 mg, 40%). HPLC purity: 96%; mp: 143 - 144 ;'H
NMR
(DMSO-d6): S 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (d, IH), 8.0 (d, IH), 7.6 (m, 5H), 7.1 (d, 2H), 7.0 (d, IH), 6.3 (s, IH), 4.0 (s, 3H), 3.9 (s, 3H); 1.3 (s, 9H).
O / Br I
N, N N N ~
H H
OMe The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and p-bromophenylisocyanate (990mg) to yield 1-{3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)urea as off-white crystals (1.5g, 68%).
HPLC purity: 98%; mp: 200 - 201 ;'H NMR (DMSO-d6): S 9.3 (s, 1 H), 8.3 (s, l H), 7.4 (m, 6H), 7.0 (d, 2H), 6.3 (s, 1 H), 3.8 (s, 3H), 1.3 (s, 9H).
/ /I
.
N N N N \
H H
OMe The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and p-chlorophenylisocyanate (768 mg) into yield 1-{3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (1.3g, 65%). HPLC
purity: 98%; mp: 209 - 210 ;'H NMR (DMSO-d6): S 9.1 (s,.1H), 8.3 (s, 1H), 7.4 (m, 4H), 7.3 (d, 2H), 7.1 (d, 211), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).
, \
N N N N \
H H
OH
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 53 (500 mg) to yield 1-{3-tert-butyl-I-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (300 mg, 62%). HPLC purity: 94%; mp: 144 -145 ; 'H
NMR (DMSO-d6): S 9.7 (s, IH), 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (d, 2H), 7.3 (m, 4H); 6.9 (d, 2H), 6.3 (s, 1 H), 1.3 (s, 9H) sr N N N
H H
OH
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 52 (550 mg) to yield 1-{3-tert-butyl-l-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)urea as a white crystalline solid (400 mg, 70%). HPLC purity: 93%;
mp: 198 200 ;'H NMR (DMSO-d6): S 9.7 (s, 1H), 9.2 (s, 1H), 8.3 (s, 1H), 7.4 (d, 4H), 7.2 (m, 2H), 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H).
EXAMPLE X
I
N, N NHZ
CO2Me Methyl 4-(3-tert-butyl-5-amino-lH-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).
O
N, NO
N H
C02Me A 500mL round bottom flask was equipped with a magnetic stir bar and an ice bath. The flask was charged with Example X(1 g) and this was dissolved in CH2C12 (100 mL). Saturated sodium bicarbonate (100 mL) was added and the rriixture rapidly stirred, cooled in an ice bath and treated with diphosgene (1.45 g) and the heterogeneous mixture stirred for I h. The layers were separated and the CH2C12 layer treated with tert-butanol (1.07 g) and the solution stirred overnight at RT. The solution was washed with H20 (2 x 150 mL), dried (Na2SO4), filtered, concentrated in vacuo, and purified by flash chromatography using 1:2 ethyl acetate: hexane as the eluent to yield tert-buthyl 1-(4-(methoxycarbonyl)phenyl)-3-tert-butyl-lH-pyrazol-5-ylcarbamate (100 mg) as an off-white solid. 'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 6.3 (s, 1 H), 3.3 (s, 3H), 1.3 (s, 18H).
CI
N
, N N N a H H
COZMe The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.37 g) andp-chlorophenylisocyanate (768 mg) to yield methyl4-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-l-yl}benzoate as white crystals (1.4 g 66%).
HPLC purity:
98%; mp: 160 - 161 ;'H NMR (DMSO-d6): S 9.2 (s, ]H), 8.6 (s, 1H), 8.1 (d, 2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (d, 2H), 6.4 (s, 1 H), 3.9 (s, 3H), 1.3 (s, 9H).
O OMe N. N H H\
CO2Me The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.27 g) and 1-isocyanato-4-methoxy-naphthalene (996 mg) to yield methyl4-{3-tert-butyl-5-[3-(1-methoxynaphthalen-4-yl)ureido]-1H-pyrazol-1-yl}benzoate as white crystals (845 mg, 36%). HPLC purity: 98%; mp: 278 280 ; 'H NMR (DMSO-d6): S 8.76 (s, 1H), 8.73 (s, IH), 8.1 (m, 3H), 7.9 (d, IH), 7.7 (d, 2H), 7.6 (m, 3H), 7.0 (d, IH), 7.0 (d, IH), 6.3 (s, 1 H), 4.0 (s, 3H), 3.9 (s, 3H),1.3 (s, 9H).
Br N/ O / I
\
N N ~ N\
H H
CO2Me ~
The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.37 g) and p-bromophenylisocyanate (990 mg) to yield methyl 4-{3-tert-butyl-5-[3-(4-bromophenyl)ureido]-1H-pyrazol=l -yl}benzoate as white crystals (1.4 g, 59%). HPLC purity:
94%; mp: 270 272 ; 'H NMR (DMSO-d6): 8 9.2 (s, 1 H), 8.6 (s, 1 H), 8.1 (d, 2H), 7.7 (d, 2H), 7.4 (d, 4H), 6.4 (s, 1 H), 3.9 (s, 3H), 1.3 (s, 9H).
O
'k / Br N/ ~ I
N NN
H H
OH
To asolution of Example 59 (700mg) in 30 mL of toluene at -78 C, was added dropwise a solution of diisobutylaluminum hydride in toluene (1M in toluene, 7.5 mL) over 10 min. The reaction mixture was stirred for 30 min at -78 C, and then 30 min at 0 C. The reaction mixture was concentrated in vacuo to dryness and treated with H20. The solid was filtered and treated with acetonitrile. The solution was evaporated to dryness and the residue was dissolved in ethyl acetate, and precipitated by hexanes to afford yellow solid which was dried under vacuum to give 1-[3-tert-butyl-l-(4-hydroxymethyl)phenyl)-1H-pyrazol-5-y1]urea (400 mg, 61%). HPLC
purity: 95%;'HNMR (DMSO-d6): S 9.2 (s,1H), 8.4 (s,1H), 7.5 (m, 8H), 6.4 (s,1H), 5.3 (t,1H), 4.6 (d, 2H), 1.3 (s, 9H).
Example 1 Example 2 N \ O ~~ C~ N \ 0 NN~
~N N~N ~N N),N
H H H H
\ I \ I
D D
Example 3 Example 4 N O S
N\N H H~N NN NN~
H H H N
Y
\D Y--I D
Example 5 Example 6 N~ A, / I \ N a\\/) NH
N N N N N N N
H H H H
\ I
Y, D Y-1 D
Wherein Y is 0, S, NR6, -NR6SO2-, NR6CO-, alkylene, 0-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or Y is a direct bond; D is taken from the groups identified in Chart I:
Chart I
O
Ra R4 0 NRa S NRa p NR4 S N ON\ ~p O~S~,NRa ~ ~ O O ~0 N ' /~O I /N~g>=O
NS~ /N~N~ / ~N N ~N >r0 Q-1 R Rs 4R0 R4 Q-2 Q-3 a Q-4 Q-NRa R4 R4 O o 0 p a /Z)R4 I /A\ 0 NRe Ra R
aN/S\N~R N
N H I H
iv" Ra Q-8 Q-9 Q-10 , Q-I1 O 0 ~~ Re~ O Ra\N RaN lj~ NH Ra\N~NH R,\N OR6 ~ I OR6 y~0 2yL0 I O Rs Re ''~ Rs RS p Q-12 Rs O OH SH
R4 R4 0 ~ 0 CO H O ~ 0 N Rs ~O N CO ~ HOW N W" W W ' W
p H3C CH3 II
H3C H3C -c-L-O O O N R 0 H H ZRa pN~s NRa~
HNNlS/Z,Ra S_0 O /n1 8 N~ pO
H R4 H SO3H p O
W'A~ W
I/\\W I/\\W
rCOZRa SO3R6 O O ~
N COZRd Ra I N , n O
SOzN(Ra)2 Ra OR O~ 0 N R4 N J
GZ.Ra I ~ I \ I \ I \ O
I \ I \ 8 n Example 7 Example 8 O ~ O NN
N/ \ /~ CI N /k '~
~ ,, N N H N H N N N
H H
\ I \ I
~_S
N ~S
O
ON O N
H H
Example 9 Example 10 O S
N\ N H Nl' H N H N
N N N N
~ H H-\\
N
NS LNS
>=o O
O N N
H H
Example 11 Example 12 N~ ~ ~ / I \ N~ ~ ll ~ / NH
N N NN
N H H N N H H
\ I \ I
NS LN~S
>==o ~
O N O N
H H
Example 13 Example 14 O
~ CI \ O N1~;,-N
N" N N~N N,~ N NxN
H H H H
N~N CHs >==o N
~
O" SN I >==o ~S
O H O~II
Example 15 Example 16 O
~ 0 S
N\N H H H N\N N N~
H H N
I / I I /
N~N CH3 I >=O N'N
O.S~N 1 >=0 O H 0"~~ N
Example 17 Example 18 O
N Nl~N N NH
N H H N N N N
H H
\ I \
CHa CH3 N 'N NN
>==o I >=O
N H 0~lb, N
0 p Example 19 Example 20 r CI \
N, NJ~NII ~~ N N~N
N H H N H H
' \ \
NN-S\
NH
H3C H3C-~ /NH
H3C C H3C/ ~O
Example 21 Exarimple 22 O
\i \ ~ S
NN H H N N N N~
H N H H N
S~ 0 00 N' \NH N-S
H3C 0 H3C ~O
Example 23 Example 24 / / \ O
~ l \ l~ ~ NH
N ~ N N N N N /
N H H N N H H
\ I \ I
.N
NH NH
N
HH < H3C ~ /
Example 25 Example 26 ~ CI
NN N~N ~~ N~ N N~N
H H H H
\0 0 0 ~ p N N
Example 27 Example 28 N~ A, //~~ / \ CII S
N H HN N NI~N~\
~S CH3 00 \\ 'C 0 O~H~ N/ ONN/CH3 Example 29 Example 30 N ~ NH
N N NN NN N N H H H H
\ I \ I
/S"I CH3 II NNCH3 0 H N 0 H i Example 31 Example 32 O O
6N~ CI N N
N N~N N~N N~N
H H H H
\ \ I
N OH N OH
N OH N OH
i Example 33 Example 34 N O S
N/ N\ N~N~N N/ N~N~ {
H H H N H H
O O
N OH N OH
N OH OH
O O
Example 35 Example 36 x O O
NH
N N~N ~N ~ N N N
N H H H H
\ I \
O.
N OH N OH
N OH N OH
0 i O
Example 37 Example 38 CI N N
\ II
N, N\ N~N N N N/~N
H H H H
H t ON HN_ON
Example 39 Example 40 O
N,, N NA, N~ \/ / \ O S I
H H H NN N~N
H H N
HN~ ON
O HN t_,(/
ample 41 Example 42 Ex ~ O / \ O
N J /
N /
N N N N \
N H H N N NH
HNfto N HN~ //O N .
O~"
Example 43 Example 44 O N OI, NN
N
CE
N NN \ / N H H
H H
/ I I
N
N lI ~SO
vs ~O \O
\O
Example 45 Example 46 S
N \ ~ti. \ f f \ J. {
~N N N N NN N N~
H H H H H
N N
S~~O S\ O
~O \O
Example 47 Example 48 l~ / \ O
N/ N N N"N N~H /
N H H H
\ ~ ~ I
N/~1 N, 1 SZZ--O SIyO
\\O ~\O
Example 49 Example 50 O O N~N
~ CI
N" N\ N~N \~ N*~ N x N
H H N H H
O N CH3 0 N~ CH3 H H
Example 51 Example 52 N \ O S
N H H H N~N N~N 10:
H H N ~~/~ o ~S \ s/
O H CH3 O N~ ~CH3 H
Example 53 . Example 54 O / \ O
N ~ ~ ~ / NH
,N N
N N H H N N H H /
\
O \ ~ O
'V/
O HN ~S~CH3 O H~ CH3 Example 55 Example 56 N \ ~ N N~ N~~'/
H H N H H
\ I \ I
O NI-I''CONHCH3 O N~\CONHCH3 CONHCH3 L~",CONHCH3 Example 57 Example 58 6 Nf \ N \/ \ O S
~N N NJN N N~N~
H H H N H H
\ \
O NCONHCH3 O N-,-,~CONHCH3 Example 59 Example 60 NH
N~
N N~N
H H N H H
N
\ \
O CONHCH3 O N/~CONHCH3 ~'CONHCH3 CONHCH3 Example 61 Example 62 O ~ \ O
CI NN
. NN N NN N N N~N ~
H H H H
SO2NHPh SO2NHPh Example 63 Example 64 O
NI \ II \ II S
~N H~H N N~ N~N~ ~
H N H H N
\ I \ I /
SO2NHPh SOZNHPh Example 65 Example 66 NI ~ ll / I \ NI ~ ~ ~ / NH
N N~N N N N N
H H H H
SOzNHPh SOZNHPh Example 67 Example 68 X O
~ CI N N
N N N N,N H H
H H
\ I ~ I
\ OEt O~\ OEt O \NH NH
Example 69 Example 70 S
\ ~ ~ \ / N/
N
N N N N ,,N N N~
H H H H H N ~
\ I \ I /.
~,OEt -OEt O NH NH
Example 71 Example 72 / =~ O ~
O NH
N~N N~N ~N N H H
H H
/
\ I \ I
_,OEt _,OEt / NH
~ O
O NH
Example 73 Example 74 N ~ N Ou N \ X\ ~ \ ~ / 1 X\N, O=
N~ N N
N H H N H H
\ I \
Y--p Y-p Example 75 Example 76 X
H / I I\ / N\ 0 X
N I\
l N ~
N H N \ /N N N N \ /N
H H
\ I \ .
Y-p Y'D
Example 77 Example 78 / X I ~N X
N N\ NN \ N \ '' / I N
H H I ~N N N
/ I \ H H
Y--p Y~p wherein X or Y is 0, S, NR6, -NR6SO2-, NR6CO-, alkylene, O-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or X
or Y is a direct bond; D is taken from the groups identified in Chart I:
Chart I
R4 R4 Rq ~ 0 NRq 0 ~ 0 O~N S~N 0 0 N SN ~S O O i-N~O
0 jl' I
N\S~ N\S~ N\. >~O ~NN O ~N ~N~N
D-1 3 Ra D-4Ra D-5R R4 D-2 D- D-6 0 O N R4~ O R4 R~ 0 \ \SO ~N /N R4 0 NR4 NR4 ~ Z H ~~ H/ \1/
RS 0 o 0 D-10 D-11 0 0 0 R4, ~~
Ra\ R+~ N NH N NH i ORe N ~ ORa p /N
OR6 ~ ORa Rs OR6 RS R5 p ~ O
RS 'nn R4~N R4 0 / 0 CpzH O ~ O
R5 ~ 0 N C H0/ N W ~ W W ~ W
/ ?? 0 H3C CH3 0 r I I
O~ i H3C CHa H3C CHa /
3C ~~%
0 0 0 p 0 ~O N R 0 t1uN~SZRa pNN ~ HN' N~\S,Z~R4 JS_O 0 S a II 0~%0 H Rq H S03H N'~/ 0np 0 W W W W W~W I I
"o, D-24 D.25 D-27 D-28 COZR4 = O 0 S03Ra ~ 0 N~
NH RB
0 NCOZRa SOzN(R4h 0 N R9 I~O~ 0 N ~ N J
I \ I ~ I \ N
N / I \ I \ I \
~~-NH
i, '4, Specific examples of the present invention are illustrated by their structural formulae below:
Example 79 Example 80 0 O O~~N N/
' ~"/
N~N N N H
H H I H
\ ~ \ ( O Q
'S S~
N >=
0/N p N
H
Example 81 Example 82 Nl \ O /( I N NJ ~ ~ /( O I\
O
NN N N N
N H H N H H
~s ~s j ~o j >=o p~=N N
H H
Example 83 Example 84 \ ~
N,N H H N N N~N \ I I/
H H
\ I ~ ~
N~S --S
O~ ~ H o ~~ NO
Fi Example 85 Example 86 0 / O / O\/~N
II a N ~ /II~.
NN NN 'N H H\
H H
N'-N i ~-N
/)c0 ~O
Example 87 Exainple 88 J ~ i N ~~
~
N N N N NN N N ~/ N
H H H H
\ I ~ \ ( N~N N
~ >=O I >==O
0'N 0;: ISI N
O H O H
Example 89 Example 90 O ON O
N ~ ~
~N H H\ ~ NN N
H H
\~ \I
NN\ CH3 ' >=o N~N
~ >=o 011'N GS~ N
0 H O ~p H
Example 91 Example 92 0 N/', OI' / O\/\\ N N I ~ ~ I ~\O \ J~ ~/
N
NN N N N H H ~ H
H H
O N S!
O O
N ~S\ \
NH
~ H3C
Example 93 Example 94 O O
N N\ NN T{I~~/'1N N~ N\ NN I N
H H H H
\ I ~ \ I
~
Of0 OO
N''S NiS\
I NH NH
H3C-~ H3C
Example 95 Example 96 O
N \ N ~ N ~ I I / ~ ~ / \h1/~~
N H H NN N N
H H
\ I \ ~
O p O O
N
~ 'NH NH
H3C-~~ H3C ~
Example 9?
Example 98 O
NN a~\N/, N! N~ M~N /
H H 'y/ H H
a N S N~CH3 aANN,.CHg ~J( 4H C, H3 H CH3 Example 99 Example 100 0 d N N~N N N N~ NN \( N
H H H H ~
/ ~ \ fr a ~ Q Sr .'CHg Op % O
O M N O/'N"g\NCH3 Example 101 Example 102 N N' NN ( Nf \
O O rlD
H H N \ N N"
\ ~ H H
a~ 'N~,S" NI,CH3 ~ 0 aS~//~a ICH
~ ,J+., 3 H ~H3 O H ~H
Example 103 Example 104 O / O~\N \ N O O
~ ll I \ o x I N ~
H \H H \
NN N~N \ N
I \
N OH N OH
N OH ~N OH
Example 105 Example 106 O O / O N~ \ N~N I I% NN\ O H H N~N N
H H
i OH N OH
~N OH N OH
i Example 107 Example 108 N N NN \ I I/ N \
H H N N N~
H H
\ \
O
I OH N OH
/N N OH
Example'109 Example 110 O O\~\N I \ O / I O\/\N' N
N~ N\ N~N I ~ ,N H H
H
\
~I \
HN~fO N
H3C HNt N
f O CH3 H3C CH3 Exem ple 111 Example 112 N~ N NN \\y/N
N~ \ NN N
O O O
H H I H H
\~ \ \~
HN~f/O N HN~//O N
OT Oi Example 113 Example 114 O N O / N
N N\ NI~N / N \ I I/
H H N N N
H H
\ I \ ~
HN~f/O N HN O N
OT
CH O
Example 115 Example 116 ~~ N OII O~~N' ' , /~ ~/ .
N N\ N~N N H H \
H H
\ ~ \ I
S O' S O
\
O O
Example 117 Example 118 o ~ ~
N N NN N N
N NN \ I I/N
H H H H
N
Qo \\O
Example 119 Example 120 OII N
NN\ NN \ I I/ N O
H H N N N
H H
N
O oo VSp o Example 121 Example 122 O O / O
~~\N O
N N \ I v0 NN\ N~N ~ I v N H H ~ H H
\ I \ I 00 0 0 'V/
O N ~S \
O N~
H H
Example 123 Example 124 O
II
\ N /~N N N~ N \ I 1 N
N H H N\ N H H
,~ O 0 0 N/ O H I\
H ~
Example 125 Example 126 O O '~'N 0 / O N
~
NN NN I ~/ N NJ~.N \ I I/
H ~ N H H
\
O N~ \ O N/
H I / .
Example 127 Example 128 N ~ N N
N N N }~ H
H H \ I ' I
0 N CONHCH3 0 NII~~ CONHCH3 ~CONHCH3 LCONHCH3 Example 129 Example 130 O O~~i~~~ \ O O\\///~
N \ NN N NN NN N
N H H H H
0 CONHCH3 O N-,,~CONHCH3 CONHCH3 CONHCHa Example 131 Example 132 \ O 0 / N
H
N NH N~ NN~
H H
\ ~ ~ I
N~-ICONHCH3 O Nl-~~CONHCH3 Example 133 Example 134 \ 0 O~~N O O / I O~~N' ~=
N N/~N NN NJ~N- /
N H H H H
\ I \
S02NHPh S02NHPh Example 135 Example 136 N ~ N~N / N N~ N~N \ I \\V/// N
\\/// /N
N O O O O
H H H H
\ I \ \ I
S02NHPh S02NHPh Example 137 Example 138 NN N~N ~ N \ ~ \ I /
~ O ~ O I N 0 / ~N
H H N N N
\ ~ H H
\ I \ I
S02NHPh S02NHPh Example 139 Exampie 140 N O O\~~N~ O O~~~N
N NN NN H H
H H
I \
~OEt iOEt Oo~,~\NH O N H
Example 141 Example 142 N \ ~ / I O I N N/
N N N N N
N H H N H H
OEt s~OEt 0% \\
NH NH
Example 143 Example 144 ~
N ~
N~ H H N
N N'kN
H H
_--OEt \ ~OEt O \NH 0NH
Example Y
NHNH2.HCI
OEt To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CHZC12 (200 mL) was added (triphenyl-15-phosphanylidene)-acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) dropwise at 0 C, which was stirred for 2 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 %) 'H-NMR (400MHz, CDC13): 8.42 (s, 1 H), 8.23 (d, J= 8.0 Hz, 1 H), 7.82 (d, J= 7.6 Hz, 1 H), 7.72 (d, J =
16.0 Hz, 1 H), 7.58 (t, J= 8.0 Hz, 1H), 6.56 (d, J= 16.0 Hz, 1H), 4.29 (q, J= 7.2 Hz, 2H), 1.36 (t, J
6.8 Hz, 3H).
A mixture of 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi of H2 at RT for 2 h then filtered over celite. After removal the solvent, 14 g of 3-(3-amino-phenyl)-propionic acid ethyl ester was obtained and used directly without further purification. 'H-NMR (400 MHz, CDC13): 7.11 (t, J= 5.6 Hz, 1H), 6.67 (d, J= 7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13 (q, J=7.2 Hz,' 2H), 2.87 (t, J= 8.0 Hz, 2H), 2.59 (t, J= 7.6 Hz, 2H), 1.34 (t, J= 6.8 Hz, 3H).
To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g, 72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution (10 mL) of NaNO2 (5 g, 72.5 mmol) at 0 C and the resulting mixture was stirred for I h. A solution of SnC12.2H20 (33 g, 145 mmol) in concentrated HCI (150 mL) was then added at 0 C.
The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid, which was used without further purification.
Example Z
\
N, >NNH2 A mixture of Example Y(13 g, 53.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester (14.3 g, 45.4 mmol) as a white solid. 'H NMR (DMSO-d6): 7.39-7.32 (m, 3H), 7.11 (d, J = 6.8 Hz, IH), 5.34 (s, 1 H), 5.16 (s, 2H), 4.03 (q, J =
7.2 Hz, 2H), 2.88 (t, J =7.6 Hz, 2H), 2.63 (t, J =7.6 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J 7.2 Hz, 3H).
Example 145 O
N~ \ XN
N H
O
A solution of 4-fluoro-phenylamine (111 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then added to a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT
overnight then added to water (50 mL). The reaction mixture was extracted with ethyl acetate (3x50 mL) and the combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester (150 mg, 33%). 'H-NMR
(CDC13):
7.91 (s, 1 H), 7.42 (d, J= 4.8 Hz, 1 H), 7.37-7.34 (m, 2H), 7.28 (s, 1 H), 7.17-7.16 (m, 2H), 6.98 (t, J 8.8 Hz, 2H), 6.59 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.03 (t, J=
7.2 Hz, 2H), 2.77 (t, J= 7.2 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J= 7.2 Hz, 3H); MS (ESI) m/z:
(M+H+).
Example 146 F
O
- -- N/ ' N H
N H
b OH
O
A solution of Example 145 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, extracted with ethyl acetate (3x20 mL), the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[3- (4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid, (37 mg, 90%). 'H
NMR (CD3OD): 7.63-7.62 (m, 2H), 7.56 (s, 1 H), 7.53-7.48 (m, 1 H), 7.41-7.38 (m, 2H), 7.04 (t, J= 8.8 Hz, 2H), 5.49 (s, 1 H), 3.07 (t, J= 7.6 Hz, 2H), 2.72 (t, J
7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 415 (M+H).
Example 147 OMe O ~ I
N~ 1 l~ N11 N
N H H
OEt O
A mixture of 4-methoxy-phenylamine (123 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was. then added a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT
overnight then quenched with of water (50 mL). The reaction mixture was extracted with ethyl acetate (3x50 mL) and the combined organic extracts were washed with brine, dried (NaSOA filtered, concentrated under reduced presume to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (210 mg, 45%). 1H-NMR
(CD3OD): 7.46 (t, J= 7.6 Hz, 114), 7.3 8 (s, 1 H), 7.34 (d, J= 7.6 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.38 (s, IH), 4.09 (q, J= 7.2 Hz, 2H), 3.75 (s, 3H), 3.00 (t, J= 7.6 Hz, 2H), 2.68 (t, J 7.6 Hz, 2H), 1.33 (s, 9H), 1.20 (t, J 7.6 Hz, 3H);
MS (ESI) m/z: 465 (M+H+).
Example 148 OMe O ~ 1 N~ NXN ~
N H H
OH
Utilizing the same synthetic procedure as for Example 61 and starting with Example 147, 3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid is synthesized.
Example 149 O
N, N Hj N
b--A solution of isoquinoline-l-carboxylic acid (346 mg, 2.0 mmol), Example Z
(315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), and NMM
(1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3- { 3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-l-yl } -phenyl)-propionic acid ethyl ester, (380 mg, 80%). 1H-NMR (DMSO-d6): 8.83 (d, J= 8.4 Hz, IH), 8.85 (d, J= 5.2 Hz, 1 H), 8.09 (s, 1 H), 8.07 (d, J= 8.4 Hz, 1 H), 7.82 (t, J= 8.0 Hz, 1 H), 7.72 (t, J
= 8.0 Hz, 1 H), 7.52 (s, 1 H), 7.44 (d, J= 8.0 Hz, 1 H), 7.3 9(t, J= 5.2 Hz, 1 H), 7.22 (d, J=
8.0 Hz, 1 H), 6.57 (s, I H), 3.98 (q, J= 7.2 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 2.57 (t, J=
7.6 Hz,.2H), 1.32 (s, 9H), 1.10 (t, J 7.6 Hz, 1 H); MS (ESI) m/z: 471 (M+H+) Example 150 O
N~
, N H N
b-- OH
O
A solution of Example 149u (47 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH
(3 mL) was stirred at RT. overnight. The reaction mixture was neutralized to pH = 4, extracted with ethyl acetate (3x20 mL), and the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (39 mg, 87%). 'H-NMR (DMSO-d6): 10.77 (s, 1 H), 9.68 (d, J 7.6 Hz, 1 H), 8.44 (d, J=
5.2 Hz, IH), 7.89-7.44 (m, 2H), 7.78-7.74 (m, 2H), 7.49-7.47 (m, 3H), 7.30-7.27 (m, 3H), 6.95 (s, 1 H), 3.05 (t, J 7.2 Hz, 2H), 2.75 (t, J 7.6 Hz, 2H), 1.42 (s, 9H); MS
(ESI) m/z: 443 (M+H+).
Example 151 O
N~ \ N ' ' N H
A solution of pyridine-2-carboxylic acid (246 mg, 2.0 mmol), Example Z (315mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (300 mg, 70%). 1H-NMR (CDCL3): 8.53 (d, J = 4.4 Hz, 1 H), 8.26 (d, J 7.2 Hz, 1 H), 7.90 (t, J= 8.0 Hz, 1 H), 7.48-7.43 (m, 4H), 7.27 (s, 1 H), 6.87 (s, IH), 4.13.(q, J= 7.2 Hz, 2H), 3.04 (t, J= 7.6 Hz, 2H), 2.71 (t, J= 7.6 Hz, 2H), 1.39 (s, 9H), 1.24 (t, J 7.2 Hz, 3H); MS__(ESI)_mlz_ 421 (M+H+).
Example 152 N~
, H 1 /
b A solution of Example Z (315 mg, 1.0 mmol) and Barton's base (0.5 mL) in anhydrous CH2C12 (5 mL) under N2 was stirred at RT for 30 min, and then added to a solution of naphthalene-l-carbonyl fluoride (348 mg, 0.2 mmol) in anhydrous CH2CI2 (5 mL). The resulting mixture was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-l-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester, (350 mg, 74%). 'H-NMR (CDCL3): 8.29 (d, J= 8.0 Hz, 1H), 7.98 (d, J
= 7.2 Hz, 2H),'7.89 (d, J = 7.2 Hz, 1H), 7.62-7.57 (m, 3H), 7.49-7.28 (m, 4H), 7.03 (s, 1 H), 3.94 (q, J= 7.2 Hz, 2H), 2.96 (t, J= 7.2 Hz, 2H), 2.58 (t, .1 7.2 Hz, 2H), 1.45 (s, 9H), 1.13 (t, J= 7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Example 153 o 'N,N H 1 /
b OH
O
A solution of Example 152 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (38 mg, 86%). 'H NMR (DMSO-d6): 7.99 (d, J= 8.0 Hz, IH), 7.90 (m, 2H), 7.62 (m, 1H), 7.54-7.42 (m, 6H), 7.3 5(m, 1 H), 6.54 (s, 1 H), 2.94 (t, J 7.6 Hz, 2H), 2.57 (t, J
7.2 Hz, 2H), 1.38 (s, 9H); MS (ESI) m/z: 443 (M+H+).
Example 154 N~N
/ H.
A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCIZ (10 mL) was heated to reflux for 2 h. After concentration under reduced pressure, the residue was dissolved into CH2CI2 (5 mL) and was dropped into a solution of Example Z(315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0 C, and was then stirred at RT overnight.
After quenching with water (50 mL), the reaction mixture was extracted with CHZCIz (3x 100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified. by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino)-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (180 mg, 38%). 'H-NMR (CDCL3): 8.24 (s, 1 H), 8.21 (s, 1 H), 7.91 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 1 H), 7.73 (d, J= 8.4 Hz, IH), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J= 7.2 Hz, 2H), 3.04 (t, J= 7.6 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 1.43 (s, 9H), 1.17 (t, J 7.2 Hz, 3H);
MS (ESI) m/z: 470 (M+H+).
Example 155 O
N \
'N H
OH
O
A solution of Example 154 (47 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH-=
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-2-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid, (37 mg, 84%). 'H-NMR (CDCL3): 8.25 (s, 1 H), 8.18 (s, 1 H), 7.91-7.86 (m, 3H), 7.75 (d, J= 8.0 Hz, 1 H), 7.59-7.55 (m, 2H), 7.48-7.39 (m, 3H), 7.28 (s, 1 H), 6.81 (s, IH), 3.02 (t, J= 7.6 Hz, 2H), 2.69 (t, J 7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Example 156 O
N~ \ \ ~
N H N
A solution of isoquinoline-3-carboxylic acid (346 mg, 2.0 mmol), example Z
(315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), and NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts we're washed with-brine, -dried-(NaSO4)-and-filtered-After-concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-l- yl}-phenyl)-propionic acid ethyl ester (250 mg, 54%). 1 H-NMR (CD3OD): 9.24 (s, 1 H), 8.63 (s, 1 H), 8.17 (d, J= 8.0 Hz, IH), 8.11 (d, J= 8.0 Hz, 1 H), 7.88 (t, J= 7.6 Hz, 1 H), 7.81 (t, J= 7.6 Hz, IH), 7.50 (s, 1 H), 7.48 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 7.6 Hz, 2H), 7.36 (d, J= 7.6 Hz, 1 H), 6.75 (s, 1 H), 4.04 (q, J= 7.6 Hz, 2H), 3.01 (t, J= 7.6 Hz, 214), 2.69 (t, J= 7.6 Hz, 2H), 1.39 (s, 9H), 1.14 (t, J 7.6 Hz, 3H); MS (ESI) m/z: 471 (M+H+).
Example 157 O
N%~
N N
/ H
\ I OH
O
A solution of Example 156 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (39 mg, 88%). 'H NMR (CDCL3): 10.49 (s, 1 H), 9.16 (s, 1 H), 8.69 (s, 1 H), 8.03 (d, J= 7.6 Hz, 2H), 7.81 (t, J= 7.2 Hz, 1H), 7.73 (t, J= 7.2. Hz, 1H), 7.48-7.39 (m, 3H), 7.28 (br s, 1H), 6.94 (s, 1 H), 3.02 (t, J= 7.6 Hz, 2H), 2.79 (t, J= 7.6 Hz, 2H), 1.42 (s, 9H);
MS (ESI) m/z: 442 (M+H}) .Example 158 O
N/
'N h~ , / CI
b A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOC12 (10 mL) was heated to reflux for 2 h. After removal of the solvent, the residue was dissolved into CHZCIZ (5 mL) and was dropped into a solution of Example Z (315 rng, 1.0 mmol) in CH2C12 (10 mL) at 0 C, was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2C12 (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4) arid filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]- phenyl}-propionic acid ethyl ester (290 mg, 64%). 'H-NMR (CDCL3): 8.02 (s, IH), 7.67 (d, J = 8.4 Hz, 2H), 7.46 (t, J =
7.6 Hz, 1 H), 7.44 (d, J=-8.4 Hz, 2H), 7.36 (t, J= 8.4 Hz, 3H), 6.87 (s, 1 H), 4.06 (q, J=
7.6 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=
7.6 Hz, 3H); MS (ESI) m/z: 454 (M+H+).
Example 159 N~
'N H , / CI
b OH
O
A solution of Example 158 (45 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-{3-[3-t-butyl-5- (4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid, (38.5 mg, 87%).
'H NMR (DMSO-d6): 10.38 (s, IH), 7.85 (d, J 8.4 Hz, IH), 7.56 (d, .I = 8.4 Hz, 2H), 7.3 9(s, 1 H), 7.32 (d, J= 4.8 Hz, 2H), 7.15 (t, J= 4.8 Hz, 1 H), 6.3 8 (s, 1 H), 2.80 (t, J=
7.6 Hz, 2H), 2.44 (t, J 7.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 426 (M+H)+.
Example AA -NHZ
N
EtO2C
To a solution of m-aminobenzoic acid (200.0 g, 1.46 mmol) in concentrated HCI
(200 mL) was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mmol) at and the reaction mixture was stirred for 1 h. A solution of SnC12.2H20 (662 g, 2.92 mmol) in concentrated HCl (2000 mL) was then added at 0 C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-hydrazino-benzoic acid hydrochloride as a white solid, which was used for the next reaction without further purification. 'H NMR (DMSO-d6):
10.85 (s, 3 H), 8.46 (s, 1 H), 7.53 (s, I H), 7.48 (d, J = 7.6 Hz, 1 H), 7.37 (m, J 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, I H).
A mixture of 3-hydrazino-benzoic acid hydrochloride (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-l-yl)- benzoic acid (93 g, 36%). 3- (5-amino-3-t-butyl-pyrazol-l-yl)-benzoic acid and ethyl ester: 'H NMR (DMSO-d6): 8.09 (s, 1 H), 8.05 (brd, J= 8.0 Hz, 1 H), 7.87 (br d, J= 8.0 Hz, 1 H), 7.71 (t, J= 8.0 Hz, 1 H), 5.64 (s, I H), 4.3 5(q, J 7.2 Hz, 2 H), 1.34 ---(t;-J-= 7.2 Hz, 3 H), 1.28 (s, 9H).
Example BB
N, N NH2 \
HO I /
To a stirred solution of Example AA (19.5 g, 68.0 mmol) in THF (200 mL) was added LiAlH4 powder (5.30 g, 0.136 mol) at -10 C under N2. The mixture was stirred for 2 h at RT and excess LiAlH4 was destroyed by slow addition of ice. The reaction mixture was acidified to pH = 7 with diluted HCI, the solution concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic extracts were concentrated to give [3 -(5 -amino-3-t-butyl-pyrazol- 1 -yl)-phenyl] -methanol (16.35 g, 98%) as a white powder. 'H NMR (DMSO-d6): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, I H), 6.41 (s, 1H), 4.60 (s, 2 H), 1.28 (s, 9 H);
MS (ESI) m/z:
415 (M+H+).
Example CC
CI I /
A solution of Example BB (13.8 g, 56.00 mmol) and SOC12 (8.27 mL, 0.11 mol) in THF (200 mL) was refluxed for 3 h and concentrated under reduced pressure to yield 5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-ylamine (14.5 g, 98%) as white powder which was used without further purification. 'H NMR (DMSO-d6), 57.62 (s, 1 H), 7.53 (d, J= 8.0 Hz, 1 H), 7.43 (t, J= 8.0 Hz, 1 H), 7.31 (d, J= 7.2 Hz, l H), 5.3 8(s, I
H), 5.23 (br s, 2 H), 4.80 (s, 2H), 1.19 (s, 9 H). MS (ESI) m/z: 264 (M+H+).
Example DD
ON O
N"
I \ 1 NH
Me0 ~ ~J
O
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 rnmol) in (20 mL) at 0 C was added 2-methyl-propan-2-ol (0.74 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of glycine ethyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in CHZCl2 (20 mL) was added at such a rate that the reaction temperature didn't rise above C. When the addition was completed, the solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCl and extracted with CH2C12.
The organic layer was washed with saturated NaCI, dried (Mg2SO4) and filtered.
After removal of the solvent, the crude product was washed with CH2C12 to afford ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85 %). 1H-NMR(DMSO):- S
10.85 (s, 1 H), 8.04 (t, J 6.0 Hz, I H), 4.07 (q, J = 5.6 Hz, 2H); 3.77 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J= 7.2 Hz, 3H).
To a solution of (4-methoxyphenyl)-methanol (1.4 ga 8.5 mmol) and triphenyl-phosphane (2.6 g, 8.5 mol) in dry THF was added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0 C under N2 atmosphere. The mixture was stirred at 0 C for 2 h, warmed to RT and stirred overnight. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford ethyl2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate (2.3 g, 69%) as a white solid. 'H-NMR(CDC13): S 7.32 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.71 (m, IH), 4.76 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.80 (s; 3H), 3.55 (d, J 5.2 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J= 7.2 Hz,3H).
To a solution of HCl in methanol (2 M) was added ethyl 2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (2.0 g, 5.0 mmol) in portions at RT and the mixture was stirred for 3 h. After the solvent was removed in vacuo, the residue was washed with diethyl ether to afford ethyl2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate (1.0 g, 70%). 'H-NMR (DMSO-d6): S
7.43 (t, J= 6.0 Hz, l H), 7.287 (t, J= 6.4 Hz, 1 H), 7.21 (d, J= 8.4 Hz, 2H), 6.86 (d, J= 8.4 Hz, 2H), 3.94 (d, J= 4.8 Hz, 2H), 3.71 (s, 3H), 3.64 (d, J= 6.0 Hz, 2H), 3.62 (s, 3H), To a solution of ethyl 2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (1.0 g, 3.47 mmol) in DMF (50 mL) was added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 atmosphere at RT. The mixture was stirred overnight then quenched with HCI/ methanol (2 M). After the solvent was removed in vacuo, the residue was washed with water to afford 2-(4-methoxy-benzyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one (480 mg, 54 %). 'H-NMR(CDCl3): S 7.36 (d, J= 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.87 (m, 1 H), 4.68 (s, 2H), 4.03 (d, J 7.2 Hz, 2H), 3.80 (s, 3H).
Example EE
OMe ~ ~
O~~O -HN ~N
O
IA
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 nunol) in (20 mL) at 0 C was added benzyl alcohol (1.08 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After stirring for 1.5 h, a solution of L-alanine methyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in (20 mL) was added at such a rate that the reaction temperature didn't rise above 5 C.
When the addition was completed, the reaction solution was allowed to warm up to RT
and stirred overnight. The reaction mixture was poured into 10% HCI, extracted with CHZC12, the organic extracts washed with saturated NaCl, dried (Mg2SO4), and filtered.
After removal of the solvent, the crude product was recrystallized in PE/EA
(10:1) to afford the desired product (2.5 g, 79 %), which was used directly in the next step. 'H-NMR(DMSO): S 11.31 (s, IH), 8.43 (d, J= 8.0 Hz, IH), 7.37-7.32 (m, 5H), 5.11 (s, 2H), 4.03 (m, 1 H), 3.57 (s, 3H), 1.23 (d, J= 7.2 Hz, 3H).
A mixture of material from the previous reaction (2.5 g, 12 mmol) and Pd/C (10 %, 250 mg) in methanol was stirred for 4 h at 50 C under H2 atmosphere (55 psi). After the catalyst was removed by suction, the filtrate was evaporated to afford the desired compound (1.37 g, 92%) as a white solid, which was used directly in the next step. jH-2l7 NMR (CDC13): 6 5.51 (d, J= 5.6 Hz, 1 H), 4.94 (br, 2H), 4.18 (m, 1 H), 3.78 (s, 3H), 1.46 (d, J = 7.2 Hz, 3H).
To a solution of 2.0 N of NaOMe in methanol (20 mL) was added a solution of compound form the previous reaction (1.2 g, 6.1 mmol) in methanol and the resulting mixture was heated to reflux overnight. After cooling down, a solution of HC1 in methanol was added to acidify to pH 7. The resulted salt was filtered off and the filtrate was evaporated to dryness to afford a light yellow solid which was used directly in the next step (600 mg, 66%). 'H-NMR (DMSO-d6): 8 6.04 (d, J 4.8 Hz, 1 H), 3.60 (m, 1 H), 1.11 (d, J= 7.2 Hz, 3H).
A mixture of compound from the previous step (500 mg, 3.33 , mmol) and 1-chloromethyl-4-methoxybenzene (156 mg, 1.0 mmol) in acetonitrile was heated to reflux overnight together with K2C03 (207 mg, 1.5 mmol) and KI (250 mg, 1.5 mmol) under N2 atmosphere. After cooling, the salt was filtered off and the filtrate was purified by column to afford 2-(4-methoxybenzyl)-(S)-4-methyl-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one as a white solid (200 mg), which was used without further purification.
Example 160.
N~
H N H H
O N ~ ~~ \ \
~
NOI~
---. . _ ~,.. _ -- ---- --- To a solution of Example EE (100 mg, 0.37 mmol) in.
anhydrous DMF (3 mL) was added NaH (18 mg, 0.44 mmol) at 0 C. After stirring for 0.5h at 0 C, a solution of Example E (160 mg, 0.37 mmol) in anhydrous DMF (3 mL) was added to the reaction mixture,.which was_stirred overnight at RT and subsequently concentrated under reduced pressure to yield a-crude solid which was used- without further purification.
A solution of the crude material from the previous reaction (60 mg, 0.090 mmol ) in trifluoroacetic acid (3 mL ) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative HPLC to afford 1-{5-t-butyl-2-[3-((S)-3-methyl-1, 1,4-trioxo- 1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3 -yl } -3-naphthal-en-1-yl-urea as white power (45 mg). 'H NMR (DMSO-d6): 9.04 (s, 1H), 8.87 (s, 1H), 8.02 (d, J= 8.0 Hz, 1 H), 7.89 (d, J= 7.2 Hz, 2 H), 7.62 (d, J= 8.0 Hz, 2 H), 7.41-7.52 (m, 6 H), 6.40 (s, I H), 4.31-4.49 (dd, J= 8.0 Hz, 2 H), 4.03 (q, J= 6.8 Hz, I
H), 1.27 (s, 9 H), 1.17 (d, J= 8'.0 Hz, 3 H). MS (ESI) m/z: 547 (M+H+).
Example FF
HN'S N \ / OMe )-0 2-(4-methoxy-benzyl)-(R)-4-methyl-1,1-dioxo-1 X6-[ 1,2,5]thiadiazolidin-3-one was prepared from D-alanine ethyl ester using the same procedure as Example EE.
Example 161 O
N ~ N~N
N O ~N H H
O
O
To a solution of Example FF (60 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added NaH (11mg, 0.27 mmol) at 0 C. After stirring for 0.5h at 0 C, a solution of Example D (100 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added to the.reaction mixture, which was stirred overnight at RT. The crude reaction mixture was concentrated unjder reduced pressure and the residue by purified through preparative HPLC
to yield 1-(5-t-butyl-2- { 3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1 k 6-[
1,2,5]-thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-y1)-3-naphthalene-l-yl-urea (20 mg ).
'H NMR (DMSO-d6): 8.98 (s, 1H), 8.81 (s, IH), 8.00 (d, J = 8.0 Hz, 1 H), 7.90 (d, J
7.2 Hz,2 H), 7.62(s, 2 H), 7.51-7.55 (m, 6H), 7.44 (d, J= 7.6 Hz, 2 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.86 (d, J= 8.8 Hz, 2 H), 6.40 (s, 1H), 4.57-4.62 (dd, J= 8.0 Hz, 4 H), 4.53 (q;
J= 7.6 Hz, I H), 3.71 (s, 3H), 1.30 (d, J= 8.0 Hz, 3 H), 1.27 (s, 9 H). MS
(ESI) m/z: 653 (M+H+).
A solution of 1-(5-t-Butyl-2-{3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1X6-[1,2,5]- thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea (20 mg, 0.030 mmol) in trifluoroacetic acid (2 mL) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative-HPLC to afford 1-{5-t-butyl-2-[3-((R)-3-methyl-1,1,4-trioxo-1,6-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3- naphthalen-1-yl-urea 'as a white power (6 mg). 1H NMR (D1vISO-d6):
8.99 (s, 1 H), 8.80 (s, 1 H), 8.00 (d, J= 7.2 Hz, I H), 7.90 (d, J= 7.2 Hz, 2 H), 7.60-7.64 (m, 2 H), 7.44-7.54 (m, 7 H), 6.41 (s, I H), 4.31-4.49 (dd, J= 8.0 Hz, 2 H), 4.03 (q, J=
7.6 Hz, 1 H), 1.27 (s, 9 H), 1.19 (d, J 8.0 Hz, 3 H). MS (ESI) m/z: 533 (M+H).
Example 162 O
~ F
'k I
O N~N H H ~
HN~ ~
O S1 N I ~
O
To a solution of Example CC (0.263 g, 1.0 mmol) in THF (2.0 mL) was added a solution of 1-fluoro-4-isocyanato-benzene (0.114 mL, 1.10 mrnol) in THF (5.0 mL) at 0 C. The mixture was stirred at RT for 1 h then heated until all solids were dissolved. The mixture was stirred at RT for 3 h and poured into water (20 mL). The resulting precipitate was filtered, washed with diluted HCI and H20, dried under reduced pressure to yield 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-urea (400 mg) as a white power. 'H NMR (DMSO-d6): 8.99 (s, 1H), 8.38 (s, 1H), 7.59 (s, IH), 7.44-7.51 (m, 3H), 7.38-7.40 (m, 2H), 7.08 (t, J= 8.8 Hz, 2H), 6.34 (s, IH), 4.83 -(s; 2H),-1:26-(s5-9H): MS-(ESI)-m/z: .401-(M_+..I-T+-).
To a solution of 2-(4-methoxy-benzyl)-1,1=diox6-lX6=[17,2;5]thiadiazolidin-3-one (64 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added NaH (11mg, 0.27 mmol) at C. After stirred for 0.5h at 0 C, a solution of 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3- (4-fluoro-phenyl)-urea from the previous reaxtion (100 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added to the reaction mixture, then was stirred ovemight at RT. The crude was purified through prepared-HPLC to yield 1-(5-t-butyl-2-{ 3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3-(4-fluoro- phenyl)-urea (45 mg ). 1H NMR (DMSO-d6): 8.95 (s, IH), 8.37 (s, IH), 7.50-7.54 (m, 3H), 7.36-7.41 (m, 3H), 7.25 (d, J= 8.8 Hz, 2H), 7.07 (t, J
8.8 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 6.35 (s, 1H), 4.64 (s, 2H), 4.47 (s, 2H), 4.19 (s, 2H), 3.75 (s, 3H), 1.26 (s, 9H). _MS (ESI) m/z: 515 (M+H*).
ioxo-l~6-A solution of 1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-tr [1,2,5]thiadia- zolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea (40 mg, 0.060 mmol) in trifluoroacetic acid (3 mL ) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative HPLC to afford 1-{ 5-t-butyl-2-[3-(3-(R)-methyl-1,1,4-trioxo-1 k 6-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea as a white power (12 mg). IH NMR (DMSO-d6):
8.98 (s, I H), 8.39 (s, 1 H), 7.37-7.51 (m, 6 H), 7.07 (t, J= 8.8 Hz, 2 H), 6.35 (s, I H), 4.21 (s, 2 H), 3.88 (s, 2 H), 1.26 (s, 9 H). MS (ESI) m/z: 501 (M+H+).
Example GG
N'~~CI
To a stirred suspension of K2CO3 (5.5 g, 40 nunol) and 1-bromo-3-chloro-propane (3.78 g, 24 mmol) in acetonitrile (lOmL) was added a solution of N-methyl piperazine (2.0 g, 20 mmol) in acetonitrile (lOmL) dropwise at RT. After the addition was completed, the reaction mixture was stirred for 3 h then filtered. The filtrate was concentrated and dissolved in -CHZC12, washed with brine, dried (NaSO4) and filtered.
After removal of the solvent; -the -residue 'was dissolved in ether. To the above solution was added the solution of HCl and filtered to afford the desired product (2.3g, 65.7%). 1H
NMR (D20): 3.61 (t, J = 6.0 Hz, 2H), 3.59 (br, 8H), 3.31 (t, J= 8.0 Hz, 2H), 2.92 (s, 3H), 2.15 (m, 2H).
Example 163 O
N/ N
N H H
N
To a solution of Example 41 (100 mg, 0.25 mmol) in acetonitrile (lOmL) was added Example GG (75 mg, 0.30 mmol) and K2C03 (172 mg, 1.25 mmol). The resulting mixture was stirred at 45 C for 3 h before filtered. After the filtrate was concentrated, the residue was purified by preparative TLC to afford 1-(5-t-Butyl-2-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl }-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea (31mg, 23 %). 'H-NMR (CD3OD): 7.93 (m, 1H), 7.88 (m, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.66 (d, J
= 7.6 Hz, 1 H), 7.43-7.50 (m, 4H), 7.14 (m, 2H), 7.05 (m, 1 H), 6.43 (s, 1 H), 4.10 (t, J =
6.0 Hz, 2H), 3.09-3.15 (br, 4H), 2.74-2.86(br, 6H), 2.72 (s, 3H), 1.99 (t, J=
6.8 Hz, 2H), 1.35 (s, 9H). MS (ESI) m/z: 541 (M+H+).
Example HH
O NH
>r--kA OEt Intermediate HH was synthesized according to literature procedures starting from 4,4-dimethyl-3-oxo-pentanenitrile (10 mmole) in absolute ethanol and HCl in quantitative afford.
Example II
O
O N O
~ ~ .
OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2Cl2 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 1-napthylchloroformate is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for I h.
The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-naphthalen-l-yl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 164 \ II I
N, N NJ~,O
H I
O
OEt Example II (10 mmol) is dissolved in absolute EtOH (50 mL) at RT and Example Y (10.5 nimol) is added dropwise over 5 min. The reaction mixture is stirred for 30 min at RT, poured in water (100 mL) and ethyl acetate (100 mL). After shaking, the organic layer is washed with 5% HCI, water, dried (MgSO4) and concentrated 'to afford naphthyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 165 N O
H
O
OH
A solution of Example 164 (0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) is stirred at RT overnight. The reaction mixture is neutralized to pH = 4, extracted with ethyl acetate (3x20 mL), the combined organic extracts are washed with bri ne, dried (NaSO4) and filtered. The filtrate is concentrated to afford 1-napthyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example JJ
O
O N)~ O
OEt Example JJ is synthesized utilizing Example HH and 2-napthylchloroformate according to the procedure described for Example II to afford (Z)-naphthalen-2-y1-1-ethoxy-4,4-dimethyl-3 -oxopentyli denecarbamate.
Example 166 O
N, N H 0 /
O
yfl \
OEt Example 166 is synthesized utilizing Example Y and Example JJ according to the procedure described for Example 79 to afford 2-naphthyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 167 N,N NO
H
OH
Example 167 is synthesized utilizing Example 166 according to the procedure described for Example 165 to afford 2-napthyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example KK
cl 0 ~ \
~
OEt Example KK is synthesized utilizing Example HH and p-chlorophenylchloroformate according to the procedure described for Example II
to afford (Z)-4-chlorophenyl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 168 CI
N/
N H O
O
OEt Example 168 is synthesized utilizing Example Y and Example KK according to the procedure described for Example 164 to afford 4-chlorophenyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 169 CI
N/ ~ O~ I
\ N H
Y~6 O
OH
Example 169 is synthesized utilizing Example 168 according to the procedure described for Example 165 to afford 4-chlorophenyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example LL
OMe OEt Example LL is synthesized utilizing Example HH and p-methoxyphenylchloroformate according to the procedure described for Example II
to afford (Z)-4-methoxyphenyl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 170 COMe N H
OEt Example 170 -is synthesized utilizing Example Y and Example LL according to the procedure described for Example 164 to afford 4-methoxyphenyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 171 OMe O
N~ a ~ ~ ~ N H 0 O
OH
Example 171. is synthesized utilizing Example 170 according to the procedure described for Example 165 to afford 4-methoxyphenyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example MM
O p 0 N O
N
OEt Example MM is synthesized utilizing Example HH and quinolin-8-yl-chloroformate according to the procedure described for Example II to afford (Z)-quinolin-8-yl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate Example 172 N/ N J~
O
H
N
O
OEt Example 172 is synthesized utilizing Example Y and Example MM according to the procedure described for Example 164 to afford quinolin-8-yl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 173 o H
N
OH
Example 173 is synthesized utilizing Example 172 according to the procedure described for Example 165 to afford quinolin-8-yl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 174 OMe N/ \ N~H
N H
OEt Example 174 is synthesized utilizing a mixture of 4-methoxy-l-naphthylamine and Example Z according to the procedure described for Example 147 to afford 3-(3-{3-t-butyl-5-[3-(4-methoxy-l-naphthyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester.
Example 175 OMe N/ N~ H
N H
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 174, 3-(3-{3-t-butyl-5-[3-(4-methoxy-l-naphthtyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid is synthesized.
Example 176 O N/ N N N
H
OEt O
Example 176 is synthesized utilizing a mixture of indoline and Example Z
according to the procedure described for Example 147 to afford ethyl 3-(3-(3-t-butyl-5-(indoline-l-carboxamido)-1 H-pyrazol-l-yl)phenyl)propanoate.
Example 177 O
N/ \ N
N N
H
b OH
O
Utilizing the same synthetic procedure as for Example 146 and starting with Example 173, .3-(3-(3-t-butyl-5-(indoline-l-carboxamido)-1 H-pyrazol-1-yl)phenyl) propionic acid is synthesized.
Example NN
NHNH2.HCI
OEt O
Utilizing the same synthetic procedure as for Example Y and starting with: p-bromo nitrobenzene, 3-(4-hydrazino-phenyl)-propionic acid ethyl ester is synthesized.
Example 178 ~ \ \ I
N" N ~ O
H
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example II (10 mmol) and Example NN (10.5 mmol) are combined to afford 1-naphthyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3 -t-butyl- I H-pyrazol-5-ylcarbamate.
Example 179 N/ )~
\N O
H
Example 179 is synthesized utilizing Example 178 according to the procedure described for Example 165 to afford 1-napthyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 180 p / I \
N NO
H
Et0 O
Utilizing the same synthetic procedure as for Example 164, Example JJ (10 mmol) and Example NN (10.5 mmol) are combined to afford 2-naphthyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 181 O r I \
N, N N~O
H
HO O
Example 181 is synthesized utilizing Example 180 according to the procedure described for Example 165 to afford 2-napthyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 182 232.
cl N/ \ l~ \ I
~N H
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example KK (10 mmol) and Example NN (10.5 mmol) are combined to afford p-chlorophenyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 183 cl N \
N J,O\ I
H
~
HO O
Example 183 is synthesized utilizing Example 182 according to the procedure described for Example 165 to afford 4-chlorophenyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 184 OMe N, \ ~ ~ I
, N H O
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example LL (10 mmol) and Example NN (10.5 mmol) are combined to afford p-methoxyphenyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 185 OMe N/ ~ ~
.N H O
Example 185 is synthesized utilizing Example 184 according to the procedure described for Example 165 to afford p-methoxyphenyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 00 . ~
O
O
OEt Ethyl bromoacetate is reacted with meta-nitrophenol under standard conditions to afford ethyl 2-(3-nitrophenoxy)acetate, which is elaborated to ethyl 2-(3-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Example PP
O
O N N
OEt Example HH and 1-naphthylisocyanate are combined utilizing the same synthetic procedure as for Example II to afford (Z)-1-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-3-(naphthalen-l-yl)urea.
Example 186 O
N, N NN
" "
O \
~ /
O- - -OEt Utilizing the same synthetic procedure as for Example 164, Example PP (10 mmol) and Example 00 (10.5 mmol) are combined to afford 3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid ethyl ester.
Example 187 N/ \ ~ \ I
\N H H
O
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 186, 3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid is synthesized.
Example QQ
cl O
O N N
H
OEt Example HH and 4-chlorophenylisocyanate are combined utilizing the same synthetic procedure as for Example II to afford (Z)-1-(4-chlorophenyl)-3-(1-ethoxy-4,4-dimethyl-3 -oxopentyl idene)urea Example 188 cl N~ ~ O
N N"'r \N H
H
Oi - - ~
OEt Utilizing the same synthetic procedure as for Example 164, Example QQ (10 mmol) and Example 00 (10.5 nunol) are combined to afford 3-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 189 CI
N H H \ I
O
O
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 188, 3-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid is synthesized.
Example RR
~ OEt O---~O
Ethyl bromoacetate is reacted with para-nitrophenol under standard conditions to afford ethyl 2-(4-nitrophenoxy)acetate, which is elaborated . to ethyl 2-(4-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Example 190 N/ \ ~ \ I
\N H H
O
O OEt Utilizing the same synthetic procedure as for Example 164, Example PP (10 mmol) and Example RR (10.5 mmol) are combined to afford 4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 191 N
" N H H
\ \ -O
~
O OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 190, 4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid is synthesized.
Example 192 cl N \
N J, H\ I
\
H
O
O OEt )--, Utilizing the same synthetic procedure as for Example 164, Example QQ (10 mmol) and Example RR (10.5 mmol) are combined to afford 4-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 193 cl N/ \ , \ ( ~N H H
O
O OH
)--Utilizing the same synthetic procedure as for Example 146 and starting with Example 192, 4-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid is synthesized.
Example DD
~OSO
N 'NH
O~J
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 mmol) in (20 mL) at 0 C was. added 2-methyl-propan-2-ol (0.74 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of glycine ethyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in CH2C12 (20 mL) was added at such a rate that the reaction temperature didn't rise above C. When the addition was completed, the solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCl and extracted with CH2C12.
The organic layer was washed with saturated NaCI, dried (Mg2SO4) and filtered.
After removal of the solvent, the crude product was washed with CH2ClZ to afford ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85 %). IH-NMR(DMSO): S 10.85 (s, 1 H), 8.04 (t, J= 6.0 Hz, 1 H), 4.07 (q, J= 5.6 Hz, 2H), 3.77 (d, J= 6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J 7.2 Hz, 3H).
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amirio)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF
dropwise at 0 C under N2 atmosphere. The mixture is stirred at 0 C for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
To a solution of HCl in methanol (2 M) is added ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate from the previous step (5.0 mmol) in portions at RT
and the mixture is stirred for 3 h. After the solvent is removed in vacuo, the residue is washed with diethyl ether to afford ethyl 2-((N-methylsulfamoyl)amino)acetate To a solution of ethyl 2-((N-methylsulfamoyl)amino)acetate from the previous step (3.5 mmol) in DMF (50 mL) is added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 at RT. The mixture is stirred overnight then quenched with HCl/
methanol (2 M). After the solvent is removed in vacuo, the residue is washed with water to afford 2-methyl-l,l-dioxo-lk6-[1,2,5]thiadiazolidin-3-one (480 mg, 54 %). 'H-NMR(CDC13): S
7.36 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.87 (m, 1 H), 4.68 (s, 2H), 4.03 (d, J=
7.2 Hz, 2H), 3.80 (s, 3H).
Example 194 'J~
N- S'O
N
Example E and Example 00 are combined utilizing the procedure for Example 160 to afford 1-(5-t-butyl-2-{3-[5-methyl-1,1,4-trioxo-lX 6-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3-naphthyl-urea.
Example 195 O
N~ \ N XN
N H
H
CO2Et To a solution of Example X (2.9 g, 10 mmol) in THF (50 mL) was added a solution of 1-naphthyl isocyanate (1.7 g, 10 mmol) in THF (20 mL) at 0 C. The mixture was stirred at RT for 1 h and heated until all solids dissolved. The mixture was then stirred at RT for 3 h and poured into water (200 mL). The precipitate was filtered, washed with diluted HCI and H20, dried under vacuum to give 4.3 g of 4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol- 1-yl]-benzoic acid ethyl ester, which was used without further purification.
Example 196 O
N~ N XN' N H
H
OH
To a solution of Example B (228 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 solution and aqueous HCl solution (10%), extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent removed iri vacuo and the residue purified by column chromatography to afford 1-{5-t-butyl-2-[3-(1-hydroxy-l-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea (150 mg, 67 %). 'H NMR
(DMSO-d6): 9.00 (s, 114), 8.75 (s, I H), 7.98 (d, J = 7.6 Hz, I H), 7.92-7.89 (m, 2 H), 7.65-7.62 (m, 2 H), 7.52-7.44 (m, 5 H), 7.37 (d, J= 6.8 Hz, 1 H), 6.39 (s, I
H), 5.13 (s, 1 H), 1.45 (s, 6 H), 1.27 (s, 9 H); MS (ESI) m/z: 443 (M+H+).
Example 197 CI
O
N/ N H
N H
I \ -.
OH
To a solution of Example C (220 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for I h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 and aqueous HCl solution (10 %), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography to afford 1-{5-t-butyl-2-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]- 2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea (174 mg, 81 %). IH
NMR (DMSO-d6): 9.11 (s, 1 H), 8.34 (s, I H), 7.59 (s, 1H), 7.46 (t, J = 8.8 Hz, 1 H), 7.43-7.40 (m, 3 H), 7.31-7.28 (m, 3 H), 6.34 (s, I H), 5.13 (s, 1 H), 1.42 (s, 6H), 1.27 (s, 9 H); MS (ESI) m/z: 428 (M+H+).
Example 198 O ~ I
N/ N H
N H
HO
To a solution of Example 195 (228 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methylmagnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 and aqueous HCl solution (10%), extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent was removed in vacuo and the residue purified by column chromatography to afford 1-{5-t-butyl-2-[4-(1-hydroxy-l-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea (180 mg, 81 %). 'H NMR
(DMSO-d6): 9.06 (s, 1 H), 8.83 (s, 1 H), 7.99 (d, J 8.0 Hz, 1 H),. 7.92 (t, J
= 8.0 Hz, 2H), 7.64-7.61'(m, 3H), 7.55-7.43 (m, 5H), 6.40 (s, 1H), 5.13 (s, IH), 1.47 (s, 6H), 1.27 (s, 9 H); MS (ESI) mJz: 443 (M+H+).
Example 199 CI
o N/ H
N H
HO
To a solution of Example 57 (220 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4Cl and aqueous HCl solution (10 %), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent removed in vacuo and the residue was purified by column chromatography to afford 1-{5-t-butyl-2-[4-(1-hydroxy-l-methyl-ethyl)-phenyl]- 2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea (187 mg, 87 %). 'H-_NMR (CDC13): 9.14 (s, 1 H), 8.42 (s, 1 H), 7.58 (d, J= 8.4 Hz, 2 H), 7.42 (d, J= 5.6 Hz, 2 H), 7.40 (d, J= 4.8 Hz, 2 H), 7.29 (d, J= 8.8 Hz, H), 6.34 (s, 1 H), 5.11 (s, 1 H), 1.44 (s, 6 H), 1.25 (s, 9 H); MS (ESI) m/z: 427 (M+H+).
Example PP
~ Br To a solution of 3-bromo-phenylamine (17 g, 0.1 mol) in concentrated HCl (200 mL) was added an aqueous solution (20 mL) of NaNO2 (7 g, 0.1 mol) at 0 C and the resulting mixture was stirred for 1 h. A solution of SnC1Z.2HZ0 (45 g, 0.2 mmol) in concentrated HCI (500 mL) was then added at 0 C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give (3-bromo-phenyl)-hydrazine as a white solid, which was used for the next reaction without further purification Example QQ
t-Bu ~
N
Br A mixture of Example PP (22.2 g, 0.1 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (18.7 g, 0.15 mol) in ethanol (250 mL) was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue purified by column chromatography to afford 2-(3-bromo-phenyl)-5-t-butyl-2H-pyrazol-3-ylamine as a white solid. 'H NMR (DMSO-d6): 7.85 (s, 1H), 7.68 (d, J =7.6 Hz, 1H), 7.62 (d, J
=7.2 Hz, IH), 7.50 (t, J =8.0 Hz, 1 H), 5.62 (s, 1 H), 1.27 (s, 9H).
---Example-RR--t-Bu /~
N~ NH2 N
( \ -/ COOEt To a mixture of Example QQ (2.94 g, 10 mmol), Pd(OAc)2 (1 mmol), PPh3 (20 mmol), and K2CO3 ( 20 mmol) in MeCN (50 mL) was added 2-methyl-acrylic acid ethyl ester (20 mmol). The resulting mixture was heated to reflux overnight, filtered, concentrated, and the residue was purified by column chromatography to afford 1.2 g of 3-[3-(5-Amino-3-t-butyl-pyrazol-1-yl)-phenyl]- 2-methyl-acrylic acid ethyl ester. 'H
NMR (CDC13): 7.41 (s, IH), 7.40-7.36 (m, 2H), 7.15 (d, J = 6.8 Hz, 1 H), 6.24 (s, 1H), 5.51 (s, 1H), 4.27 (q, J= 7.2 Hz, 2H), 2.12 (s, 3H), 1.33 (s, 9H), 1.27 (t, J
7.2 Hz, 3H).
Example SS
t-Bu N~
6 COOEt A mixture of Example RR (1.2 g,) and Pd / C (120 mg, 10 %) in methanol (50 mL) was stirred under 40 psi of H2 at RT overnight, filtered. And concentrated to afford 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-2-methyl-propionic acid ethyl ester as a racemate (1.1 g), which was used for the next reaction without further purification.
Example 200 .t-Bu O
N \ NXN
N H
I \
~ COOEt To a solution of Example SS (100 mg, 0.3 mmol) and Et3N (60 mg, 0.6 mmol) in CH2CI2 (10 mL) was added 1-isocyanato-naphthalene (77 mg, 0.45 mmol). The resulting mixture was stirred at RT overnight, added to water (50 mL), extracted with (3x30 mL) and the combined organic extracted were washed with brine, dried (Na2SO4), and filtered. After concentration under reduced pressure, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester as a racemate (50 mg, 33 %). IH-NMR
(CDC13): 7.99 (s, 1 H), 7.91 (d, J= 8.4 Hz, 1 H), 7.84 (t, J= 7.2 Hz, 2H), 7.67 (d, J= 8.4 Hz, 1 H), 7.49=
7.41 (m, 3H), 7.35-7.33 (m, 3H), 7.21 (s, 1H), 7.14-7.13 (m, IH), 6.65 (s, IH), 3.98 (q, J
= 6.0 Hz, 2H), 2.92-2.88 (m, 3H), 1.36 (s, 9H), 1.24 (d, J 6.0 Hz, 3H), 1.08 (t, J 7.2 Hz, 3H); MS (ESI) m/z: 499 (M+H~.
Example 201 t-Bu 0 ~LO..
N H
A solution of Example 200 (17 mg, mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT over night. The reaction mixture was adjusted to pH = 4, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After the filtrate was concentrated, the residue was purified by preparative-TLC to afford 3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-l-yl]-phenyl}-2-methyl-propionic acid as a racemate (15 mg, 92 %). 'H
NMR
(DMSO): 11.81 (br s, 1 H), 9.58 (s, 1 H), 8.56 (s, 1 H), 7.95 (d, J= 7.6 Hz, 1 H), 7.82 (d, J
= 8.4 Hz, IH), 7.55 (d, J= 7.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.28 (d, J= 8.0 Hz, 1H), 7.14 .(t, J= 7.6 Hz, 1 H), 6.52 (s, 1 H), 3.77 (m, 1 H), 2.65 (m, 1 H), 2.36 (m, 1 H), 1.27 (s, 9H), 1.00 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 471 (M+H+).
Example 202 CI
t-Bu H H
COOEt To a solution of Example SS (100 mg, 0.3 mmol) and Et3N (60 mg, 0.6 mmol) in CH2C12 (10 mL) was added 1-chloro-4-isocyanato-benzene (77 mg, 0.45 mmol). The resulting mixture was stirred at RT overnight, and then added to water (50 mL). The solution was extracted with CH2C12 (3x30 mL) and the combined organic extracts were washed with brine, dried (Na2SO4),and filtered. After concentration under reduced pressure, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl }-phenyl)-2-methyl- propionic acid ethyl ester as a racemate (51 mg, 35 %). 'H-NMR (CDC13): 8.20 (s, 1 H), 7.39 (d, J= 4.4 Hz, 2H), 7.37 (d, J= 8.8 Hz, 2H), 7.21 (t, J= 8.4 Hz, 2H), 7.14-7.11 (m, 2H), 6.59 (s, 1 H), 4.04-3.99 (m, 2H), 3.00 (m, 1 H), 2.93 (m, 1 H), 2.83 (m, 1 H), 1.34 (s, 9H), 1.17 (d, J
6.4 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 483 (M+H+).
Example 203 CI
t-Bu rN H
N' H
A solution of Example 202 (15 mg, mmol) and 2N LiOH (3 rnL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was adjusted to pH = 4, extracted with ethyl acetate (3x20 mL), the combined organic extracts were washed with brine, dried (NaZSO4),and filtered. After the filtrate was concentrated, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)- uxeido]-pyrazol-l-yl}-phenyl)-2-methyl-propionic acid as a racemate (13 mg, 90%). 'H NMR (DMSO):
12.48 (br s, IH), 9.35 (br s, 1 H), 7.55 (d, J= 8.8 Hz, IH), 7.34-7.32 (m, 2H), 7.26 (d, J=
8.4 Hz, 1 H); 7.24 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1 H), 6.45 (s, 1 H), 2.74 (m, 1 H), 2.65 (m, 1 H), 2.31 (m, 2H), 1.26 (s, 9H), 0.99 (d, J= 6.8 Hz, 3H); MS
(ESI) m/z:
455 (M+H+).
Example 204 O ~ I
N~ N N
N H
HO
To a stirred solution of Example 195 (500 mg, 0.83 mmol) iri THF (10 mL) was added LiAlH4 powder (65 mg, 1.66 mmol) in portion at 0 C under N2. The mixture was stirred for 2 h at RT, excess LiA1H4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH = 7 with dilute HCI. After the solvent was removed, the residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After concentration in vacuo, the crude product was purified by preparative-TLC to afford 1-[2-(4-hydroxymethyl-phenyl)- 5-isopropyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (415 mg, 92 %). 'H NMR (DMSO-d6): 9.04 (s, 1 H), 8.78 (s, 1 H), 7.98 (d, J= 8.0 Hz, I H), 7.90 (d, J= 7.2 Hz, 2H), 7.63 (d, J= 8.4 Hz, I H), 7.55-7.42 (m, 7 H), 6.39 (s, 1 H), 5.30 (t, J 5.6 Hz, 1 H), 4.56 (d, J 5.6 Hz, 2 H), 1.27 (s, 9 H); MS (ESI) m/z: 415 (M+H+).
Example 205 >o=
N/ /~_ N
N H H
O
To a solution of Example 204 (200 mg) in CH2C12 (50 mL) was added Mn02 (450 mg) at RT. The suspension was stirred for 2 h then filtered through celite.
The filtrate was concentrated under reduced pressure to afford 150 mg of 1-[5-t-butyl-2-(4-formyl=
phenyl)-2H-pyrazol-3-yl]-3-naphthalen-1-yl- urea, which was used without further purification.
Example 206 O
N/ N H
N H
\ .
To a solution of (trifluoromethyl)trimethylsilane (77 mg) and TBAF (10 mg) in THF (10 mL) was added Example 205 (150 mg) in THF (10 mL) under N2 atmosphere in ice-bath. The resulting mixture was stirred at 0 C for 1 h and then warmed to RT for an additional hour. To the reaction was then added 0.5 mL of 3 N HCL, which was then stirred at RT overnight. After removal the solvent, the residue was dissolved in CHZCIZ
(50 mL). The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by preparative-TLC to afford the final product 1-{5-t-Butyl-2-[4-(2,2,2-trifluoro-l-hydroxy- ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea ( 110 mg, 63 %). 'H NMR (DMSO-d6): 9.07 (s, IH), 8.89 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.90 (d, J 7.6 Hz, 2H), 7.67-7.62 (m, 5H), 7.55-7.51 (m, 2H), 7.44 (t, J= 8.0 Hz, 1 H), 6.95 (d, J 6.0 Hz, 1 H), 6.42 (s, 1 H), 5.27 (m, 1 H), 1.28 (s, 9H). MS (ESI) m/z: 483 (M+H+).
Example 207 CI
O
N/ \ N~ N
N H
H
HO
To a stirred solution of Example 57 (500 mg, 1.1 mmol) in THF (10 inL) was added LiA1H4 powder (65 mg, 1.66 mmol) in portion at 0 C under N2. The mixture was stirred for 2 h at RT, excess LiA1H4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH = 7 with diluted HCI. After the solvent removal, the residue was extracted with ethyl acetate, and the combined organic extracts were washed with brine, d dried (Na2SO4), and filtered, After solvent removal, the crude product was purified by preparative TLC to 1-[5-t-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea (380 mg, 92%) as a white powder. 'H-NMR (CDC13):
8.17 (br s, I H), 7.22 (s, 4 H), 7.17 (d, J= 8.0 Hz, 2 H), 7.09 (d, J= 8.0 Hz, 2 H), 7.04 (s, H), 6.38 (s, 1 H), 4.51 (s, 1 H), 1.22 (s, 9 H); MS (ESI) m/z: 399 (M+H+).
Example 208 CI
O
N/ N H
N H
O
To a solution of Example 207 (200 mg) in CH2C12 (50 mL) was added Mn02 (450 mg) at RT. The suspension was stirred for 2 h, then filtered through celite.
The filtrate was concentrated to afford 160 mg of 1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea, which was used without further purification.
Example 209 CI
O
N/ \ NX N
N H
H
To a solution of (trifluoromethyl)trimethylsilane (86 mg) and TBAF (10 mg) in THF (10 mL) was added Example 208 (160 mg) in THF (20 mL) under N2 atmosphere in ice-bath. The resulting mixture was stirred at 0 C for 1 h and then warmed to RT for an additional hour. To the reaction was added 0.5 mL of 3 N HCI, which was then stirred at RT overnight. After removal of the solvent, the residue was dissolved in CH2CI2 (100 mL). The organic extracts were washed with saturated NaHCO3 and brine, dried (Na2SO4), and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by preparative-TLC to afford the final product 1-{5-t-butyl-2-[4-(2,2,2-trifluoro-l- hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea ( 120 mg, 64 %). 'H-NMR (DMSO-d6): 9.15(s, 1H), 8.50 (s, IH), 7.61 (d, J = 8.4 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 8.8 Hz, 2 H), 7.28 (d, J= 8.8 Hz, 2 H), 6.91 (d, J= 5.6 Hz, 1 H), 6.36 (s, 1 H), 5.25 (m, IH), 1.26 (s, 9 H); MS (ESI) m/z: 467 (M+H+).
Example 210 O
N~
N
H
OH
O
A solution of Example 151 (42 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT over night. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid (30 mg, 76%). 8.45 (d, 4.0 Hz, 1 H), 8.24 (d, 8.0 Hz, 1 H), 7.92 (s, 1 H), 7.88 (t, 7.6 Hz, 1 H), 7.67 (d, 8.0 Hz, I H), 7.36 (t, 5.6 Hz, 1 H), 7.23 (t, 7.6 Hz, 1 H), 6.96 (d, 6.8 Hz, 1 H), 6.67 (s , 111), 2.77 (t, 7.6 Hz; 2H), 2.22 (t, 7.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z:
393 (M+H+).
Example 211 J, N H H I
OyNH
C;) Example I is reacted with CDI and N-methyl piperazine using the procedure for Example 145 to afford the title compound.
Example 212 ' CI
H ~
N\
N H \
OyNH
CN) N
Example J is reacted with CDI and N-methyl piperazine using the procedure for Example 145 to afford the title.compound.
Example 213 N~ ~ J1, 1 N H H
OyNH
N
Example I is reacted with CDI and piperdine using the procedure for Example 145 to afford the title compound.
Example 214 N
\N H H
\ \
. ~ /
Oy NH
CN
O
Example I is 'reacted with CDI and morpholine using the procedure for Example 145 to afford the title compound.
Example 215 N/ ~
\N H N H
Oy NH
U
Example I is reacted with CDI and pyrrolidine using the procedure for Example 145 to afford the title compound.
Example 216 N~, ~ J~ \ 4 N H H
Oy NH
Example I is reacted with CDI and dimethylamine using the, procedure for Example 145 to afford the title compound.
Example 217 O /
H CI
N/ \ J~ \ I
N H
O\ /NH
~N"
Example J is reacted with CDI and piperdine using the procedure for Example 145 to afford the title compound.
Example 218 O / CI
N\~ J~ ~~
N H H
Oy NH
CN
O
Example J is reacted with CDI and morpholine using the procedure for Example 145 to afford the title compound.
Example 219 CI
N H H
Oy NH
U
Example J is reacted with CDI and pyrrolidine using the procedure for Example 145 to afford the title compound.
Example 220 / CI
O
N \ J~ \ I.
\N H H
O\ /NH
Example J is reacted with CDI and dimethylamine using the. procedure for Example 145 to afford the title compound.
Example 221 O N/
~
N,N H 1 /
O
~..
Isoquinoline-8-carboxylic acid and Example Z are reacted using the procedure for Example 149 to afford ethyl 3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)-1H-pyrazol-l-, yl)phenyl)propanoate.
Example 222 N/
N/
.N H
/ I
~ OH
O
Example 222 is reacted using the procedure for Example 150 to afford 3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)- I H-pyrazol-1-yl)phenyl)propanoic acid.
Example 223 O
N N~N
H H I
OEt Example E is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 224 N ~ I
.N ~ NN
H H
O
p OH
Example 224 is reacted using the procedure for Example 150 to afford 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-l-yl)benzyl)-2-methylpropanoic acid Example 225 / CI
\ I
N H N H
O
OEt Example G is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 226 CI
N/ \ 'J~ \ I
N H H N
p O
OH
Example 226 is reacted using the procedure for Example 150 to afford 2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-1-yl)benzyl)-2-methylpropanoic acid.
Example TT
O
N~ ~ XN
N H H ' /
CI
Example 204 is reacted using the procedure for Example E to afford 1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea Example UU
CI
O
NN H H
CI
Example 122 is reacted using the procedure for Example G to afford 1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 227 /
N ~ J, I
'N H H
I / .
O OEt Example TT is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(4-(3-t-butyl-5-(3-(naphthalen=1-yl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 228 O
N \
~N N~N
H H
OH
Example 227 is reacted using the procedure for Example 150 to afford 2-(4-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol- I -yl)benzyl)-2-methylpropanoic acid.
Example 229 CI
N
~ N ~ H<) H
OEt Example UU is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate Example 230 O / CI
N/ ~ I
\N H H
OH
Example 144 is reacted using the procedure for Example 150 to afford 2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-l-yl)benzyl)-2-methylpropanoic acid.
Example VV
~ ~/CI
N
NJ
N-methyl piperazine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-methylpiperazine hydrochloride.
Example WW
~ ~/CI
r N
OJ
Morpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 4-(2-chloroethyl)morpholine ~..
Example XX
NCI
OJ
Morpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 4-(3-chloropropyl)morpholine.
Example Yl' ~~CI
OH
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-methylpiperidin-4-ol.
Example ZZ
CI
OH
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 1-(3-chloropropyl)-4-methylpiperidin-4-ol.
Example AAA
N
O =SJ
A solution of 4,4-dioxothiomorpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 4-(2-chloroethyl)-4,4-dioxo-4-thiomorpholine.
Example BBB
O =S
A solution of 4,4-dioxothiomorpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 4-(3-chloropropyll)-4,4-dioxo-4-thiomorpholine.
Example CCC
~~CI
OH
A solution of 4-(trifluoromethyl)piperidin-4-ol and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-(trifluoromethyl)piperidin-4-ol.
Example DDD
N--~CI
OH
A solution of 4-(trifluoromethyl)piperidin-4-oI and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 1-(3-chloropropyll)-4-(tri fluoromethyl)piperidin-4-ol.
Example 231 N/ \ J~ \ ( \N H H
I \
O ~
N
Example 4.1 and Example WW are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-morpholinoethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen- I -yl)urea.
Example 232 N/ \ ~ \ I
,N H H
O
O
Example 41 and Example XX are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-morpholinopropoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-(naphthalen-l-yl)urea.
Example 233 N H H
\
~ /
O
(N) N
Example 41 and Example VV are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3 -(naphthalen-l-yl)urea.
Example 234 O
N H I \ \
/
N O
ONH
Example CC, 2-naphthoic acid chloride and Example DD were combined utilizing the same general approach for Example 162 to yield N-(3-tert-butyl-l-(3-([5-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]phenyl)-1 H-pyrazol-5-yl)-naphthamide. 'H-NMR (DMSO-d6): 10.50 (s, 1H), 8.45 (s, 1H), 8.15-8.05 (m, 3H), 7.90 (s, 1 H), 7.60 (t, J= 7.2 Hz, 3H), 7.45 (s, 1 H), 7.3 8(t, J= 8.0 Hz, 1 H), 7.27 (d, J= 7.2 Hz, 1 H), 6.44 (s, 1 H), 4.05 (s, 2H), 1.31 (s, 9H). MS (ESI) m/z: 518 (M+H+).
Example 235 N H H
Ob N
C~
oso Example 41 and Example AAA are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)ethoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 236 ~ \ ~ \I
N
\N H H
O \
~ /
~ O
O
Example 41 and Example BBB are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)propoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3 -(naphthalen-1-yl)urea.
Example 237 N H H
O ~
~ /
N
OH
Example 41 and Example YY are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-methylpiperidin-4-ol)ethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 238 N H H
O
OH
Example 41 and Example ZZ are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-(4-methylpiperidin-4-ol-)propoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 239 II
N NN
H H
~ \
O /
Example 41 and Example CCC are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-(trifluoromethyl)piperidin-4-ol)ethoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 240 r \ O
N~N N'J~N
H H
\
~ j O
v _N
OH
Example 41 and Example DDD are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-(4-(trifluoromethyl)piperidin-4-ol)propoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 241 t-Bu 0 N \ XN
N H H
Example D is reacted using the procedure for Example 205 to afford 1-(3-t-butyl-1-(3-formylphenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 242 N/ \ ~ ~ I
~N H H I
OH
Example 242 is reacted using the procedure for Example 206 to afford 1-(3=t-butyl-l-(3-(2,2,2-trifluoro-l-hydroxyethyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 243 CI
t-Bu 0 ~
N/ \
N N~ N
H H
Example F is reacted using the procedure for Example 208 to afford 1-(3-t-butyl-1-(3-formylphenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 244 N \ ~C!
~ ~
\N H H
b Y
OH
Example 244 is reacted using the procedure for Example 209 to afford 1-(3-t-butyl-l-(3-(2,2,2-trifluoro-l-hydroxyethyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea Example 245 N~ O
, N N~N
H H
F I ~
F
OH
Example B is saponified using the procedure for Example 150. The resulting acid is reacted with trifluorotriazine in pyridine to afford the acid fluoride which is directly reacted with CsF and TBAF according to literature procedures (see J. Org.
Chem. USSR
(Engl. Transl.), 11, 1975, 315-317) to afford 1-(3-t-butyl-l-(3-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 246 icI
N H H
~ \
F /
F
OH
Example C is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-l-(3-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 247 O
~
N~N NN
H H
F OH
F
Example 205 is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-l-(4-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3 -(naphthalen-l-yl)urea.
Example 248 cl N H H \ I
F OH
F
Example 57 is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-1 -(4-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example EEE
. I \
N
Boc Example EEE (tert-butyl 7-hydrazinyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate) was synthesized according to literature procedures.
Example 249 O
N N~N
H H
Boc,N
Utilizing the same synthetic procedure as for Example 164, Example EEE (10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl 7-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)-3,4-dihydroisoquinoline-2( I H)-carboxylate.
Example 250 CI
N/ \ J~
N H H \ I
P
Boc~N
Utilizing the same synthetic procedure as for Example 164, Example EEE (10 mmol) and Example QQ (10.5 mmol) are combined to afford t-butyl7-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)-3,4-dihydroisoquinoline-2( I H)-carboxylate Example 251 N H H
HN
Example 249 is reacted with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 252 CI
N H H \ I
HN
Example 250 is reacted with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea:
Example 253 N H H
O~N
HN,~ i0 S'O
/N\
Example 251 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[1-N-[[(1-dimethylaminolsulphonyl)amino] carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 254 O / CI
\ I
N H H
O\/N
H~N", i0 S
Example 252 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[1-N-[[(1-dimethylaminolsulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-pyrazol-5-yl)- 3-(4-chloropheny))urea.
Example 255 /. I CI
O
N, N N~N \
H H
O\ /N
H~N",, i0 s 1'O
Example 252, CDI, and methanesulfonamide are reacted under standard conditions to yield 1-(3-t-butyl-l-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1 H-pyrazol-5-yl)- 3-(4-chlorophenyl)urea.
Example 256 N/ J, \N H H
' \ \
O\ /N
O
H~N", //O
s 1'O
Example 251, CDI, and methanesulfonamide are reacted under standard conditions to yield 1-(3-t-butyl-l-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)- 3-(1-naphthyl)urea.
Example FFF
I ~ Boc N
Commercially available 3-nitrobenzoic acid is reacted with methylamine and EDC under standard conditions to afford N-methyl-3-nitrobenzamide, which is reduced with LAH under standard conditions to afford N-methyl(3-nitrophenyl)methanamine, which is protected with benzylchloroformate under standard conditions to yield t-butyl 3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced to yield t-butyl 3-hydrzazinobenzylmethylcarbamate.
Example 257 N~ \ O
N NJN
H H
Boc Utilizing the same synthetic procedure.as for Example 164, Example FFF (10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl 3-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)benzylmethylcarbamate.
Example 258 N/ \ J~ \ I
N H H
,NH
Example 257 is deprotected with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(3-((methylamino)methyl)phenyl)-IH-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 259 N/ \ ~ \ I
\N H H
H
N, S, N D
p p ~\O
Example 258 is reacted with chlorosulfonyl isocyanate then piperdine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinylsulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 260 N. \ O ~ I
N NJN
H H
H
jN,,(Nll S/N
O O \O
Example 258 is reacted with chlorosulfonyl isocyanate then morpholine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-morpholinyl=
sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-I -yl)urea.
Example 261 N/ J~
.N H H
H
N N~ ~N
~ p~0 Example 258 is reacted -with chlorosulfonyl isocyanate then pyrrolidine according to the procedure for Example 7 to afford 1-(3-t-butyl-1-[[3-[[(1-pipeidinyl-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 262 N H H
H
N~N-~ S/N\
Example 258 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-dimethylamino-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 263 O
N H H
\. \
H
Ny N,,S~NH2 Example 258 is reacted with chlorosulfonyl isocyanate then ammonia according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-aminosulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-(naphthalen-l-yl)urea.
Example 264 I~
N NN
H H
~ CN
N N'S/hI 00 Example 258 is reacted with chiorosulfonyl isocyanate then N-methyl piperzine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(N-methylpiperzinyl)sulphonyl)amino] carbonyl]-((methylamino)methyl)phenyl)-114-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 265 N J
N H H
I \ S~O \
H
N,~rNl~ ,N
Example 258 is - reacted-with chlorosulfonyl- isocyanate then- -4,4-dioxo-4-thiomorpholine according to the procedure for Example 7 to afford 1-(3-t-butyl-l.-[[3-[[(1-(4,4-dioxo-4-thiomorpholinyl)sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyraiol-5-yl)-3-(naphthalen-l-yl)urea.
Example 266 H H
\
/
H
N
Cchlorosulfonyl isocyanate, piperdine, then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinylcarbonyl)amino] sulphonyll]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 267 OII
N NN
H H
H O
,-IN~"N~NJ
O Ol 0 Chlorosulfonyl isocyanate, morpholine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-morpholinyl-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 268 N~ \ \ I
N H N ~H
H
,N,S_NyNO
O~~l -Chlorosulfonyl isocyanate, pyrrolidine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinyl-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 269 N H N H ( \
~ /
H
N
,-IO, S' Ny 'O( 0 --Chlorosulfonyl isocyanate, dimethylamine, -then--Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-dimethylamino-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 270 N ~
\N ~ H H
rbH
NNyNHZ
Chlorosulfonyl isocyanate, ammonia and then Example 258 are reacted according to the procedure for Example 7 to afford 1-_(3-t-butyl-l-[[3-[[(1-aminocarbonyl)amino]sulphony]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 271 O
N NN
H H
\
~ / N
H
N ~N~N~
O, II
Chlorosulfonyl isocyanate, N-methyl piperzine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(N-methylpiperzinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 272 N \ ~
\N N N
O
S'O
N" g~N INJ
o~ Il y Chlorosulfonyl isocyanate, 4,4-dioxo-4-thiomorpholine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(4,4-dioxo=4-thiomorpholinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-pyrazol-5-yl)-3-(naphthal en- 1 -yl)urea.
Example GGG
O
I NH
N-i O
Commercially available 3-nitrobenzamide is reduced .with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with 4-methoxybenzylisocyanate to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)urea.
This material is subsequently reacted with oxalyl chloride to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione whose nitro group is reduced and oxidized to -afford-l-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione.
This material is deprotected with TFA under standard conditions to afford the title compound 1-(3-hydrazinylbenzyl)imidazolidine-2,4,5-trione.
Example 273 o N, N N~N
H H I
O N~O
NH
O
Utilizing the same synthetic procedure as for Example 164, Example GGG (10 mmol) and Example PP (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea Example 274 CI
N/ \ J~ \ I
\N H H
O N~O
NH
O
Utilizing the same synthetic procedure as for Example 164, Example GGG (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example HHH
\ O -~~rA
I NH
O
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with N-4-methoxybenzylsulfamic acid and EDC to afford 1-(4-methoxybenzyl)-3-benzylsulfonylurea. This material is reacted with oxalyl chloride to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione whose nitro group is reduced and oxidized to afford 1-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione. This material is deprotected with TFA under standard conditions to afford the title compound 1-(3-hydrazinyl benzyl )imi dazoli dine-2,2-dioxo-2-thi o-4, 5-trione.
Example 275 N/ \ , O N~~O
NHO
O
Utilizing the same synthetic procedure as for Example 164, Example HHH (10 mmol) and Example PP (10.5 nunol) are combined to afford 1-(3-t-butyl-l-(3-((2,2-dioxo-2-thio-4,5--diioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 276 CI
O
N NN
H H
O N%~~O
NHO
O
Utilizing the same synthetic procedure as for Example 164, Example HHH (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-1-(3-((2,2-dioxo-2-thio-4,5-diioxoimidazolidin-1 -yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 277 OMe N H H
N
O ~
NH
Example CC, 4-methoxy-l-aminonaphthalene and Example E are reacted using the procedure for Example 162 to afford 1-(5-t-butyl-2-{3-[1,1,4-trioxo-lk 6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-methoxynaphth-1-yl)-urea:
Example III
H2N, NH
N -O
O
//~~NH
O
A solution of 1-(chloromethyl)-3-nitrobenzene and Example DD are combined using the procedure for Example 77 to yield 2-(4-methoxybenzyl)-5-(3-nitrophenylmethyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one. This material is reduced under standard condition to yield 2-(4-methoxybenzyl)-5-(3-aminophenylmethyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one, which was nitrosated and acidified to yield 5-(3-hydrazinophenylmethyl)- 1, 1 -dioxo- 1 %6-[ 1,2,5]thiadiazolidin-3-one.
Example JJJ
O
O i OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2C12 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 2-naphthoic acid chlorideis added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for 1 h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-2-naphthamide.
Example KKK
O OP, o i OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2C12 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 1-naphthoic acid chloride is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for I h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-1-naphthamide Example LLL
O
O N
N
OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2CI2 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and isoquinoloic acid chloride is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for 1 h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)isoquinoline-3-carboxamide.
Example 278 (I
NIN, N NQ
H
NO
O
NH
Utilizing the same synthetic procedure as for Example 164, Example III (10 mmol) and Example 11 (10.5 mmol) are combined to afford 1-naphtyl 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3 -(naphthalen-l-yl)carbmate.
Example 279 / \ O
N H I \ \
N~~rl "O
NH
Utilizing the same synthetic procedure as for Example 164, Example III (10 mmol) and Example JJJ (10.5 mmol) are combined to afford 1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-2-naphthamide.
Example 280 / O
N
~N H I
/ .
\
NO
O NH
Utilizing the same synthetic procedure as for Example 164 Example III (10 mrnol) and Example KKK (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-1-naphthamide.
Example 281 O
\
N H N
N~'O
NH
O
Utilizing the same synthetic procedure as for Example 149, Example III (10 mmol) and Example KKK (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)isoquinoline-3-carboxamide.
Example _MMM
O
(:Ao N
O
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with succinic anhydride under standard conditions to afford 1 -(3 -nitrobenzyl)pyrroli dine-2,5 -di one.
This material is reduced at the nitro group and oxidized to afford 1-(3-hydrazinobenzyl)pyrrolidine-2,5 -dione.
Example 282 ~. /
O
ll NN NH/\H
b 0=~ \J
Utilizing the same synthetic procedure as for Example 164, Example MMM (10 mmol) and Example PP (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 283 O CI
NN NH H
N O
Utilizing the same synthetic procedure as for Example 164, Example MMM (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,5-dioxopyrrolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 284 ' CI
O
\
N"N N H
H
OH
O
Example C was reacted with LiOH utilizing the procedure for Example 146 to yield 3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-l-yl)benzoic acid in 90%
overall yield. 'H NMR (DMSO-d6): 9.00 (s, 1 H), 8.83 (s, 1 H), 8.25 - 7.42 (m, 11 H), 6.42 (s, 1 H), 1.26 (s, 9 H); MS(ESI): Expected: 412.88 Found: 413.00.
Example 285 O
N( \ N~H \ ~ 1 N H
O
OH
Example B was reacted with LiOH utilizing the procedure for Example 146 to yield 3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzoic acid in 90%
overall yield. 1 H NMR (DMSO- d6): S 9.11 (s, 1 H), 8.47 (s, 1 H), 8.06 (m, 1 H), 7.93 (d, J
= 7.6 Hz, 1 H), 7.81 (d, J= 8.0 Hz, 1 H), 7.65 (dd, J= 8.0, 7.6 Hz, 1 H), 7.43 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, 1 H), 1.27 (s, 9H); MS (ESI) Expected: 428.49 Found: 429.2 (M+1).
Example NNN
O~NH
N\S~O
To the solution of phenyl-urea (13.0 g, 95.48 mol) in THF (100 mL) was slowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT. The reaction mixture was refluxed overnight, the volatiles removed in vacuo yielded 2-phenyl-1,2,4-thiadiazolidine-3,5-dione as a white solid (4.0 g, 20%). 'H NMR (DMSO-d6): S
12.49 (s, IH), 7.51 (d, J= 8.0 Hz, 2H), 7.43 (t, J= 7.6 Hz, 2H), 7.27 (t, J= 7.2 Hz, 1 H).
Example 286 o N/ )-N
N H H
I \
/
O,l/ N rO
N-S
Example E and Example NNN were reacted together utilizing the same general approach as for Example 160 to afford 1-(3-t-butyl-l-(3-((3,5-dioxo-2-pheny1-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
'H NMR
(DMSO- d6): 58.96 (s, 1 H), 8.01 - 7.21 (m, 16 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H); MS (ESI): Expected: 590.21, Found 591.26 (M+1).
Example 287 o N~ N)-N
N H
. I ~
/
p ~N
S
HN
Example CC, 1-naphthylisocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-lX6-[1,2,5]thiadia- zolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-naphthylurea.
'H NMR
(DMSO- d6): S 9.0 (s, IH), 8.81 (s, IH), 7.99 - 7.42 (m, 11H), 6.41 (s, 1H), 4.33 (s, 2H), 1.27 (s, 9H); MS (ESI).Exact Mass: 532.19 Found: = 533.24 Example 288 ci -- - - o N N H H
O
O
iN
HN
O
Example CC, p-chlorophenylisocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3 -(4-chloro-phenyl)-urea. 'H NMR (DMSO- d6): 6 9.07 (s, 1H), 8.42 (s, 1H), 7.52 - 7.272 (m, 8H), 6.36 (s, 1 H), 4.60 (s, 2H), 1.26 (s, 9H); MS (ESI) Exact Mass: 516.13 Found:
= 517.1 Example 289 CI
O
- -- - ~ ~ ~
N NH
N H
I \
/
0,'/N~0 \N-S
Example G and Example NNN were reacted together utilizing the same general approach as for Example 160 to afford 1-(3-t-butyl-l-(3-((3,5-dioxo-2-phenyl-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
IH NMR
(DMSO- d6): 59.02 (s, IH), 8.51 (s, 1H), 7.52 - 7.24 (m, 13H), 6.36 (s, 1 H), 4.90 (s, 2H), 1.27 (s, 9H); MS (ESI): Expected: 574.16 Found: 575.26 (M+l) Example 290 CI
N~ \ ~ \ I
'N H H
b CI
C\/
Example Z and 2,6-dichlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.46 - 7.26 (m, 7H), 6.3 5 (s, 1 H), 4.11 (q, J= 7.2Hz, 2H), 3.31 (t, J= 5.2 Hz, 2H), 2.68 (t, J= 5.6 Hz, 2H), 1.32 (s, 9H), 1.24 (t, J = 7.2Hz, 3H); MS(ESI): Expected::
502.15 Found: = 503.1 (M+1).
Example 291 CI
N/ ~ I
,N H H
Cl I / OH
Example 290 was reacted utilizing the same condition as for Example 146 to yield 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1 H-pyrazol-l-yl)phenyl)propanoic acid in >90% yield. 'H NMR (DMSO- d6): S 8.70 (s, IH), 8.60 (s, 1H) 7.50 - 7.24 (m, 7H), 6.26 (s, IH), 2.87 (t, J= 5.2 Hz, 2H), 2.57 (t, J= 5.6 Hz, 2H), 1.25 (s, 9H);
MS(ESI):
Expected: 474.12 Found: 475.18 (M+1).
Example 000 N/
,N NHz A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
A solution of the crude material from the previous reaction (1.5 g, 8.4 nunol) was dissolved in 6 N HCI (9 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After lh, tin (II) chloride dihydrate (5 g) in 6 N HCI (10 ml) was added. The reaction mixture was stirred at 0 C for 3h. The pH was adjusted to pH 7 to yield ethyl3-(4-(3-t-butyl-5-amino-IH-pyrazol-l-yl)phenyl)propanoate.
Example 292 -CI
CI
H H
~~O O
Example 000 and 2,6-dichlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(4-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.45 - 7.24 (m, 711), 6.36 (s, 1 H), 4.10 (q, J 7.2Hz, 2H), 3.02 (t, J 5.2 Hz, 2H), 2.70 (t, J= 5.6 Hz, 2H), 1.33 (s, 9H), 1.22 (t, J 7.2Hz, 3H); MS(ESI): Expected::
502.15 Found: = 503.1 (M+1).
Example 293 CI
N H H
CI
V
Example 292 was reacted utilizing the same condition as for Example 146 to yield 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1 H-pyrazol-1-yl)phenyl)propanoic acid in >90% yield. 'H NMR (DMSO- d6): S 8.66 (s, 1H), 8.58 (s, IH) 7.50 - 7.28 (m, 7H), 6.27 (s, 1H), 2.85 (t, J= 5.2 Hz, 2H), 2.48 (t, J= 5.6 Hz, 211), 1.24 (s, 9H);
MS(ESI):
Expected: 474.12 Found: 475.18 (M+1).
Example 294 CI
O
N/ N~N
.N H H
~~O 0 Example 000 and p-chlorophenylisocyanate were reacted utilizing. the same conditions as for Example 145 to yield ethyl 3-(4-(3-tert-butyl-5-(3-(4-chlorophenyI)ureido)-1 H-pyrazol-I -yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.34 - 7.19 (m, 9H), 6.36 (s, 1 H), 4.10(q, J= 7.2Hz, 2H), 2.92 (t, J= 5.2 Hz, 2H), 2.58 (t, J=
5.6 Hz, 2H), 1.32 (s, 9H), 1.25 (t, J 7.2Hz, 3H); MS(ESI): Exact Mass: 468.19 Found: = 469.21 (M+1).
Example 295 CI
O
N.N\ H H
----- I \
O
Example Z and p-chlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-tert-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
9.12 (s, I H), 8.37 (s, 1 H), 7.41 - 7.27 (m, 8H), 6.34 (s, 1 H), 5.73 (s, 1 H), 4.01 (q, J 7.2Hz, 2H), 2.90 (t, J= 5.2 Hz, 2H), 2.62 (t, J= 5.6 Hz, 2H), 1.25 (s, 9H), 1.125 (t, J= 7.2Hz, 3H); MS(ESI): Exact Mass: 468.19 Found: = 469.21 (M+1).
Example 296 N~ ~-N
N H H
~~O O
Example 000 and 1-naphthylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(4-(3-tert-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)phenyl)propanoate. S 7.88 - 9.95 (m, 13H), 6.27 (s, 1 H), 4.04 (q, J = 7.2Hz, 2H), 2.75 (t, J = 5.2 Hz, 2H), 2.42 (t, J = 5.6 Hz, 2H), 1.27 (s, 9H), 1.20 (t, J= 7.2Hz, 3H); MS(ESI): Exact Mass: 484.25 Found: = 485.26 (M+1).
Example 297 O
N~ ~ ~N
N H H ~
Example Z and 1-naphthylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-tert-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): 6 9.01 (s, 1H), 8.80 (s, IH), 8.0 -7.27 (m, 11 H), 6.41 (s, 1 H), 4.01 (q, J= 7.2Hz, 2H), 2.95 (t, J= 5.2 Hz, 2H), 2.72 (t, J
5.6 Hz, 2H), 1.27 (s, 9H), 1.15 (t, J = 7.2Hz, 3H); MS(ESI): Exact Mass:
484.25 Found: = 485.26 (M+1).
Example 298 OMe N/ \ ~ \ ( \N H H I
ONH
Example CC, 1-(4-methoxynaphthyl)isocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1 ~ 6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-(4-methoxynaphthyl)urea. 'H NMR (DMSO- d6): S 8.69 (s, 1H), 8.61 (s, 1H), 8.15 -6.90 (m, IOH), 6.36 (s, 1H), 4.37 (s, 2H), 3.93 (s, 3H), 1.22 (s, 9H); MS (ESI) Exact Mass:
562.20 Found: = 563.2.
Example PPP
N\
In a 250 mL Erlenmeyer flask with a magnetic stir bar, 3-phenoxyphenylamine (4.81 g, 0.026 mol) was added to 6 N HCI (40 mL) and cooled with an ice bath to 0 C.
A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop -wise:- After 30 min, SnC12'2H20 (52.0 g, 0.23 mol, 8.86 eq.) in 6 N HCI (100 mL) was added and the reaction mixture was allowed to stir for 3 h; and then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for 4h, concentrated in vacuo and the residue extracted with EtOAc (2 X 100 mL) and purified by column chromatography using hexane/EtOAc/Et3N (8:2:0.2) to yield 3-tert-butyl-l-(3-phenoxyphenyl)-1H-pyrazol-5-amine (1.40g, 17%). mp: 108 - 110 C; 'H NMR
(CDC13): S 7.3 (m, I OH), 5.7 (s, 1 H), 4.9 (brs, 2H ), 1.3 (s, 9H).
Example 299 a p ""
o In a dry vial with a magnetic stir bar, Example PPP (0.184 g; 0.60 mmol) was dissolved in 2 mL CH2C12 (anhydrous) followed by the addition of phenylisocyanate (0.0653 mL; 0.60 mmol; 1 eq.). The reaction was kept under Ar and stirred for 18h.
Evaporation of solvent gave a crystalline mass that was recrystallized from EtOAc/hexane and then filtered washing with hexane/EtOAc (4:1) to yield 1-[3-tert-butyl-l-(3-phenoxyphenyl)-1H-pyrazol-5-yl]=3-phenylurea (0.150 g, 50%). HPLC
purity:
96%; 'H NMR (CDC13): S 7.5 (m, 16H), 6.8 (s, IH), 6.5 (s, 1H), 1.4 (s, 9H).
Example QQQ
N~
N /
O~
[<,N
To a stirred solution of Example L (1.2 g, 3.5 mmol) in THF (6 ml) was added borane-methylsulfide (9 mmol). The mixture was heated to reflux for 90 min and cooled to RT, and 6 N HCI was added and heated to reflux for 10 min. The mixture was basified by adding sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-amine (0.78 g), which was used without further purification.
Example 300 Nr N /
15r HNO /
A mixture of Example QQQ (0.35 g, 1.07 mmol) and 1-naphthylisocyanate (0.18 g, 1.05 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using 5 % methanol in CH2C12 (with a small amount of TEA) as the eluent (0.18 g, off-white solid) to yield 1-{3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-naphthalen-1-yl)urea. mp: 88 - 90 C; IH NMR (200MHz, DMSO- d6): S 9.07 (s, 1H), 8.80 (s, IH), 8.06-7.92 (m, 3H), 7.69 - 7.44 (m, 7H), 7.40 - 7.29 (m, 114), 6.44 (s, IH), 3.57 - 3.55 (m, 4H), 3.33 - 3.11 (m, 4H), 2.40 - 2.38 (m, 4H), 1.32 (s, 9H);
MS
Example 301 N~
N /
/ O
~ HN~/
Ui~ \
HN O CI
The title compound was synthesized in a manner analogous to Example 23 utilizing Example QQQ (0.35 g, 1.07 mmol) and 4-chlorophenylisocyanate (0.165 g, 1.05 mmol) to yield 1-{3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea. mp: 82 - 84 C; 'H NMR (200MHz, DMSO- d6): S 9.18.(s, IH, s), 8.40 (s, 1H), 7.53 - 7.26 (m, 8H), 6.37 (s, 1H), 3.62 - 3.54 (m, 4H), 2.82-2.78 (m, 4H), 2.41-2.39 (m, 4H), 1.30 (s, 9H); MS
All of the references above identified are incorporated by reference herein.
In addition, two simultaneously applications are also incorporated by reference, namely Modulation of Protein Functionalities, S/N 10/746,545, filed December 24, 2003, and Anti-Cancer Medicaments, S/N 10/746,607, filed December 24, 2003.
Compounds of Formula I wherein Q is taken from Q-30 are prepared as shown in Scheme 23. Readily available N-BOC anhydride 143 (see S. Chen et al, J. Am.
Chem. Soc.
(1996) 118:2567) is reacted with amines HN(R4)2 or alcohols R6OH to afford acids 144 or 145, respectively. Intermediates 144 or 145 are further reacted with amines HN(R4)2 in the presence-of-an acid-activating reagent, preferably PyBOP-and-di-isopropylethylamine, to give diamides 146 or ester-amides 147. Intermediate 145 is converted to the diesters 148 by reaction with an alkyl iodide in the presence of base, preferably potassium carbonate.
Intermediates 146-148 are treated with HCI/dioxane to give the secondary amines 149-151, which are then condensed with acids 152 in the presence of PyBOP and di-isopropylethylamine to give compounds of Formula 1-153.
Scheme 23 HOZ C ON(R4)2 2(R4)NC O 0 N(Ra O O 0 NN(It4)2 N 1) PyBOP, i-Pr2NEt NJ
~. ~ -i BOC 144 BOC L4 N or R60H 0 ORe 2) HN(R4)2 O
BOC HO2C 2(R4)NCO OR6 143 N' 145 BOC N 14;
BOC
R61, base 0 OR6 R602C ~ N 148 BOC
HCI, die CO-X, \ /
2(Ra)NC O O ~1' N(R, N
0 ~ PyBOP, i-Pr2NEt 0 OH J
\\ /
2(R4)NC O OF
[Rs '~' 02G(NH)p14-D-E Y IRs02C-(NH)p1Q-D-E ,Y J
li XI, XZ are N(R4)2 O OR
XI is N(R4)2, X2 is OR6 R602C
XI,XzareOR6 N 151 H
Compounds of Formula I wherein Q is taken from Q-31 or Q-32 are prepared according to the sequences illustrated in Scheme 24. Treatment of readily available sulfenamides 154 with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =-CH=CH2), gives rise to compounds of Formula 1-155. Treatment of sulfenamides 1-155 with iodosobenzene in the-presence of alcohols R~OH gives rise to the sulfonimidates of Formula 1-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively, compounds 1-155 (Z
=-CH=CH) may be optionally reduced to the saturated analogs 1-156 (Z = CH2-CH2-), which are converted to the corresponding sulfonimidates 1-157.
Treatment of readily available sulfonylchlorides 154.1 with amines HN(R4)2 and base gives rise to compounds of Formula 1-154.2.
Scheme 24 [ReOZC-(NH)pjq-D-E-Y,, ZH
37, Z = NH
Pd(O), phosphine, base O\
0\S/ NH2 SONH2 PhI=O
[RBOyC-(NH)p)q-D-E-Y~
ZH --~ i/
37,Z=0 R60H, Cu(I), base [Rso2C-(NH)pjq-D-E-Y-Z
M [RBO2C-(NH)pjq-D-E-Y-Z MeCN I-157 [ReO2C-(NH)p1q-D-E-Y~ Ph ZH R6' 37, Z = CH=CH2 Mf Pd(0), phosphine, O"S/
base Z = CH=CH-Hydrogenation [R6O2C-(NH)pjq-D-E-Y-(CH2);
S02NH2 SOZN(R4)2 I \ HN(4)z [R602C-(NH)pjq-D-E-Y [R602C-(NH)pjq-D-E-Y
154.1 1-154.2 Compounds of Formula I wherein Q is taken from Q-33 are prepared as shown in Scheme 25. Readily available nitriles 158 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =-CH=CH2) to afford compounds of Formula 1-159.
Compounds 1-159 (wherein Z = CH=CH-) are optionally reduced to their saturated analogs 1-160 by standard catalytic hydrogenation conditions. Treatment of compounds 1-159 or 1-160 with a metal-azide (preferably sodium -azide- or -zinc-azide)- gives rise to-tetrazoles of Formula 1-161.
Scheme 25 [R6O2C-(N H)p]q-D-E-Y~, ZH
37, Z = NH
N_ Pd(0),phosphine, N
base CN
CN ~3 [R6O2C-(NH)p]q-D-E-Y~
ZH
[R602C-(NH)p]q-D-E-Y-Z
I ~ 37,Z=0 [R602C-(NH)p)q-D-E-Y-Z 1-159 1-16 M Cu(1), base [R6O2C-(N H)p]q-D-E-Y,, ZH
37, Z = CH=CH2 =
Pd(O), phosphine, Z CH=CH-.
~
base Hydrogenation ~
i [ R602C-( N H) p]q-D-E-Y -(C H;
Compounds of Formula I wherein Q is taken from Q-34 are prepared as shown in Scheme 26. Readily available esters 162 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z = -CH=CH2) to afford compounds of Formula 1-163.
Compounds 1-163 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-164 by standard hydrogenation conditions. Compounds 1-163 or 1-164 are converted to the desired phosphonates 1-165 by an Arbuzov reaction sequence involving reduction of the esters to benzylic alcohols, conversion of the alcohols to the benzylic bromides, and treatment of the bromides with a tri-alkylphosphite. Optionally, phosphonates 1-165 are converted to the flourinated analogs 1-166 by treatment with diethylaminosulfur trifluoride (DAST).
COZZ = CH=CH- 6R6 Scheme 26 Hydrogenation [ReOzC-(NH)p}q-D-E-Y-(CH2)Z
[ReOzC-(NH)p)q-D-E-Y1.1 ZH 1-164 37, Z= NH 1) reduction to alcc (LiBH4) Pd(0), phosphine, 2) CBr4, Ph3P
base 3) P(OR6)3 C02R6 1) reduction to alcohol 0\\ /
IR602C-(NH)plq-D-E-Y~1 I \ (LiBH4) P-ORe 37,Z=0 . ZH / _ [R602C-(NH)plq-D-E-Y-Z 2) CBr4, Ph3P
M C~(I), base 3) P(OR6)3 ~
162 1-163 [ReO2C-(NH)plq-D-E-Y-Z
[R602C-(NH)p]q-D-E-Y~ZH . 1-165 37, Z = CH=CH2 ~ DAST
Pd(O), phosphine, base ORB
O~P OR6 F
[R602C-(NH)p)q-D-E-Y-Z
Compounds of Fonnula I wherein Q is taken from Q-35 are prepared according to Scheme 27. Readily available acid chlorides 167 are reacted with oxazolidones in the presence of base to afford the N-acyl oxazolidinones 168. Intermediate 168 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z =.-CH=CH2) to afford the N-acyl oxazolidinones of Formula 1-169. Compounds I-169 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-170 under standard hydrogenation conditions.
Scheme 27 [R602C-(NH)p]q-D-E-Y,,, ZH
37,Z=NH
Pd(O), phosphine, OO
O O base O N
HN~O O COCI R4 t R4 [R602C-(NH)p]q-D-E-Y~, ZH I \
\ R4 37, Z= 0 I1~/ base Cu(I), base [R602C-(NH)p]q-D-E-Y-Z
[R6O2C-(N H)p]q-D-E-Y,, ZH hydrogenation 37, Z = CH=CH2 (Z = CH=CH) Pd(O), phosphine, base O~
O
O N
I \
[R602C-(N H)p]q-D-E-Y-(CHZ)2 Compounds of Formula I wherein Q is taken from Q-35 are also prepared as illustrated in Scheme 27.1. Intermediate 8a, wherein M is a suitable leaving group such as chloride, bromide or iodide, is refluxed with triethyl phosphite and the resulting phosphoryl intermediate saponified under mild conditions to yield 1-165.
Scheme 27.1 ~~OH
[R602C-(NH)p]q-D-E-Y'M 1. P(OEt)3 [R602C-(NH)p]q-D-E-Y~ OH
8a 2. saponification 1-165 Compounds of Formula I wherein Q is taken from Q-36 are prepared as illustrated in Schemes 28.1 and 28.2. Reductive alkylation of the t-butylsulfide substituted piperazines with the readily 'available aldehydes 131 gives rise to the benzylic piperazines 171.
Intermediates 171 are reacted with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z
_-CH=CH2) to give compounds 172, 173, or 174, respectively. Optionally, intermediates 174 are converted to the saturated analogs 175 under standard hydrogenation conditions.
CHO HN~N-\-St-Bu N \_/N-St-Bu Scheme 28.1 I NaBH(OAc)3 ' I \
M M
r-1 N N-~
IRsO2C-(NH)p1q-D-E-Y~. V S
37. Z = NH ZH ~/N,-St-Bu 37, Z CH=CH2 171 \ - 171 (E
Pd(0), phosphine, I Pd(0), phosphine, ~ 174 base [~02C (NH)pjq D-E-Y-N / 17Z base [R602C-(NH)p]q-D-E-Y
reduction (hydrogenation or diimide) N \-/N-\-St-Bu [R602C-(N H)p]q-D-E-Y,, ZH
37,Z=0 171 L VN-\-St-8u Cu(I), base IR602C-(NH)pjq-D-E-Y-O
[R602C-(NH)p]q-D-E-Y
Scheme 28.2 illustrates the conversion of intermediate t-butylsulfides 172-175 to the sulfonic acids, employing a two step process involving acid-catalyzed deprotection of the t-butyl sulfide to the corresponding mercaptans, and subsequent peracid oxidation (preferably with peracetic acid or trifluoroperacetic acid) of the mercaptans to the desired sulfonic acids of Formula 1-176.
Scheme 28.2 N \-N
N N-'- 1 St-Bu ] ) H+
\ - I \
2) peracid oxidation [R602C-(NH)p]q-D-E-Y-Z
[R602C-(NH)p]q-D-E-Y - Z
Z = NH, 0, CH=CH, CH2-CH2 In some instances a hybrid p38-alpha kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety RI-X-A.
The synthesis of functionalized intermediates of-formula Ri-X-A are accomplished as shown in Scheme 29. Readily available intermediates 177, which contain a group M
capable of oxidative addition to palladium(0), are reacted with amines 178 (X = NH) under Buchwald Pd(0) amination conditions to afford 179. Alternatively amines or alcohols 178 (X = NH or 0) are reacted thermally with 177 in the presence of base under nuclear aromatic substitution reaction conditions to afford 179. Alternatively, alcohols 178 (X = 0) are reacted with with 177 under Buchwald copper(I)-catalyzed conditions to afford 179. In cases where p = 1, the carbamate of 179 is removed, preferably under acidic conditions when R6 is t-butyl, to afford amines 180. In cases where p = 0, the esters 179 are converted to the acids 181 preferably under acidic conditions when R6 is t-butyl.
Scheme 29 Rj-XH
M-A-(NH)p-C02R6 178 R X-A- NH CO R
-~ ~ ( )P- z s 177 heat or Pd(O) catalysis 179 H+ H+
RjX-A-NHZ RjX-A-CO2H
Another sequence for preparing amines 180 is illustrated in Scheme 30.
Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 wherein M is a leaving group, preferably M is fluoride, or M is a group capable of oxidative insertion into palladium(0), preferably M
is bromo, chloro, or iodo, gives intermediates 183. Reduction of the nitro group under standard hydrogenation conditions or treatment with a reducing metal, such as stannous chloride, gives amines 180.
Scheme 30 Rj-XH
reduction M-A-N02 - 178 RiX-A-N02 RjX-A-NH2 182 heator 183 180 Pd(0) catalysis In instances when hybrid p38-alpha kinase inhibitors are prepared, compounds of Formula 1-184 wherein q is I may be converted to amines 1-185 (p = 1) or acids I-186 (p = 0) by analogy to the conditions described in Scheme 29. Compounds of Formula 1-184 are prepared as illustrated in previous schemes 1.1, 2.1, 2.2, 3, 4, 5, 6; 7.1, 7.2, 8, 9, 10, 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, or 28.2.
Scheme 31 [R602C-(NH)plq-D" E, Y'Q
q H+ H+
~ i H N-D~ E. Y .Q HO2C-D~ E. Y .Q
Compounds 1-184 are taken from schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24,.25, 26, 27, 28.2 The preparation of inhibitors of Formula I which contain an amide linkage -CO-NH-connecting the oxyanion pocket binding moieties and Rj-X-A moieties are shown in Scheme 32. Treatment of acids 181 with an activating agent, preferably PyBOP in the presence of di-iso-propylethylamine, and amines 1-185 gives compounds of Formula I.
Alternatively, retroamides of Formula I are formed by treatment of acids 1-186-with PyBOP in the presence of di-iso-propylethylamine and amines 180.
Scheme 32 O
H N-D,E, Y'Q RtX-A-CO2H PyBop, i-Pr2NEt ~
z + R~X-A N" D~E~Y.
~ H
Compounds 1-185 taken Compounds 181 taken from scheme 31 from scheme 29 Amides of Formula I
(hybrid inhibitors, possessing oxyanioi pocket-binding moiety Q and moiety RI-) ~E, ~Q RIX-A-NHz HOZC-D Y + PyBop, i-Pr2NEt R,X-A-NH D'E~Y'O
Compounds I-186 taken Compounds 180 taken from from scheme 31 schemes 29 or 30 RetroamideFormula I
(hybrid inhibitors, possessing oxyanic pocket-binding moiety Q and moiety Ri-:
The preparation of inhibitors of Formula I which contain an urea linkage NH-CO-NH- connecting the oxyanion pocket binding moieties and the RI-X-A moieties are shown in Scheme 33. Treatment of amines 1-185 with p-nitrophenyl chloroformate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I.
Scheme 33 ,E, Q p-nitrophenyl chloroformate R,X-A-NHz HZN-D Y - a;'- O HN.DE, YQ
base I0 Compounds 180 taken fi Compounds I-185 taken O2Nschemes 29 or 30 from scheme 31 187 O-R,, X.1 A11 N"k NDll~ E"Y.Q
H H
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RI-X-A) Alternatively, inhibitors of Formula I which contain an urea linkage NH-CO-NH-connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are prepared as shown in Scheme 33. Treatment of amines 180 with p-nitrophenyl chloroformate and base affords carbamates 188. Reaction of 188 with amines 1-185 gives ureas of Formula I.
Scheme 34 RIX-A-NH2 p-nitrophenyl chloroformate H2N-D Y
(oyHNAXRl Compounds 10 taken from base schemes 29 or 30 I/ O Compounds 1-185 ta}
OZN from scheme 31 Rt, XA1~ N"k N,D~EiY'Q
H H
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RI-X-A) The preparation of inhibitors of Formula IB can be generally accomplished starting from a variety of readily available beta-ketonitriles 189, wherein R40 is alkyl, phenyl, or perfluoroalkyl. As illustrated in Scheme 35, reaction of 189 with an alcohol R4OH, preferably methanol or ethanol, under anhydrous acidic conditions, preferably anhydrous HCI, leads to the formation of imidates 190. Reaction of 190 with acyl chlorides, isocyanates, para-nitrophenylcarbamates, or substituted chloroform.ates in the presence of a base, preferably pyridine, triethylamine, di-iso-propylethylamine, Barton's base, or an alkali metal carbonate, affords key intermediates 191 and 192 as a mixture of tautomers, wherein T
is alkylene, NH, 0, or when T is absent, then the carbonyl side chain and A
are connected by a direct bond.
Scheme 35 p 0 HN ~T'A
O O NH. HX ~ jj ~ T ~ +
~CN Rao~OR41 tR40'0R41 Rao /
Rao H2N-NH-(E)y(Y)t-Q
O
H
N~ N 1, TA
Q,, (Y)t (E)4 The mixture of tautomers 191/192 are not separated from each other, but are reacted as,a mixture with a substituted hydrazine 193, wherein the Q moiety is optionally protected by a protecting group that diminishes its reactivity with the 191/192 mixture.
This cyclodehydration reaction is performed in the presence of base, acid catalysis, or under neutral conditions optionally in the presence of a dehydrating agent to afford the desired pyrazoles 194. Preferable reaction solvents include dichloromethane, ethyl acetate, acetonitrile, or an alcoholic solvent taken from methanol, ethanol, or 2-propanol.
The reaction sequence initiating from 190 and yielding 194 may take place as two separate reactions, wherein the tautomeric mixture 191/192 is isolated, and then in a second reaction step this 191/192 mixture is reacted with a substituted hydrazine 193 to afford the desired pyrazoles 194. Alternatively, the reaction sequence initiating from 190 and yielding 194 may take place in a one-pot procedure, without isolation of the intermediate 191/192 mixture.
In a further modification, the reaction sequence initiating from 190 and yielding 194 may take place in a parallel array format, wherein phase-trafficking reagents, including scavenging reagents, are utilized to allow purification and isolation of intermediates and products. Scheme 36 illustrates this modification. Excess imidate 190 is reacted with a limiting amount of electrophile in the presence of a polymer-supported base 195 to afford the acylated imidates 191/192 as a mixture of tautomers. The crude mixture of 191/192 is optionally purified by incubation with a polymer-supported electrophile 196, preferably a polymer-supported isocyanate or acid chloride. Reaction of 196 with any remaining imidate 190 sequesters this imidate as polymer-supported 197. Filtration- gives purified 191/192. In the second step, purified acylated imidates 191/192 are reacted with the substituted hydrazines 193 to afford desired crude products 194. A polymer-supported hydrazine 198 is optionally utilized to scavenge any remaining 191/192 from solution phase as derivatized 199. Filtration gives rise to purified desired pyrazoles 194.
Scheme 36 E)ectriles Q-Base O JO
O- - NH ..HX -- -- A--- -- --- / IT'A
II II Acid chloride, 15 0 N ~T" 0 HN
R~o/~/~OR~~ + Isocyanate, --, ~ ~I +
p-Nitrophenylcarbamate, R40 \/ ~OR41 R4o / ORfl 190 Anhydride, or - Substituted chloroformate Excess relative 191 192 to Electrophile Quenching of Electrophile excess Imidate 190 %dF-Electrophile-quenched imidate 190 HzN-NH-(E)a(Yk-0 -~ ~
191/192 + N O
N NIUIT"A
(puri5ed) 193 O'(Y)t(E)q H
194 (purified) O
Quenching of any N~
~--NH-NHZ remaining 191/192 N H~T" A
Scheme 37 illustrates the preparation of compounds wherein Q is Q-40. Readily available amine 200; wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with p-nitrophenyl chloroformate to give rise to carbamate 201.
Intennediate 201 is reacted with a substituted amino acid ester with a suitable base to afford urea 202. Further treatment with base results in cyclization to afford hydantoin 203. The protecting group P is removed to afford the key amine-containing intermediate 204.
Alternatively, if P is a nitro group, then 203 is converted to 204 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 204. is converted to 205A by reaction with an isocyanate; 204 is converted to amide 205B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 204 is converted to carbamate 205C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 37 H
p-Nitrophenyl 0 NOz ~N COZR3 D ~,)\ chloroformate P,p\ /(Y)\ ~
~O R<
P (E)Q NHz Base (E)Q H
Base 'K 0 Ro R4 Base p (Y)t O Deprotection or ~p\ (Y)\ Pi \(E)q NR4 reduction P (E)Q N N COzRa H ~
O
D (Y)~ 0 A-T,-N=C=O A-T, ~ /D\ /(Y)t O
H2N (E)4 ~~ R4 H H (E)Q ~~~ R4 O N R4 205A p N R4 204 R4 A-T-COCI 0 h4 -- /\ ip\ (Y)t O
Base A T H (E)q O~,N/Ra nR4 205B 205C j4 Scheme 38 illustrates the synthesis of key substituted hydrazine 210. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The nitrophenyl substituted amine 206 is reacted with p-nitrophenyl chloroformate to give rise to carbamate 207. Reaction of 207 with a suitable amino acid ester affords urea 208, which is cyclized under basic conditions to give hydantoin 209. Reduction of the nitro group of 209, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 210.
Scheme 38 H
p-Nitrophenyl OZN (Y)t 0 N02 R4/N~COzR3 Oz N ~-/~.)\ chloroformate ~N~O R4 R4 / NH H
z Base Base 206 207 0 Ro Ra Base OzN (Y)t O
OzN (Y)t 1) Pd/C, H2 N~NA C02R3 I ~~Ra H I N R4 2) NaNO2, HCI
Ra R4 3) SnCIZ
H
H N- N \/~~\ 0 z I j N~Ra O~ N Rn Scheme 39 illustrates the synthesis of key substituted hydrazines 213 and 216, utilized to prepare compounds of formula IB wherein Q is Q-42 and G is oxygen.
Nitrophenol 211 is reacted with an alpha-hydroxy acid, wherein R42 is H or alkyl and R43 is alkyl, under Mitsunobu reaction conditions to give 212; alternatively 211 is reacted under basic conditions with a carboxylic acid ester containing a displaceable Q, group to afford 212.
Conversion of 212 to the hydrazine 213 is accomplished by standard procedures as described above.
Scheme 39 HOI_t~ CO2R43 O2N O~/ COzR43 1) Pd/C, HZ HN
-- ~ I --= HZN~ \ O\~ C02Ra3 Mitsunobu R42 2) NaNO2, HCI I
O2N OH Reaction 212 3) SnC12 R'~
~ 213 211 Qx1~1 COZR43 Base OZI% R N \/O C02R43 Hydrolysis QZN /O CO H NH(R h 02N O O
v Y 2 _ \ \ N
R42 EDC, HOBT RT42 R
212 214 1) Pd/C, HZ
2) NaNOZ, HCI
3) SnCIZ
O
HZN' HN I \ O'T'NR4 I
Alternatively, the ester group of 212 is hydrolyzed to afford carboxylic acid 214, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 215. Conversion of 215 to the substituted hydrazine 216 is accomplished by standard procedures. Hydrazines 213 and 216 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 40 illustrates the synthesis of key substituted hydrazines 219 and 222, utilized to prepare compounds of formula I_B wherein Q is Q-42 and G is ]nethylene.
Nitrophenyl bromide 217 is reacted with an alpha-beta unsaturated ester using Pd(0) catalyzed Heck reaction conditions, . to afford ester 218. This intermediate is converted to the substituted hydrazine 219 by standard procedures involving concomitant reduction of the alpha-beta unsaturated bond. Alternatively, ester 218 is hydrolyzed to the carboxylic acid 220, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 221. Conversion of 221 to the substituted. hydrazine 222 is accomplished by standard procedures. Hydrazines 219 and 222 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 40 Raz C02R43 O2N \ COzR43 1) Pd/C, H2 -- I % /~/ -- H2N.HN C02~s Heck _IR42 2) NaNOZ, HCI
OzN \~Br Reaction 3) SnCI2 R'Z
OZN Hydrolysis OzN NH(R4)2 OZN O
I /\ /COZR~~ I ~ ~COzH - I \ \ NR4 \R4Z EDC, HOBT
Raz R4z R4 1) Pd/C, H2 2) NaNOZ, HCI
3) SnC12 O
HZN- HN I N.R4 Scheme 41 illustrates an alternative synthesis of key substituted hydrazines 225 and 228, utilized to prepare compounds of formula IB wherein Q is Q-42, G is methylene, and one or both of R42 are carbon-containing substituents. Nitrobenzyl acetate.223 is reacted with a substituted silylketene acetal to afford ester 224. This intermediate is converted to the substituted hydrazine 225 by standard procedures. Alternatively, ester 223 is hydrolyzed to the carboxylic acid 226, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 227. Conversion. of 227 to the substituted hydrazine 228 is accomplished by standard procedures. Hydrazines 225 and 228 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 41 OTMS
R4z -(~OEt 02R~z N \ COZEt 1) Pd/C, H2 HN
I % ~ HzN' \ COzEt Mg(ClO4h, DCM R+z R02 2) NaN02, HCl I/ ~z O N I\ 3) SnC12 Wz ~OAC
OzN CO Et Hydrolysis OzN NH(R4)2 OzN O R
z COZH . e ~z R42 R42R+2 R/'R4z EDC,HOBT
~
4z 1) Pd/C, HZ
2) NaNO2, HCI
3) SnClz HzN,HN I \ N.W
R4z ~z Ra Scheme 42 illustrates an alternative synthesis of key substituted hydrazines 231 and 234, utilized to prepare compounds of formula IB wherein Q is Q-42 and G is NH.
lodoaniline 229 is reacted with an alpha-keto ester under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford ester 230. This intermediate is converted to the substituted hydrazine 231 by Cu(I)-catalyzed reaction with N-BOC
hydrazine.
Alternatively, ester 231 is hydrolyzed to the carboxylic acid 232, which is reacted with an amine NH(R4)2 in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 233. Conversion of 233 to the substituted hydrazine 234 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazines 231 and 234 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCI-dioxane.
Scheme 42 A I H
~COzR~y NHZ-NHBOC ~N,N I\ N
R4Z C02R43 N \ /COzR43 T
~ Na BH(OAc)3 ~~ Cu(I) R4Z
I H Hydrolysis I H NH(R4)Z H O
~NyC02R43 N COZH NNW
R Y EDC,HOBT
R42 Rr2 Cu(I) BOC O
Ru R4 Scheme 43 illustrates an alternative synthesis of key substituted hydrazine 239, utilized to prepare compounds of formula IB wherein Q is Q-42, G is oxygen, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
lodophenol 235 is reacted with an alpha-hydroxy acid under Mitsunobu reaction conditions to give 236;
alternatively 235 is reacted under basic conditions with a carboxylic acid ester containing a displaceable Q,, group to afford 236. Ester_236 is hydrolyzed to the carboxylic acid 237, which is reacted with an amine X-H in the presence of a coupling reagent, preferably EDG/HOBT, -to give-amide -238. Conversion-of--238 to the substituted hydrazine 239 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazine 239 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCl-dioxane.
Scheme 43 HO'k COzRa3 ~ I \ /O\~CO2R43 --- T
Mitsunobu / R42 Reaction 236 Raz 235 OXI)__I CO2Ra3 Base O
~ /OyCO2R43 Hydrolysis I\/OyC02H X H O\ ~X
~ R42 Raz EDC, HOBT 7Raz IrLrv '~IV lfvv Cu(1) CNJ \S/ ~ BOC O
G ~
Ril 0 p R120 R13 H2N.N p\/\uX
Rlaz Scheme 44 illustrates an alternative synthesis of key substituted hydrazine 241, .5 utilized to prepare compounds of formula IB wherein Q is Q-42, G is NH, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
Carboxylic acid 237 is reacted with an amine X-H in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 240. Conversion of 240 to the substituted hydrazine 241 is accomplished by Cu(I)-catalyzed-reaction with N-BOC hydrazine.- Hydrazine 241 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting gr~oup, preferably with trifluoroacetic acid or HCI-dioxane.
Scheme 44 BOC
1 H X-H H p NH2-NHBOC 'N O
I/NYCp2H EDC,HOBT N Cu(I) H2N I/ NTKx .,.nr .rw llvv .rvv N N N N
x r 1 rN, rsl YOR13 'J Rip 0 Scheme 45 illustrates an alternative synthesis of key substituted hydrazine 246, utilized to prepare compounds of formula I.B wherein Q is Q-42, G is methylene, and X is taken from piperidinyl, piperazinyl, thiomorphorlino sulfone, or 4-hydroxypiperinyl.
lodobenzyl acetate 242 is reacted with a substituted silylketene acetal to afford ester 243.
Ester 243 is hydrolyzed to the carboxylic acid 244, which is reacted with an amine X-H in the presence of a coupling reagent, preferably EDC/HOBT, to give amide 245.
Conversion of 245 to the substituted hydrazine 246 is accomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazine 246 can be converted into compounds of formula LB
using the methods previously outlined in Schemes 35 and 36, after acid-catalyzed removal of the hydrazine N-BOC protecting group, preferably with trifluoroacetic acid or HCI-dioxane.
Schetne 45 OTMS
R42 _FOI__ OEt R42 ~ I \ ~ COZEt Hydrolysis COyH
Mg(CI04)2, DCM R42 R42 R42 Raz ~'~OAc BOC
O
X-H O
NH2-NHBOC ' N _r~ 244 - ~ - HzN \ X
\
EDC,HOBT ~ X Cu(I) I/
/ R42 R42 Ra2 R4z ,nnr .nnr .nnr ,nlv X N N
N I
~ N 'g~ ~
Ril 'O R7z0 R~~
O
Scheme 46 illustrates an alternative synthesis of key substituted hydrazines 248, 252, and 255, utilized to prepare compounds of formula I_B wherein Q is Q-47 or Q-48.
Nitrophenol 211 is reacted with a substituted alcohol under Mitsunobu reaction conditions to afford 247; alternatively 211 is alkylated with R4-Q,,, wherein Q,, is a suitable leaving group, under basic reaction conditions, to give rise to 247. Conversion of 247 to the substituted hydrazine 248 is accomplished under standard conditions.
The nitrobenzoic acid -249 is converted to the acid fluoride -250 by reaction with a fluorinating reagent, preferably trifluorotriazine. Treatment of acid fluoride 250 with a nucleophilic fluoride source, preferably cesium fluoride and tetra-n-butylammonium fluoride, affords the alpha-alpha-difluorosubstituted carbinol 251. Conversion of 251 to the substituted hydrazine 252 is accomplished under standard conditions.
Nitrobenzaldehyde 253 is reacted with trimethylsilyltrifluoromethane (TMS-CF3) and tetra-n-butylammonium fluoride to give rise to trifluoromethyl-substituted carbinol 254.
Conversion of 254 to the substituted hydrazine 255 is accomplished under standard conditions. Hydrazines 248, 252, and 255 can be converted into compounds of formula I_B
using the methods previously outlined in Schemes 35 and 36.
Scheme 46 HOIR4 OzN \ o' 1) Pd/C, Hy HzNHN O, R' Mitsunobu ~ 2) NaNOZ, HCI
OZN OH Reaction 247 3) SnCIZ
\ /
~ / 248 211 Ox , R' Base F
NN 0 OH 1) Pd/C, Hz H OH
J I\~ CsF, TBAF OzN I\~ HzN= N I\ F
OzN OzN
I\/C02H F~:N~F
F F F 2) NaNO2, HCI F
3) SnC12 OH
TMS-CF, OzN OH 1) Pd/C, H2 HZN- N CF
OzN \ CHO \ -~ \
" CF
3 I// TBAF ~/ " 2) NaNO2, HCI I/ ~
3) SnClz Scheme 47 illustrates the preparation of compounds of formula IB wherein Q is Q-5 59. p-Nitrophenylcarbamate 201 is reacted with a substituted alpha-hydroxy ester with a suitable base to afford carbamate 256. Further treatment with base results in cyclization to afford oxazolidinedione 257. The protecting group P is removed to afford the key amine-containing intermediate 258; alternatively, if P is a nitro group, then 257 is converted to 258 under reducing conditions such as iron/HC1, tin(II) chloride, or catalytic hydrogenation.
10 Amine -258 is converted to 259k by reaction with an isocyanate wherein TI
is alkylene or a direct bond connecting A and the carbonyl moiety; 258 is converted to amide 259B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 258 is converted to carbamate 259C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 47 H'O COzRaa O / NOZ ~/ ~ 0 R4 R4 ~D\ /(Y)~ ~O ~ I P~D(E)4 (Y)~N~OACOzR4s P (E)q H Base H
Base O Deprotection or D (Y)t O
PD(E)q (Y)N Ra reduction HzN/ \(E)4 ~N Ra - R
O~O Ra O O a O
A-T,-N=C=O A-T, ~ D /(1')t O
258 H N \(E)4 ~N~Ra H
259A O-~ O R4 258 \ 1-1 D\ (Y)~ O
Base A T ~H (E)4 NRa 259B O Ra Scheme 48 illustrates an alternative approach to the preparation of compounds of formula IB wherein Q is Q-59. Amine 260 is reacted with p-nitrophenylchloroformate under basic conditions to give rise to carbamate 261. This intermediate is reacted with an alpha-hydroxy ester in the presence of base to afford carbamate 262. Further treatment with base converts 262 into the oxazolidinedione 263. Conversion of 263 to the substituted hydrazine 264 is accomplished by standard procedures. Hydrazine 264 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 48 NOz H-0 CO2R43 p-Nitrophenyl OzN' \ t 0 ~
02N \ ~)t chloroformate N~O \ R4 R4 / , NHz Base / H
261 Base 0 R4 R4 Base OzN (Y)t O
~f~( /~ 1) Pd/C, H2 02N \ /(Y)\ /I / ~ --- I / N~R4 -~
CO
H O zRa3 O~0 R4 2) NaNO2, HCI
262 263 3) SnCIZ
H
H NiN /(Y) 0 z I / N~R4 O~O R4 Scheme 49 illustrates thee approach to the preparation of compounds of formula I_B
wherein Q is Q-57. Amine 265 is reacted with p-methoxybenzylisocyanate under standard conditions to give rise to urea 266. This intermediate is reacted with an oxalyl chloride in the presence of base to afford trione 267. Conversion of 267 to the substituted hydrazine 268 and removal of the p-methoxybenzyl protecting group is accomplished by standard procedures.
Hydrazine 264 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 49 I \ NCO O
Me0/~% OzN (Y 0 Ci CI
i\~J
OZN lY)\ )~ H H
\/ I j I\ 0 ~ NHp 266 OMe Base ozN (Y O 1) FeC13 HZNHN (y 0 / \NAN \ NA NH
\ ~ / 2) NaNOZ, HCI
O/f- OMe 3) SnCIZ 0 0 Scheme 50 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-56. Amine 269 is reacted with p-methoxybenzylsulfonylchloride under standard conditions to give rise to sulfonylurea 270. This intermediate is reacted with an oxalyl chloride in the presence of base to afford the cyclic sulfonyl urea 271. Conversion of 271 to the substituted hydrazine 272 and removal of the p-methoxybenzy]
protecting group is accomplished by standard procedures. Hydrazine 272 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 50 0 0 ~N i~
\\S%
I NHZ CICI I~ H CI
Me0 ~ -~ Me0 ~
Base O
Base OZN (Y)t 00 CICI
02N )\ I%/ \NN O
I NH y H f I I ~ ---270 OMe Base 02N ~ (Y)t O~ 1) FeC13 H2NHN ~ (Y 0 )t ~ /~
~/ \NSN a'zt:~ ~ \N-S.NH
2) NaNO2, HCI ~
OMe 3) SnC12 O// \\O
Scheme 51 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-58. Amine 273 is reacted with a cyclic anhydride e.g. succinic anhydride in the presence of base under standard conditions to give rise to imide 274.
Conversion of 274 to the substituted hydrazine 275 is accomplished by standard procedures.
Hydrazine 275 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 51 p 0 p ROZN (Ylt 0 1) FeCl3 ~2N \ j(Y)~ - ~ / ~N
~ j NHz ~ )X 2) NaNOz, HCI
0 R R4. 3) SnC12 H2NHN ~
(~~
N )X
0, R4 R4 Scheme 52 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-54 or Q-55. Carboxylic acid 276 is converted to protected amine 279 under standard conditions, which can be subsequently converted to hydrazine 280 by standard procedures. Hydrazine 280 can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36 to yield protected amine 283 which is readily deprotected to yield amine 284. Reaction of amine 284 with CDI and amine (R4)2NH
.10 yields 285 (Q=Q-54). Reaction of amine 284 with the indicated sulfamoylchloride derivative yields 286 (Q=Q-55).
Scheme 52 O,N OH 02N mri NHR4 LAH OzN~ (y)t BocZO
p- 9N}12 ~ - I- ~ O ---~ ~ / ~ ~NHz EDC,HOBT
276_ 277 278 O
OpN
~/(Y)\ 1) Pd/C HzNHN ~/(y)~ + O N~T'A + O HN T A
NBoc--- ~ /~
Ra 2) NaNO2, HCI I j NBoc ~ R4o v ORõ
3) SnCIZ R4 Ra OR41 R40 Rao Rao O
CDI
N H~TA TFA N NTA R4NHR4 N~ N NTA
H H
O
/
/ ~
BocN~ H I R4, ~ (Ot Ra-N /~ N~N(y I
(~t R+o \ O
N/
O,,,O \N HT A
R4NHR4 SOyCIZ R4, N S'Ol O' "O
Base R4 R, N'S'N~(~1 ~
Scheme 53 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-49, Q-50 or Q-51. Protected amine 287 (available by several literature procedures) is converted to deprotected hydrazine 288 is accomplished by standard procedures. Hydrazine 288 (Q=Q-49) can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. Amine 287 can be deprotected by TFA to yield amine 289 which can be subsequently converted amide 290. Amide 290 is converted to hydrazine 291 (Q=Q-50) by standard procedures, which can be subsequently converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. Alternatively, amine 289 can be reacted with CDI and amine (R4)2NH
to yield urea 292 (Q=Q-51). Urea 292 is converted to hydrazine 293 (Q=Q-51) by standard procedures, which can be subsequently converted into compounds of formula LB
using the methods previously outlined in Schemes 35 and 36.
Scheme 53 NO2 NHNH2 1) Pd/C
\ -- \
2) NaNO2, HCI
Boc N 3) SnC12 HN
287 4) TFA 288 TFA NOz NHNH2 NOz O
/ I \
RB""kOH 1) Pd/C
O N O N
EDC; HOBT 2) NaNOZ, HCI
HN
Re 3) SnC12 R8.
1) Pd/C
CDI 2) NaN02, HCI
3) SnCIZ
Oy N Oy N
Ra"IN' R4~ N\ R
Rq 4 Scheme 54 illustrates an approach to the preparation of compounds of formula IB
wherein Q is Q-52 and Q-53. Protected amine 294 (available by several literature procedures) is converted to protected hydrazine 295 is accomplished by standard procedures.
Hydrazine 295 (Q=Q-49) can be converted into compounds of formula IB to yield protected amine 298 which is readily deprotected to yield amine 299._ Reaction of amine 299 with chlorosulfonylisocyanate followed by amine (R4)2NH yields 300 (Q=Q-52).
Alternatively, reaction of chlorosulfonylisocyanate and amine (R4)2NH followed by amine 299 yields 301 (Q=Q-53).
Scheme 54 1) Pd/C ~ ~ T" A
\ - ~ \ + 0 N T~A 0 HN +
Boc N 2) NaN02, HCI /N J~~ ~/ OR41 3) SnCl2 Bx ~o OR<~
N~ A N~ A 1) CISOZNCO N~ ,A
N H T TFA N H T 2) R4NHR4 N H T
--- -~
Boc N HN O N
S,NH
R40 o~ N
~ ~ O R,~ 'w 1) C1S0 NCO N
R4NHR4 z .N H T,A
R
~
R4"N' O l 'N~ ~N 301 llf O S O
Scheme 55 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-36. Amine 302 is reacted with CDI and amine R4NH2 to yield 303, which is reacted with chlorocarbonyl sulfenylchloride to yield thiadiazolidinedione 304. Conversion of 304 to the substituted hydrazine 305 is accomplished by standard procedures.
Hydrazine 305 can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 55 O
(Y)t OZN \ /~ )\ CDI O~N ~NR4 CI~8~cl OZN I ~-~Z,,(Y)ltN'kNIR4 j NH2 Base, R4NH2 Base ~-8 1) Pd/C, H2 HzNHN ~
(Y)~ Ra 2) NaNO2, HCI N N
3) SnCIZ OIl-S
Scheme 56 illustrates an approach to the preparation of compounds of formula I_B
wherein Q is Q-37, Q-38 or Q-39. Imides 309a, 309b, and 312 are all available via several literature methods, and are-each able to be alkylated with chloride 306 to yields intermediates 307, 310 and 313 respectively. Intermediates 307, 310 and 313 are respectively converted to hydrazines 308 (Q=Q-37), 311 (Q=Q-38), and 314 (Q=Q-39) by standard procedures.
H
Scheme 56 Oy( N111~ O
N-N
02N \ (~)t R/309a~ 02N \~(Y)t-N ~NR+ 1)Pd/C,H2 HZNHN \ (Y)t~N ~NR+
I " \C1 \'N. --- --- - I / ~N.
DMF, KZC03 0/f R+ 2) NaNO2, HCI 0 R+
3) SnC)Z
H
O__-(N'O
i-0 / NN
0'~0 R ~0 ~~ R
R+ 309bR+ OZN +\/(Y)t~N - N + 1) Pd/C, H2 H2NHN (Y)t,N S,N' +
=-- f / N~ N
DMF, K2CO3 R+ 2) NaNO2, HCI R+
310 3) SnC12 311 H
O
RN ~O
R+ OR+ ~0 ~~ R+
3 2 OZN I\/(Y)t\N~S,N R+ 1) Pd/C, H2 HZNHN (Y)tN S,N R+
O~R+ 2) NaNOZ, HCl +
DMF, K2C03 3) SnC12 Scheme 57 illustrates an alternative preparation of compounds.wherein Q is Q-37.
Readily available amine 315, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with S02C12 to give rise to sulfonyl chloride 316.
Intermediate 316 is reacted with a substituted amino acid ester with a suitable base to afford sulfonylurea 317. Further treatment with base results in cyclization to afford sulfohydantoin 318_ The protecting group P is removed to afford the key amine-containing intermediate 319.
Alternatively, if P is a nitro group, then 318 is converted to 319 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 319 is converted to 320A by reaction with an isocyanate; 319 is converted to amide 320B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 319 is converted to carbamate 320C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
H
Scheme 57 R 1-1 N \ /COZR3 SOZCIs D (Y)t ~ SO 4 R4xR' pp(E)Q ~)\NHZ Base pi \(E)q ~H CI Base p Deprotection or 00 R4 R4 Base /D\ (Y)~ ~ S~ reduction p /(Y)t p (E)4 N R4 p~ (E)y ~N~ N C0ZR3 - ~
H 1 p-1- N Ra %
K4 318 Ra O~I
p (Y)t 0~ A-T~ N=C=O A-TI, /\ iD\ (~')~ ~SOO
H2N~ (E)q O~N' R4 H H (E)q ~ Ra /Y'R4 320A p N~I
-~ II p / (Y)t Base A-TH \(E)q ~N~S R4 O_ N~R
Scheme 58 illustrates an alternative synthesis of key substituted hydrazine 325 of compounds wherein Q is Q-37. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The amine 321 is reacted with SO2C12 to give rise to sulfonyl chloride 322. Reaction of 322 with a suitable amino acid ester affords sulfonylurea 323, which is cyclized under basic conditions to give sulfohydantoin 324. Reduction of the nitro group of 324, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 325.
Scheme 58 H
' /COZR3 R,N x a SOZC12 0ZN ~)t ~"~ Ra Ra 02N \(Y)t - - I _ " \N~S~CI.._ - ~ j NHz Base - /-----H JBase 0 0 Ra Ra Base OzN~/(Y ~S~ 1)Pd/C,H2 O
zN I\~(~'~NgN~COZR3 )\N Ra ~ H I O_ N~Ra 2) NaNO2, HCI
323 Ra 324 R4 3) SnClz N ) H N' \ /\ 'C
z N~S Ra NXRa Ra Scheme 59 illustrates an alternative preparation of compounds wherein Q is Q-38.
Readily available amine 326, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with SOZCIz to give rise to sulfonyl chloride 327.
Intermediate 327 is reacted with a substituted hydrazide ester with a suitable base to afford sulfonylurea 328. Further treatment with base results in cyclization to afford sulfotriazaolinedione 329. The protecting group P is removed to afford the key amine-containing intermediate 330. Alternatively, if P is a nitro group, then 329 is converted to 330 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation.
Amine 330 is converted to 331A by reaction with an isocyanate; 330 is converted to amide 331B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 330 is converted to carbamate 331C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
H
Scheme 59 R ~N~N~CO2R3 SO Cl O p 4 i z 2 D (Y)t\/S, CI R4 PD(E)q ~) 'NHz Base P/ (E)q H Base Deprotection or ~' ~O R4 Base /D\ ~)~ O 8 reduction p /(~')t s N p (E)q N , P, \(E)q ~N, N C02R3 -~ O~N N,R4 H I -~
. R4 I
p\ (Y)~ ~~ A-T,-N=C=O A-T,~ ~ D\ /(Y)~ ~S ~
H2N (E)q N' N H (E)q N \
~ N_Ra N-R4 O N 331A p N.
D / (Y)t ~\ 9 0 Base A-TH~ \(E)q \N~S\
O N i 331B 331C ~
Scheme 60 illustrates an alternative synthesis of key substituted hydrazine 336 of compounds wherein Q is Q-38. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The amine 332 is reacted with SO2Clz to give rise to sulfonyl chloride 333. Reaction of 333 with a ubstituted hydrazide ester affords sulfonylurea 334, which is cyclized under basic conditions to give sulfotriazaolinedione 335. Reduction of the nitro group of 335, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 336.
Scheme 60 H
Ra N1~ N'ICOZR3 i SO2C12 CZN ~ (Y)t ~"~ R4 02N ~(Y)t \N'S" CI llw NH2 Base H Base 02N 0~.0 R4 Base OzN/(Y)t ~S~ 1) Pd/C, HZ
~)~ S~ ~N~CO -~ I ~ N
H
O~ N R4 2) NaNO2, HCl R4 R4 3) SnCIZ
H
HzN-N (Y)t Og N~
O"L-N
336 Ra Scheme 61 illustrates the preparation of compounds wherein Q is Q-39. Readily available amine 337, wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with p-nitrophenyl chloroformate to give rise to carbamate 338.
Intermediate 338 is reacted with a substituted amino acid ester with a suitable base to afford urea 339. Further treatment with base results in cyclization to afford triazolinedione 340.
The protecting group P is removed to afford the key amine-containing intermediate 341.
Alternatively, if P is a nitro group, then 340 is converted to 341 under reducing conditions such as iron/HCI, tin(II) chloride, or catalytic hydrogenation. Amine 341 is converted to 342A by reaction with an isocyanate; 341 is converted to amide 342B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 341 is converted to carbamate 342C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
Scheme 61 H
p-Nitrophenyl 0 ~NOZ R4i N" NC02R3 chloroformate D ,(Y)t PD(E)q (Y)\NH2 Base Pi \(E)q ~H 0 Base O Deprotection or /D\ /(Y)\ 0 / Na Base PD(E)q (Y)N reduction P (E)q HN COsR3 ~ O~N N1R4 _-~
B4 ' 339 340 R4.
O O
D /(Y)t O A-T,-N=C=O A-T,, /~'I /O\(E)q (Y)\N~( H2N ~ (E)q ~ ~ \
N-R4 H H N'~
341 ~4 R4 'k, /p\ /(Y)\ 0 Base A-T H N (E)q N- \
~ N' R4 O N
342B 342C ~4 Scheme 62 illustrates an alternative synthesis of key substituted hydrazine 347 of compounds wherein Q is Q-39. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36. The nitrophenyl substituted amine 343 is reacted with p-nitrophenyl chloroformate to give rise to carbamate 344.
Reaction of 344 with a suitable amino acid ester affords urea 345, which is cyclized under basic conditions to give triazolinedione 346. Reduction of the nitro group of 346, diazotization of the resulting amine, and reduction of the diazonium salt affords key hydrazine 347.
Scheme 62 H
p-Nitrophenyl OZN mt ~ ~ I NOz ~~N~N,COzR3 OZN ~.)t chloroformate N
~
~ H
NHz Base Base OZN ~ -?a Base OZN/-(~')t O 1) Pd/C, H2 (Y)t H iNCO2R3 O~
345 N R4 2) NaNOZ HCI
R4 346 R4 3) SnC12 H
H N-N ~)~ " \
z N
j O N
Scheme 63 illustrates the synthesis of compounds wherein Q is Q-43. Morphiline is alkylated with protected bromohydrine. Removal of the alcohol protecting group yields intermediate 349, which can be oxidized to aldehyde 350. When G NH, iodoaniline 351 is reacted with 350 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 352. This intermediate. is converted to the substituted hydrazine 353 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 355 is either alkylated with 354 or reacted under Mitsunobu conditions with alcohol 349 to yield intermediate 356. This intermediate is converted to the substituted hydrazine 353 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 63 BOC
i ~ NH2 Na BH(OAc)3 _N~~ NH2-NHBOC ~ N N~
~/ o '' v 0 Cu(1) H?N I/ 1 I y N~ IC
H
351 0N v 352 353 lEo]
H
CN~ I) TBSO -1~4 Br /--\ OH
2 TBAF v O ) Mitsunobu 348 349 Reaction j~ Ox lN
~~ Bi oc /OH 354 /O\/N~ NHZ-NHBoc HsNN ~
Base / 1110 Cu(I) ~/ 1 I v 355 356 35'7 \~
Scheme 64 illustrates the synthesis of compounds wherein Q is Q-43, G=CH2.
Nitroacid 358 (readily available by anyone with normal skills in the art) is reacted with morphiline to yield amide 359, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 360. This hydrazine can be converted into compounds of formula I_B using the methods previously outlined in Schemes 35 and 36.
Scheme 64 O
O 1) LAH O
OzN~ ~ Il OH EDC, HOBT OzN ~ L) ]l 2) Pd/C HZNHN ~
~ N
I/ N I v 3) NaNO2, HCI ~/ v ~ I~
4) SnC1Z
358 Co 359 360 Scheme 65 illustrates the synthesis of compounds wherein Q is Q-44. N-methyl piperazine 361 is alkylated with protected bromohydrine. Removal of the alcohol protecting ] 5 group yields intermediate 362, which can be oxidized to aldehyde 363. When G=NH, iodoaniline 364 is reacted with 363 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 365. This intermediate is converted to the substituted hydrazine 366 by Cu(1)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 368 is either alkylated with 367 or reacted under Mitsunobu conditions with alcohol 362 to yield intermediate 369. This intermediate is converted to the substituted hydrazine 370 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 65 BOC
i I~ ryHZ Na BH(OAc)3 ' I ' v ON,R4 z NHi-NHBOH N'N I~ jN~~H Cu(I) / v N'~
364 R~- ~N () v 365 366 H /~ If01 N 1) TBSO/_~B~ ,~ OH
C / V Rq-N~\N-(')v ~J
N 2) TB~ ~ Mitsunobu R4 ~ L62 Reaction /-Ox Ra- N-() v Boc jOH 367 NH2-NHBoc HzNN I~ jO N~
I / Base v ~N.~ Cu(I) ~v ~N'~
368 %' 369 I\%' 370 Scheme 66 illustrates the synthesis of compounds wherein Q is Q-44, G=CH2.
Nitroacid 371 (readily available by anyone with normal skills in the art) is reacted with N-methyl piperazine to yield amide 372, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 373. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 66 0 0 1) LAH 0 OiN ~ EDC, HOBT 02N 2) Pd/C HyNHN
I ( OH --- I~ N~ ~ N
/ v N) 372 v N 3) NaNO2, HCI N, 371 (R44) SnCIz 373 R4 N
Rr Scheme 67 illustrates the synthesis of compounds wherein Q is Q-45.
Thiomorpholine sulphone 374 is alkylated with protected bromohydrine. Removal of the alcohol protecting group yields intermediate 375, which can be oxidized to aldehyde 376.
When G=NH, iodoaniline 377 is reacted with 376 under reductive amination conditions, preferably sodium triacetoxvborohydride, to afford intermediate 378. This intermediate is converted to the substituted hydrazine 379 by Cu(I)-catalyzed reaction with N-BOC
hydrazine. When G=O, iodophenol 380 is either alkylated with 381 or reacted under Mitsunobu conditions with alcohol 375 to yield intermediate 382: This intermediate is converted to the substituted hydrazine 383 by Cu(I)-catalyzed reaction with N-BOC
hydrazine.
Scheme 67 BOC
i I~ NH2 Na BH(OAc)3 NõM, N ~ NHZ-NHBOC H,N' N I~ N~os-0 v 0 H o Ca(I) / 377 vv 1[0]
N 1) TBSO-~4Br 0' OH
v C J 2 TBAF N v OSO ) Mitsunobu 375 Readion O~S/_~N~Ox Boc I \/OH ' 381 y i I\~O~c ~N~ NHZ-NHBOC H2NN I\ O"c ~OS=O
I / Base S=O Cu(I) l 1 O
Scheme 68 illustrates the synthesis of compounds wherein Q is Q-44, G=CH2.
Nitroacid 384 (readily available by anyone with normal skills in the art) is reacted with thiomorpholine sulphone to yield amide 385, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 386. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 68 0 0 I) LAH 0 02N' ~l x EDC, HOBT 02N \ L\ jj 2) Pd/C H2NHN I
/, N /~7/~N
O H --~ I N~
v N / v SnO 3) NaNOZ, HCI v ~S~O
~
384 C) 385 0 4) SnCIZ 386 O
O~S~O
Scheme. 69 illustrates the synthesis of compounds wherein Q is Q-46.
Piperadine derivative 387 is alkylated with protected bromohydrine. Removal of the alcohol protecting group_yields_intermediate_ 388, which can__be-oxidized_to- aldehy.de _389.__ When_ G=NH, iodoaniline 390-is reacted with 389 under reductive amination conditions, preferably sodium triacetoxyborohydride, to afford intermediate 391. This intermediate is converted to the substituted hydrazine 392 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
When G=O, iodophenol 393 is either alkylated with 396 or reacted under Mitsunobu conditions with alcohol 388 to yield intermediate 394. This intermediate is converted to the substituted hydrazine 395 by Cu(I)-catalyzed reaction with N-BOC hydrazine.
Scheme 69 H BOC
i I jNH Ne BH(OAC)3 i I\ N CkRi NHyNHBOC HN N jN
2 ' ' ' ~-~ Z ' I
~ ~\ O H oCu(I) ~ I.t Rio 390 R O>( N 391 OR" 392 OR44 ar ~/ II
Br 1) TBSO~ OH
v Rlo N
2) TBAF R440 v Miisunobu R440 RIo ~ 398 Reaction R~o RaO/N ~Ox Boc i /OH 396 j v ON NHZ-NHBOC HzNN I\ 0 N
/ Base v Rio CU(I) ~j Rio 393 394 ORM 395 OR,u Scheme 70 illustrates the synthesis of compounds wherein Q is Q-44, G=CHZ.
Nitroacid 397 (readily available by anyone with normal skills in the art) is reacted with thiomorpholine sulphone to yield amide 398, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 399. This hydrazine can be converted into compounds of formula IB using the methods previously outlined in Schemes 35 and 36.
Scheme 70 0 0 1) LAH 0 p2N EDC,HOBT 02N 2) Pd/C HzNHN
~ OH N
/ v H
R~o) NaNOq, HC Rio pR44) SnC12 399 pa4a R44p Rio AFFINITY AND BIOLOGICAL ASSESSMENT
A fluorescence binding assay is used to detect binding of inhibitors of Formula I with unphosphorylated p38-alpha kinase as previously described: see J. Regan et al, Journal of Medicinal Chemistry (2002) 45:2994.
1. P38 MAP kinase binding assay The binding affinities of small molecule modulators for p38 MAP kinase were determined using a competition assay with SKF 86002 as a fluorescent probe, modified based on published methods (C. Pargellis, et al Nature Structural Biology (2002) 9, 268-272. J..
Regan, et al J. Med. Chem. (2002) 45, 2994-3008). Briefly, SKF 86002, a potent inhibitor of p38 kinase (Kd = 180 nM), displays an emission fluorescence around 420 nm when excitated at 340 nm upon its binding to the kinase. Thus, the binding affinity of an inhibitor for p38 kinase can be measured by its ability to decrease the fluorescence from SKF
86002. The assay was performed in a 384 plate (Greiner uclear 384 plate) on a Polarstar Optima plate reader (BMG). Typically, the reaction mixture contained I M SKF 86002, 80 nM
p38 kinase and various concentrations of an inhibitor in 20 mM Bis-Tris Propane buffer, pH 7, containing 0.15 %(w/v) n-octylglucoside and 2 mM EDTA in a final volume of 65 l. The reaction was initiated by addition of the enzyme. The plate was incubated at room temperature (- 25 C) for 2 hours before reading at emission of 420 nm and excitation at 340 nm. By comparison of rfu (relative fluorescence unit) values with that of a control (in the absence of an inhibitor), the percentage of inhibition at each concentration of the inhibitor was calculated. IC50 value for the inhibitor was calculated from the %
inhibition values obtained at a range of concentrations of the inhibitor using Prism. When time-dependent inhibition was assessed, the plate was read at multiple reaction times such as 0.5, 1, 2, 3, 4 and 6 hours. The IC50 values were calculated at the each time point. An inhibition was assigned as time-dependent if the IC5o values decrease with the reaction time (more than two-fold in four hours). This is illustrated below in Table 1.
Table 1 Example # IC50, nM Time-dependent 1 292 Yes 2 997 No 2 317 No 3 231 Yes 4 57 Yes 1107 No 6 238 Yes 7 80 Yes 8 66 Yes 9 859 No 2800 No 11 2153 No 12 -10000 No 13 384 Yes 949 No 19 -10000 No 21 48 Yes 22 666 No 151 Yes 26 68 Yes 29 45 Yes 87 Yes 31 50 Yes 32 113 Yes 37 497 No 38 508 No 41 75 Yes 42 373 No 43 642 No 45 1855 No 46 1741 No 47 2458 No 48 3300 No 57 239 Yes IC50 values obtained at 2 hours reaction time P-38 alpha kinase assay (spectrophometric assay) Activity of phosphorylated p-38 kinase was determined by following the production of ADP -from- the kinase-.-reaction _through._coupling_with-_the_pyruvate-_kinase/lactate dehydrogenase system-(e.g., Schindleri et- al.--Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH was continuously measured spectrophometrically. The reaction mixture (100 l) contained phospho p-38 alpha kinase (3.3 nM. Panvera), peptide substrate (IPTSPITTTYFFFKKK-OH, 0.2 mM), ATP (0.3 mM), 1VIgC12 (10 mM), pyruvate kinase (8 units. Sigma), lactate dehydrogenase (13 units. Sigma), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 65 mM Tr_is buffer,_.pH 7.5, containing 3.5 % DMSO and 150 uM n-Dodecyl-B-D-maltopyranoside. The reaction was initiated by adding ATP. The absorption at 340 nm was monitored continuously for up to 4 hours at 30 C on Polarstar Optima plate reader (BMG). The kinase activity (reaction rate) was calculated from the slope at the time frame from 1.5 h to 2 h. Under these conditions, a turn over number (kat) of -1 s"1 was obtained. The reaction rates calculated from different time frames such as 0.5 min to 0.5 h, 0.5 h to I h, 1.5 h to 2 h or 2.5 h to 3 h were generally constant.
For inhibition detenninations, test compounds were incubated with the reaction mixture for - 5 min before adding ATP to start the reaction. Percentage of inhibition was obtained by comparison of reaction rate with that of a control well containing no test compound. IC50 values were calculated from a series of % inhibition values determined at a range of concentrations of each inhibitor using Prism to process the data and fit inhibition curves. Generally, the rates obtained at the time frame of 1.5 h to 2 h were used for these calculations. In assessing whether inhibition of a test compound was time-dependent (i.e., greater inhibition with a longer incubation time), the values of % inhibition and/or IC50 values obtained from other time frames were also calculated for the inhibitor.
The biological activity for compounds of the present invention in the spectrophotometric assay are illustrated in Tables 2 and 3.
Example # IC50, uM % inhibition concentration, uM
1 0.067 2 0.29 3 0.019 4 0.609 0.514 6 0.155 7 0.165 9 0.355 83% 10 11 0.953 12 70% 10 13 0.269 14 0.096 0.53 17 40% 10 18 60% 10 21 0.171 22 0.445 0.055 26 0.19 29 0.011 0.251 31 . 0.056 32 0.307 38 0.51 39 0.012 0.055 41 0.013 42 0.425 43 7.5 0.48 47 0.295 49 0.071 51 0.033 52 0.416 53 0.109 54 68% 1.0 0.74 57 0.782 58 0.172 59 0.709 0.264 D 0.179 F 0.437 Example # IC50, uM % Inhibition concentration, uM
146 9% 10 147 27% 10 150 5 3 % CM- 10 154 21% 10 155 58% 10 160 0.044 161 0.1 162 0.65 163 0.464 196 0.028 197 0.243 198 0.137 199 0.684 200 73% 1.0 201 0.029 202 1.9 203 0.328 204 0.008 206 0.013 207 0.033 209 0.354 284 1.95 285 0.102 286 0.079 287 0.041 288 0.104 289 1.3 291 5.1 294 2.1 295 1.2 296 0.284 297 0.34 298 0.025 299 2.3 300 0.251 301 0.63 302 0.077 Human peripheral blood mononuclear leukocyte cell assay.
Human peripheral blood mononuclear leukocytes are challenged with 25ng/mL
lipopolysaccharide (LPS) in the absence or presence of Test Compound and incubated for 16 hours as descr.ibed by. Welker P. et al, International Archives Allergy and Immunology (1996) 109: 110. The quantity of LPS-induced tumor necrosis factor-alpha (TNF-alpha) cytokine release is measured by a commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit. Test compounds are evaluated for their ability to inhibit TNF-alpha release.
Table 2 records IC50 values for inhibition of TNF-alpha release by Test Compounds of the present invention, wherein the IC50 value, in micromolar concentration, represents the concentration of Test Compound resulting in a 50% inhibition of TNF-alpha release from human peripheral blood mononuclear leukocytes as compared to control experiments containing no Test Compound. Test compounds evaluated are illustrated in Table 4.
Example Number IC50, uM
3 6.1 13 6.32 21 3.4 29 2.68 31 4.52 60 2.34 296 3.49 300 4.78 302 5.45 EXAMPLES
The following examples set forth preferred methods in accordance with the invention.
It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.
[Boc-sulfamide] aminoester (Reagent AA), 1,5,7,-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid (Reagent BB), and Kemp acid anhydride (Reagent CC) was prepared according to literature procedures. See Askew et. al J. Am. Chem.
Soc. 1989, 111, 1082 for further details.
EXAMPLE A
N~ N NH2 Et02C b To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) in concentrated HC1 was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mol) at 0 C. The reaction mixture was stirred for I h and a solution of SnCl2=2H20 (662 g, 2.92 mol) in concentrated HCI
(2 L) was then added at 0 C, and the reaction stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-hydrazino-benzoic acid hydrochloride as a white solid.
The crude material from the previous reaction (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) were heated to reflux overnight. The reaction solution was evaporated in vacuo and the residue purified by column chromatography to yield ethyl 3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)benzoate (Example A, 116 g, 40%) as a white solid together with 3-(5-amino-3-tert-butyl-1 H-pyrazol-l-yl)benzoic acid (93 g, 36%). 'H NMR
(DMSO-d6): 8.09 (s, 1 H), 8.05 (brd, J= 8.0 Hz, 1 H), 7.87 (brd, J= 8.0 Hz, 1 H), 7.71 (t, J= 8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H), 1.28 (s, 9H).
EXAMPLE B
N/ 1 J~ \ I
'N H H \ ~
EtO2C
To a solution of 1-naphthyl isocyanate (9.42 g, 55.7 mmol) and pyridine (44 mL) in THF
(100 mL) was added a solution of Example A (8.0 g, 27.9 mmol) in THF (200 mL) at 0 C. The mixture was stirred at RT for lh, heated until all solids were dissolved, stirred at RT for an additional 3h and quenched with H20 (200 mL). The precipitate was filtered, washed with dilute HCl and H20, and dried in vacuo to yield ethyl3-[3-t-butyl-5-(3-naphthalen-1-yl)ureido)-1H-pyrazol-l-yl]benzoate(12.0 g, 95%) as a white power. 'H NMR (DMSO-d6): 9.00 (s, 1 H), 8.83 (s, 1 H), 8.25 7.42 (m, 11 H), 6.42 (s, 1 H), 4.30 (q, J 7.2 Hz, 2 H), 1.26 (s, 9 H), 1.06 (t, J
7.2 Hz, 3 H); MS (ESI) m/z: 457.10 (M+H+).
EXAMPLE C
CI
N/ \
, N N N
H H
EtO2C
To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine (56 mL) and THF (30 mL) was added a solution of 4-nitrophenyl 4-chlorophenylcarbamate (10 g, 34.8 mmol) in THF (150 mL) at 0 C. The mixture was stirred at RT for 1 h and heated until all solids were dissolved, and stirred at RT for an additional 3 h. HZO (200 mL) and CHZCIZ
(200 mL) were added, the aqueous phase separated and extracted with CHZC12 (2 x 100 mL). The combined organic layers were washed with 1N NaOH, and 0.1N HCI, saturated brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield ethyl 3-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-l-yl}benzoate (8.0 g, 52%). 'H NMR (DMSO- d6):
S 9.11 (s, 1 H), 8.47 (s, 1 H), 8.06 (m, 1 H), 7.93 (d, J= 7.6 Hz, 1 H), 7.81 (d, J= 8.0 Hz, 1 H), 7..65 (dd, J
= 8.0, 7.6 Hz, 1 H), 7.43 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, IH), 4.30 (q, J=
6.8 Hz, 2H), 1.27 (s, 9H), 1.25 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 441 (M++H).
EXAMPLE D
N/ J' 'N H H
b HO To a stirred solution of Example B(8.20 g, 18.0 mmol) in THF (500 mL) was added LiA1H4 powder (2.66 g, 70.0 mmol) at -10 C under N2. The mixture was stirred for 2 h at RT
and excess LiA1H4 destroyed by slow addition of ice. The reaction mixture was acidified to pH
= 7 with dilute HCI, concentrated in vacuo and the residue extracted with EtOAc. The combined organic layers were concentrated in vacuo to yield 1- { 3-tert-butyl-l-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (7.40 g, 99%) as a white powder. 'H
NMR (DMSO-d6): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, 11 H), 6.41 (s, 1 H), 4.60 (s, 2 H), 1.28 (s, 9 H); MS (ESI) m/z: 415 (M+H+).
EXAMPLE E
N/ \ ~ \ I
, N
H H
Cl \
A solution of Example C (1.66 g, 4.0 mmol) and SOCIZ (0.60 mL, 8.0 mmol) in (100 mL) was refluxed for 3 h and concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (1.68 g, 97%) was obtained as white powder. 'H NMR (DMSO-d6): S 9.26 (s, 1 H), 9.15 (s, 1 H), 8.42 - 7.41 (m, 11 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H). MS (ESI) m/z: 433 (M+H+).
EXAMPLE F
CI
N
, N N i N \ I
H H
/ ~
HO \
To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added LiA1H4 powder (413 mg, 10.9 mmol) at -10 C under N2. The mixture was stirred for 2h and excess LiAlH4 was quenched by adding ice. The solution was acidified to pH = 7 with dilute HCI. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200 +
100 mL). The filtrate was concentrated to yield 1-{3-tert-butyl-l-[3-hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.40 g, 97%).'H NMR (DMSO- d6): S
9.11 (s, 1H), 8.47 (s, IH), 7.47-7.27 (m, 8H), 6.35 (s, IH), 5.30 (t, J 5.6 Hz, 1 H), 4.55 (d, J 5.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 399 (M+H+).
EXAMPLE G
0 / ~~
N~ N ' N J~. N\ I
H H
Cl A solution of Example F (800 mg,.2.0 mmol) and SOC12 (0.30 mL, 4 mmol) in (30 mL) was refluxed gently for 3h. The solvent was evaporated in vacuo and the residue was taken up to in CH2C12 (2 x 20 mL). After removal of the solvent, 1-{3-tert-butyl-l-[3-(chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (812 mg, 97%) was obtained as white powder.'H NMR (DMSO- d6): S 9.57 (s, 1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.50 - 7.26 (m, 7H), 6.35 (s, 1H), 4.83 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 417 (M+H+).
EXAMPLE H
To a suspension of LiAlH4 (5.28 g, 139.2 mmol) in THF (1000 mL) was added Example A (20.0 g, 69.6 mmol) in portions at 0 C under N2. The reaction mixture was stirred for 5 h, quenched with I N HC1 at 0 C and the precipitate was filtered, washed by EtOAc and the filtrate evaporated to yield [3-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)phenyl]methanol (15.2 g, 89%).
'H NMR (DMSO-d6): 7.49 (s, 111), 7.37 (m, 2H), 7.19 (d, J = 7.2 Hz, IH), 5.35 (s, 1H), 5.25 (t, J=5.6 Hz, 1 H), 5.14 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 1.19 (s, 9H); MS
(ESI) m/z: 246.19 (h'1+H+)=
The crude material from the previous reaction (5.0 g, 20.4 mmol) was dissolved in dry THF (50 mL) and SOC12 (4.85 g, 40.8 mmol), stirred for 2h at RT, concentrated in vacuo to yield 3-tert-butyl-l-(3-chloromethylphenyl)-1 H-pyrazol-5-amine (5.4 g), which was added to N3 (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixture was heated at 30 C for 2 h, poured into H20 (50 mL), and extracted with CHZCIZ. The organic layers were combined, dried over MgSO4, and concentrated in vacuo to yield crude 3-tert-butyl-l-[3-(azidomethyl)phenyl]-1H-pyrazol-5-amine (1.50 g, 5.55 mmol).
EXAMPLE I
\ 0 N~ ~
NN
N
H H
~ I
H2N ~
Example H was dissolved in dry THF (10 mL) and added a THF solution (10 mL) of isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3h, quenched with H20 (30 mL), the resulting precipitate filtered and washed with 1 N HCI and ether to yield 1-[2-(3-azidomethyl-phenyl)-5-t-butyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (2.4 g, 98%) as a white solid.
The crude material from the previous reaction and Pd/C (0.4 g) in THF (30 mL) was hydrogenated under 1 atm at RT for 2 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-(amonomethyl)phenyl}-1H-pyrazol-5y1)-3-(naphthalene-l-yl)urea (2.2 g, 96%) as a yellow solid. 'H NMR (DMSO-d6): 9.02 (s, 1H), 7.91 (d, J= 7.2 Hz,1H), 7.89 (d, J= 7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, 1H), 3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H+) EXAMPLE J
/ ci I
N% N NN \
H H
H2N \
To a solution of Example H(1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF
solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H20 (30 mL) was added. The precipitate was filtered and washed with 1N HCI and ether to give 1-{3-tert-butyl-l-[3-(amonomethyl)phenyl}-1H-pyrazol-5y1)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for next step without further purification. MS (ESI) m/z: 424 (M+H+).
EXAMPLE K
H
N~
N . N
H H
To a solution of benzyl amine (16.5g, 154 mmol) and ethyl bromoacetate (51.5g, mmol) in ethanol (500 mL) was added KZC03 (127.5g, 924 mmol). The mixture was stirred at RT for 3h, was filtered, washed with EtOH, concentrated in vacuo and chromatographed to yield N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (29g, 67%). 'H
NMR (CDC13):
8 7.39-7.23 (m, 514), 4.16 (q, J= 7.2 Hz, 4H);-3-:9T(s,-2H),-3.-54"(s; 4H);-T:26'(t; J="7:2 Hz, 6H);
MS (ESI): m/e: 280 (M++H).
A solution ofN-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (7.70g, 27.6 mmol) in methylamine alcohol solution (25-30%, 50 mL) was heated to 50 C in a sealed tube for 3h, cooled to RT and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide in quantitative yield (7.63g). 'H NMR
(CDC13): S 7.35-7.28 (m, 5H), 6.75 (br s, 2H), 3.71(s, 2H), 3.20 (s, 4H), 2.81 (d, J= 5.6 Hz, 6H); MS (ESI) m/e 250(M+H+).
The mixture ofN-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40 C under 40 psi H2 for lOh, filtered and concentrated in vacuo to yield. N-(2-methylamino-2-oxoethyl)-glycinemethylamide in quantitative yield (1.76g). 'H
NMR (CDC13):
S 6.95(br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25(br s 1H); MS
(ESI) m/e 160(M+H+) fI
N NJ~N \
N H H I
N /O /
HN IN ~ I
O
To a solution of 1-methyl-[1,2,4]triazolidine-3, 5-dione (188 mg, 16.4 mmol) and sodium hydride (20 mg, 0.52 mmol) in DMSO (I mL) was added Example E (86 mg, 0.2 mmol). The reaction was stirred at RT overnight, quenched with H20 (10 mL), extracted with CH2C12, and the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to yield 1-(3-tert-butyl-l-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]phenyl } -1 H-pyrazol-5-yl)-3-(naphthalene-l-yl)urea (Example 1, 14 mg). 'H NMR (CD3OD): 57.88-7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s, 6H); MS
(ESI) m/z: 525 (M+H+).
cl N/ \ ~ \ I
, N N N
O H H
N~ /
H N N \ ~
)r O
The title compound was synthesized in a manner analogous to Example 1, utilizing Example G to yield 1-(3-tert-butyl-l-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea'H NMR (CD3OD): 8 7.2-7.5 (m, 7H), 6.40 (s 1 H), 4.70 (s, 2H), 2.60 (d, J=14 Hz, 2H), 1.90 (m, l H), 1.50 (m, 1 H),1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H+).
OI
N N ' NJI~N
r--f O H H
HN~, ~N
OSO
A mixture of compound 1,1-Dioxo-[ 1,2,5]thiadiazolidin-3-one (94 mg, 0.69 mmol) and NaH (5.5 mg, 0.23 mmol) in THF (2 mL) was stirred at -10 C under NZ for 1 h until all NaH was --dissolved. Example E(100 mg, 0--23 mmol) was added- and the reaction was allowed to stir at RT
overnight, quenched with H20, and extracted with CHZC12. The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC to yield 1-(3-tert-butyl-1-{ [3-(1,1,3-trioxo-[ 1,2,5]thiadiazolidin-2-yl)methyl]phenyl } -1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea (18 mg) as a white powder. 'H NMR (CD3OD): 6 7.71 - 7.44 (m, 11 H), 6.45 (s, I H), 4.83 (s, 2 H), 4.00 (s, 2 H), 1.30 (s, 9 H). MS (ESI) m/z: 533.40'(M+H+).
NN N N\ I
O H H
HN" 'IN
OS\\O
The title compound was obtained in a manner analogous to Example 3 utilizing Example G. to yield 1-(3-tert-butyl-l-{[3-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'H NMR (CD3OD): S 7.38 - 7.24 (m, 8 H), 6.42 (s, 1 H), 4.83 (s, 2 H), 4.02 (s, 2 H), 1.34 (s, 9 H); MS (ESI) m/z: 517 (M+H+).
~ ci N NN ~ I
H H
H H ~ I
ONN, N ~
0 O S~O
-To a stirred solution of chlorosulfonyl isocyanate (19.8 L, 0.227 mmol) in CH2C12 (0.5 mL) at 0 C was added pyrrolidine (18.8 L, 0.227 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After stirring for 1.5 h, a solution of Example J (97.3 mg, 0.25 mmol) and Et3N (95 L, 0.678 mmol) in CHZC12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 C. When the addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10%
HCI, extracted with CH2Cl2, the organic layer washed with saturated NaC1, dried over MgSO4, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC
t o y i e 1 d 1-( 3 t e r t- b u t y 1- l -[[ 3- N-[[( 1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'H NMR(CD3OD): S 7.61 (s, 1 H), 7.43 -7.47 (m, 3 H), 7.23 -7.25 (dd, J
=6.8 Hz, 2 H), 7.44 (dd, J=6.8 Hz, 2 H), 6.52 (s, 1 H), 4.05 (s, 2 H), 3.02 (m, 4 H), 1.75 (m, 4 H), 1.34 (s, 9 H); MS (ESI) m/z: 574.00 (M+H+).
NI NJ~N
N H
a H
~ \ I
N~ N
O 0 i~0 The title compound was made in a manner analogous to Example 5 utilizing Example I
to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]-phenyl]-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.'HNMR (CDC13): S 7.88 (m, 2 H), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, 1 H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H+).
CI
O
/ II
N
H H
/
H H
N'S'N N ,~ ~
O~ ~O ~
O
To a stin=ed solution of chlorosulfonyl isocyanate (19.8 A, 0.227 ok) tv XHiXxo (0.5 A) aT 0 C, was added Example J (97.3 mg, 0.25 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of pyrrolidine (18.8 L, 0.227 mmol) and Et3N (95 L, 0.678 mmol) in CH2C12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 C. When addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10%
HCI, extracted with CH2C121 the organic layer was washed with saturated.NaCl, dried over MgZSO4, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'HNMR (CDC13): S 7.38 (m, 1 H), 7.36 - 7.42 (m, 3 H), 7.23 (d, J= 8.8 Hz, 2 H), 7.40 (d, J= 8.8 Hz, 2 H), 6.43 (s, 1 H), 4.59 (s, 1 H), 4.43 (s, 2 H), 1.81 (s, 2 H), 1.33 (s, 9 H); MS (ESI) m/z: 574.10 (M+H+).
oII
N/ NN
N H H
OtN N N \ I
OOy O
The title compound was made in a manner analogous to Example 7 utilizing Example I
to yield 1-(3-tert-butyl-l-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]-phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.'HNMR (CDC13): S 7.88 (m, 2 H), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, I H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77-1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H+).
N,N H H
p' NH
H~IY
N
To a solution of Reagent BB (36 mg, 0.15 mmol), Example I(62 mg, 0.15 mmol), HOBt (40 mg, 0.4 mmol) and NMM (0.1 mL, 0.9 mmol) in DMF (10 mL) was added EDCI (58 mg, 0.3 mmol). After being stirred overnight, the mixture was poured into water (15 mL) and extracted with EtOAc (3 5 mL). The organic layers were combined, washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to yield 1,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1 ]nonane-7-carboxylic acid 3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]benzylamide (22 mg). 'H NMR (CDC13): S
8.40 (s, 1H), 8.14 (d, J= 8.0 Hz, 2H), 7.91 (s, 1 H), 7.87 (s, 1 H), 7.86 (d, J= 7.2 Hz, 1 H), 7.78 (d, J= 7.6 Hz, 1 H), 7.73 (d, J= 8.4 Hz, 1 H), 7.69 (d, J= 8.4 Hz, 1 H), 7.57-7.40 (m, 4H), 7.34 (d, J= 7.6 Hz, 1 H), 6.69 (s, 1 H), 6.32 (t, J= 5.6 Hz, 1 H), 5.92 (brs, 1 H), 4.31 (d, J=
5.6 Hz, 2H), 2.37 (d, J=
14.8 Hz, 2H), 1. 80 (d, J= 13.2 Hz, 1 H), 1.35 (s, 9H), 1.21 (d, J= 13.2 Hz, 1 H), 1.15 (s, 3H), 1.12 (d, J= 12.8 Hz, 2H), 1.04 (s, 6H); MS (ESI) m/z: 635 (M+H+).
iO(d1 H H
O IpY,NH
The title compound, was synthesized in a manner analogous to Example 9 utilizing Example J to yield 1,5,7-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid 3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-l-yl}benzylamide.'H NMR
(CDC13): 8 8.48 (s, 1H), 7.78 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.69 (s, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.48 (d, J= 8.8 Hz, 2H), 7.26 (m, 3H), 6.62 (s, 1 H), 6.35(t, J= 6.0 Hz, 1 H), 5.69 (brs, 1H), 4.26 (d, J= 6.0 Hz, 2H), 2.48 (d, J=14.0 Hz, 2H), 1.87 (d, J=13.6 Hz,1H),1.35 (s, 9H), 1.25 (m, 6H), 1.15 (s, 6H);
MS (ESI) m/z: 619 (M+H+).
o N'\ N~N
H
/
O N O
A mixture of Example I(41 mg, 0.1 mmol), Kemp acid anhydride (24 mg, 0.1 mmol) and Et3N (100 mg, 1 mmol) in anhydrous CH2C12 (2 mL) were stirred overnight at RT, and concentrated in vacuo. Anhydrous benzene (20 mL) was added to the residue, the mixture was refluxed for 3h, concentrated in vacuo and purified by preparative HPLC to yield 3-{3-[3-t-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-l-yl]-benzyl } -1,5-di-methyl-2,4-dioxo-3-aza-bicyclo[3.3.1 ]nonane-7-carboxylic acid (8.8 mg, 14%). 'H NMR (CD3OD): S 7.3 -7.4 (m, 2H), 7.20 (m, 2H), 7.4 - 7.6 (m, 7H), 6.50 (m, 1 H), 4.80 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1H), 1.40 (m, 1H), 1.30 (m, 2H), 1.20 (s, 3H), 1.15 (s, 6H); MS (ESI) m/z: 636 (M+H+).
0 / C' ~N
NN N ~
H
CO,H
The title compound, was synthesized in a manner analogous to Example 11 utilizing Example J to yield 3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-l-yl]-benzyl}-1,5-dimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid. 'H NMR
(CD3OD): S 7.2 -7.5 (m, 7H), 6.40 (s 1 H), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1 H), 1.50 (m, 1 H), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H').
N/ \ ~ \ I
\N H H
/
HN" N O
O
The title compound was synthesized in a manner analogous to Example I
utilizing Example E and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-l-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-1-yl)methyl]phenyl} -1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea. 'H NMR
(CD3OD): S 7.88 - 7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s, 6H);MS (ESI) m/z: 525 (M+H+).
- - -/ CI
N/ \ ' N N N N
H H
HN' N O
O
The title compound was synthesized in a manner analogous to Example 1 utilizing Example G and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-l-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-l-yl)methyl]phenyl } -11Y-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
'H NMR (CD3OD): 6 7.60 - 7.20 (m, 8H), 6.43 (s, 111), 4.70 (s, 1 H), 1.34 (s, 9H), 1.26 (s, 6H);
MS (ESI) m/z: 509, 511 (M+H+).
HN N, N
O1:1) H H
N
' N O
H
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (64.2 mg, 0.15 mmol) were added HOBt (30 mg, 0.225 mmol), Example K (24 mg, 0.15 mmol) and 4-methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF (3 mL) and EDCI (43 mg, 0.225 mmol).
The reaction mixture was stirred at RT overnight and poured into HZO (3mL), and a white precipitate collected and further purified by preparative HPLC to yield 1-[1-(3-{bis [(methylcarbamoyl)methyl]carbamoyl } phenyl)-3-tert-butyl-1 H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (40 mg). 'H NMR (CDC13): S 8.45 (brs, 1 H), 8.10 (d, J 7.6 Hz; 1 H), 7.86-7.80 (m, 2H), 7.63-7.56 (m, 2H), 7.52 (s, IH), 7.47-7.38 (m, 3H), 7.36-7.34 (m, IH), 7.26 (s, IH), 7.19-7.17 (m, 2H), 6.60 (s, 1H), 3.98 (s, 2H), 3.81 (s, 3H), 2.87 (s, 3H), 2.63 (s, 3H),1.34 (s, 9H); MS
(ESI) m/z: 570 (M+H+).
/ \ ~ ~ I
HN NN N N
N I / H H
O-:--~ ~
N -~O C
H
The title compound was synthesized in a manner analogous to Example 15 utilizing Example C ( 3 7 mg) and Example K to y i e l d 1-[ 1-(3-{bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-tert-butyl-1 H-pyrazol-5-yl]-3-(4-chlorophenyl)urea. 'H NMR (CD3OD): 6 8.58 (brs, 1'H), 8.39 (brs, IH), 7.64 -7.62 (m, 3H), 7.53-7.51 (m, l H), 7.3 8(d, J= 9.2 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.44 (s, 1 H), 4.17 (s, 2H), 4.11 (s, 2H), 2.79 (s, 3H), 2.69 (s, 3H), 1.34-1.28 (m, 12H); MS (ESI) m/z:
554 (M+H+).
O
\
N,N NN
H H
O I /
p O
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (0.642 g, 1.5 mmol) in dry THF (25 mL) at -78 C were added freshly distilled triethylamine (0.202 g, 2.0 mmol) and pivaloyl chloride (0.216 g,1.80 mmol) with vigorous stirring. After stirring at -78 C for 15 min and at 0 C for 45 min, the mixture was again cooled to -78 C and then transferred into the THF solution of lithium salt of D-4-phenyl-oxazolidin-2-one [*: The lithium salt of the oxazolidinone regeant was previously prepared by the slow addition of n-BuLi (2.50M in hexane, 1.20 mL, 3.0 mmol) into THF solution of D- 4-phenyl-oxazoldin-2-one at -78 C]. The reaction solution was stirred at -78 C for 2 h and RT overnight, and then quenched with aq.
ammonium chloride and extracted with dichloromethane (100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl} -3-(naphthalen-l-yl)urea (207 mg, 24%). 'H NMR (CDC13): S 8.14 -8.09 (m, 2H), 8.06 (s, l H), 7.86 - 7.81 (m, 4H), 7.79 (s, 1 H), 7.68 - 7.61 (m, 2H), 7.51 -7.40 (m, 9H), 6.75 (s, 1 H), 5.80 (t, J=9.2, 7.6 Hz, 1 H), 4.89 (t, J= 9.2 Hz, 1 H), 4.42 (dd, J=9.2, 7.6 Hz, 1 H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H+).
N X ~ \ ( 'N H H
\
O I /
QFI.Co The title compound was synthesized in a manner analogous to Example 17 utilizing Example B and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-l-yl)urea'H NMR
(CDC13):
S 8.14 - 8.09 (m, 2H), 8.06 (s, l H),.7.86 - 7.81 (m, 4H), 7.79 (s, 1H), 7.68 -7.61 (m, 2H), 7.51 -7.40 (m, 9H), 6.75 (s, 1 H), 5.80 (t, J=9.2, 7.6 Hz, 1 H), 4.89 (t, J 9.2 Hz, 1 H), 4.42 (dd, J=9.2, 7.6 Hz, IH), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H+) O C
J ) NN N N
H H
_ --- - ~ \
O
N
IrO
O
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-(4-chlorophenyl)urea. 'H
NMR (CDC13):
6 7.91 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.79 (d, J 7.6 Hz, 1 H), 7.71 (m, 1 H), 7.65 (m, 1 H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1 H), 5.77 (dd, J= 8.8, 8.0 Hz, 1 H), 4.96 (t, 8.8 Hz, 1H), 4.44 (dd, J= 8.8, 8.0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H+) CI
~I
N N N
H H
~ \
O /
/
N
O
O
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(4-chlorophenyl)urea.'H NMR
(CDC13):
S 7.91 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.79 (d, J= 7.6 Hz, 1 H), 7.71 (m, 1 H), 7.65 (m, 1 H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1 H), 5.77 (dd, J= 8.8, 8.0 Hz, 1 H), 4.96 (t, 8.8 Hz, 1 H), 4.44 (dd, J= 8.8, 8.0 Hz, 1 H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H+) EXAMPLE L
N-N
.. ~N
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CHZC12 (40 ml, with a catalytic amount of DMF) at 0 C under NZ was added oxalyl chloride (1:1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1 -morpholin-4-yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-y1-2-(3-nitro-pheny)-ethanone (2 g) and 10 % Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCI (15 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-l-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N
HCI (I ml) were refluxed for I h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
N!
N
/
\ I HNO
H N
N
O
A mixture of Example L(0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2C12 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-l-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-l-yl)urea. mp: 194 - 196 ; 'H
NMR
(200MHz, DMSO-d6): 5 9.07 (IH, s), 8.45 (s, IH), 8.06 - 7.93 (m, 3H), 7.69 -7.44 (m, 7H), 7.33 - 7.29 (d, 6.9 Hz, 1H), 6.44 (s, IH), 3.85 (m, 2H), 3.54 - 3.45 (m, 8H), 1.31 (s, 9H); MS:
N
N
HN O
ogcl The title compound was synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-tert-butyl-l-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl} -3-(4-chlorophenyl)urea.
mp: 100 104 ;'H NMR (200MHz, DMSO-d6): S 9.16 (s, 1H), 8.45 (s, 1H), 7.52-7.30 (m, 8H), 6.38 (s, IH), 3.83 (m, IH), 3.53 - 3.46 (m, 8H), 1.30 (s; 9H); MS:
N-N
HN
N HN O
O
The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and phenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl } -3-phenylurea.
N
N
HNHN :&Ome OF
O
The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 1-isocyanato-4-methoxy-naphthalene to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl } -3-(1-methoxynaphthalen-4-yl)urea.
EXAMPLE M
O ~
N N~N ~ ~
H H
O I /
OEt The title compound is synthesized in a manner analogous to Example C utilizing Example A and phenylisocyanate to yield ethyl3-(3-tert-butyl-5-(3-phenylureido)-1 H-pyrazol-l-yl)benzoate.
EXAMPLE N
N-N
A solution of (3-nitrophenyl)acetic acid (23 g, 127 mmol) in methanol (250 ml) and a catalytic amount of concentrated in vacuo H2SO4 was heated to reflux for 18 h.
The reaction mixture was concentrated in vacuo to a yellow oil. This was dissolved in methanol (250 ml) and stirred for 18 h in an ice bath, whereupon a slow flow of ammonia was charged into the solution.
The volatiles were removed in vacuo. The residue was washed with diethyl ether and dried to afford 2-(3-nitrophenyl)acetamide (14 g, off-white solid). 'H NMR (CDC13): S
8.1 (s, 1H), 8.0 (d, 1 H), 7.7 (d, IH), 7. 5(m, 1 H), 7.1 (bd s, IH), 6.2 (brs, IH), 3.6 (s, 2H).
The crude material from the previous reaction (8 g) and 10 % Pd on activated carbon (1 g) in ethanol (100 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-aminophenyl)acetamide (5.7 g). A solution of this material (7 g, 46.7 mmol) was dissolved in 6 N HCl (100 ml), cooled to 0 C, and vigorously stirred.
Sodium nitrite (3.22 g, 46.7 mmol) in water (50 ml) was added. After 30 min, tin (II) chloride dihydrate (26 g) in 6 N HCI (100 ml) was added. The reaction mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazinophenyl)acetamide.
The crude material from the previous reaction (ca. 15 mmol) and 4,4-dimethyl-3-oxopentanenitrile ( 1.85 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1.5 ml) was refluxed for.
1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue, which was extracted with ethyl acetate. The solvent was removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)phenyl]acetamide as a white solid (3.2 g), which was used without further purification.
N-N
F HN~/O
HN
O
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2ClZ (4 ml) was stirred at RT under NZ for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-l-yl)urea as a white solid (0.22 g). mp: 230 (dec.); 'H NMR (200MHz, DMSO- d6): S 9.12 (s, 1H), 8.92 (s, 1 H), 8.32 - 8.08 (m, 3H), 7.94 - 7.44 (m, 8H), 6.44 (s, IH), 3.51 (s, 211), 1.31 (s, 9H); MS:
N--N
HN O
HzN HN 0 c, The title compound was synthesized in a manner analogous to Example 23 utilizing Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate (0.112 g, 0.73 mmol) to yield 1-{3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as a white solid (0.28 g). mp: 222 224 .(dec.);'H NMR (200MHz, DMSO- d6); S 9.15 (s,1H), 8.46 (s, IH), 7.55 - 7.31 (m, 8H), 6.39 (s, 1H), 3.48 (s, 2H), 1.30 (s, 9H); MS:
O
SNJLN
I H H
OEt The title compound is synthesized in a manner analogous to Example C utilizing Example A and 1-isocyanato-4-methoxy-naphthaleneto yield ethyl 3-(3-tert-butyl-5-(3-(1-methoxynaphthalen-4-yl)ureido)-1 H-pyrazol-l-yl)benzoate.
"+ H H
o The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and D-4-phenyl-oxazolidin-2-one to yield D-1-{ 5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-phenylurea.
N/ N N ~ . ~
H H
\
O I /
/
N O
i .. ~ \ ~
C O
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3-phenylurea.
EXAMPLE P
N
N
/ I
~ I NH2 O
MeO
A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10 % Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal of the volatiles in vacuo provided 3-(3-amino-phenyl)propionic acid methyl ester (6 g).
A vigorously stirred solution of the crude material from the previous reaction (5.7 g, 31.8 mmol) dissolved in 6 N HCl (35 ml) was cooled to 0 C, and sodium nitrite (2.2 g) in water (20 ml) was added. After lh, tin (II) chloride dihydrate (18 g) in 6 N HCI (35 ml) was added. And the mixture was stirred at 0 C for 3 h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided methyl 3-(3-hydrazino-phenyl)propionate (1.7 g).
A stirred solution of the crude material from the previous reaction (1.7 g, 8.8 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.2 g, 9.7 mmol) in ethanol (30 ml) and 6 N
HC1(2 ml) was refluxed for 18 h and cooled to RT. The volatiles were removed in vacuo and the residue dissolved in EtOAc and washed with I N aqueous NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo and the residue was purified by column chromatography using 30 %
ethyl acetate in hexane as the eluent to provide methyl 3-[3-(3-tert-butyl-5-amino-lH-pyrazol -1-yl)phenyl]propionate (3.2 g), which was used without further purification N
N
HNO
O HN
HO
A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19 g, 1.05 mmol) in dry CHZC12 (5 ml) was stirred at RT under N2 for 20 h. The solvent was removed. in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc and dilute citric acid solution. The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column chromatography using 3 % methanol in CH2C12 as the eluent to yield 3-(3-{3-tert-butyl-5-[3-(naphthalen-l-yl)ureido]-1H-pyrazol-l-yl)phenylpropionic acid (0.22 g, brownish solid). mp: 105-107 ;'H NMR (200MHz, CDC13):
S 7.87 - 7.36 (m, l OH), 7.18 - 7.16 (m, 1 H), 6.52 (s, 1 H), 2.93 (t, J= 6.9 Hz, 2H), 2.65 (t, J=
7.1 Hz, 2H), 1.37 (s, 9H); MS
Nf N
HN O
O HN
HO \ / CI
The title compound was synthesized in a manner analogous to Example 29 utilizing Example P(0.30g, 0.95 mmol) and 4-chlorophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3-{ 3-tert-butyl-5-[3-(4-chloropnehyl)ureido]-1 H-pyrazol-1-yl)phenyl)propionic acid (0.05 g, white solid). mp:85 87 ;'H NMR (200MHz, CDC13): S 8.21 (s, lH), 7.44 - 7.14 (m, 7H), 6.98 (s,1H), 6.55 (s, 1 H), 2.98 (t, J 5.2 Hz, 2H), 2.66 (t, J= 5.6 Hz, 2H), 1.40 (s, 9H);
MS
EXAMPLE Q
N
N /
Et0 HN-.~O
HN ~
O
A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for l 8h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
A solution of the crude material from the previous reaction (1.5 g, 8.4 mmol) was dissolved in 6 N HCl (9 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After lh, tin (II) chloride dihydrate (5 g) in 6 N HCl (10 ml) was added.
The reaction mixture was stirred at 0 C for 3h. The pH was adjusted to pH 14 with solid KOH
and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided ethyl3-(4-hydrazino-phenyl)-propionate(1 g).
The crude material from the previous reaction (1 g, 8.8 mmol) and 4,4-dimethyl-oxopentanenitrile ( 0.7 g) in ethanol (8 ml) and 6 N HCl (1 ml) was refluxed for 18h and cooled to RT. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with I N aqueous sodium hydroxide solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography using 0.7 %
methanol in CH2C12 as the eluent to provide ethyl 3-{4-[3-tert-butyl-5-(3-(naphthalene-l-yl)ureido]-1 H-pyrazol-1-yl } phenyl)prpanoate (0.57 g).
N
N /
O
HO HN
HN
O
A mixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13 g, 0.8 mmol) in dry CH2C12 (5 ml) was stirred at RT under NZ for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3h at RT and diluted with EtOAc and diluted citric acid solution.
The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column chromatography using 4 % methanol in CH2C12as the eluent to yield 3- {4-[3-tert-butyl-5-(3-(naphthalene-l-yl)ureido]-1 H-pyrazol-l-yl } phenyl)propanonic acid (0.18 g, off-white solid). mp: 120 122 ;'H NMR (200MHz, CDC13): S 7.89 - 7.06 (m, 11 H), 6.5 (s, 1 H), 2.89 (m, 2H), 2.61 (m, 2H), 1.37 (s, 9H); MS
Nr N
HO HN~O
HN ~
O CI
The title compound was synthesized in a manner analogous to Example 31 utilizing Example Q(0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate (0.077 g, 0.5 mmol) to yield 3-{4-[3-tert-butyl-5-(3-(4-chlorphenyl)ureido]-1H-pyrazol-1-yl}phenyl)propanonic acid acid (0.16 g, off-white solid). mp: 112 - 114 ; 'H NMR (200MHz, CDC13): S 8.16 (s, 1 H), 7.56 (s, 1 H), 7.21 (s, 2H), 7.09 (s, 2H), 6.42 (s, 1H), 2.80 (m, 2H), 2.56 (m, 2H), 1.32 (s, 9H); MS
EXAMPLE R
N
N
A 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with 3-nitrobiphenyl (20 g, 0.10 mol) dissolved in THF (-100 mL) and 10% Pd/C (3 g).
The reaction vessel was charged with H2 (g) and purged three times. The reaction was charged with 40 psi H2 (g) and placed on a Parr shaker hydrogenation apparatus and allowed to shake overnight at RT.
HPLC showed that the reaction was complete thus the reaction mixture was filtered through a bed of Celite and evaporated to yield the amine: 16.7g (98% yield) In a 250 mL Erlenmeyer flask with a magnetic stir bar, the crude material from the previous reaction (4.40 g, 0.026 mol) was added to 6 N HCI (40 mL) and cooled with an ice bath to - 0 C. A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop wise. After 30 min, SnC12-2HZ0 (52.0 g, 0.23 mol, 8.86 eq.) in 6N HCI (100 rnL) was added and the reaction mixture was allowed to stir for 3h, then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for.4h, concentrated in vacuo and the residue extracted with EtOAc (2x100 mL). The residue was purified by column chromatograph using hexane/
EtOAc/Et3N (8:2:0.2) to yield 0.53g of Example R. 'H NMR (CDC13): S 7.5 (m, 18H), 5.8 (s, 1H), 1.3 (s, 9H).
O /
~ I
HN' N
N H
N
In a dry vial with a magnetic stir bar, Example R(0.145 g; 0.50 mmol) was dissolved in 2 mL CHZC12 (anhydrous) followed by the addition ofphenylisocyanate (0.0544 mL; 0.50 mmol;
I eq.). The reaction was kept under argon and stirred for 17h. Evaporation of solvent gave a crystalline mass that was triturated with hexane/EtOAc (4:1) and filtered to yield 1-(3-tert-butyl-1-(3-phenylphenyl)-11Y-pyrazol-5-yl)-3-phenylurea (0.185 g, 90%). HPLC purity:
96%; mp: 80 84 ;'H NMR (CDCI,): 8 7.3 (m, 16 H), 6.3 (s, IH), 1.4 (s, 9H).
\
~ o ~ ci I . HN~N
~
H
N N
N
The title compound was synthesized in a manner analogous to Example 33 utilizing Example R(0.145 g; 0.50 mmol) andp-chlorophenylisocyanate (0.0768 g, 0.50 mmol, I eq.) to yield 1-(3-tert-butyl-l-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea (0.205 g, 92%). HPLC purity: 96.5%; mp: 134 136 ; 'H NMR (CDC13): 8 7.5 (m, 14H), 7.0 (s, 1H), 6.6 (s, 1 H), 6.4 (s, 1 H), 1.4 (s, 9H).
EXAMPLE S
F
/
N N N
\ Fi H
O I /
O Et The title compound is synthesized in a manner analogous to Example C utilizing Example A and. 4-fluorophenyl isocyanate yield ethyl 3-(3-tert-butyl-5-(3-(4-flurophenyl)ureido)-1 H-pyrazol-l-yl)benzoate.
OMe _ I
N\
O I /
~ \ N
~-O
O
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl } -3--(naphthalen-l-yl)urea.
N
N
HN
HN
S O
HO F
The title compound is synthesized in a manner analogous to Example 29 utilizing Example P(0.30g, 0.95 mmol) and 4-fluOrophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3-(3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol-l-yl)phenyl)propanoic acid.
EXAMPLE T
N-N
NHZ
NHBoc To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane-methylsulfide (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCl was added and heated to reflux for.10 min. The mixture was basified with NaOH
and extracted with EtOAc. The organic layer was dried (NazSO4) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5 amine (0.9 g).
A mixture of the crude material from the previous reaction (0.8 g, 3.1 mmol) and di-tert-butylcarbonate (0.7 g, 3.5 mmol) and catalytically amount of DMAP in dry CHZCIZ (5 ml) was stirred at RT under N2 for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using 1% methanol in CH2C12 as the eluent to yield tert-butyl 3-(3-tert-butyl-5-amino-lH-pyrazol-1-yl)phenylcarbamate (0.5 g).
N-N
HN/O
HN
A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate (0.123 g, 0.73 mmol) in dry CH2C12 (5 ml) was stirred at RT under N2 for 48 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 1% methanol in CH2C12as the eluent (0.15 g, off-white solid). The solid was then treated with TFA
(0.2ml) for 5 min and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 1-{3-tert-butyl-l-[3-(2-Aminoethyl)phenyl]-1 H-pyrazol-5-yl} -3-(naphthalen-l-yl)urea as a solid (80 mg). mp: 110-112 ;'H NMR (200MHz, DMSO-d6): S 9.09 (s, 1 H), 8.90 (s, l H), 8.01 - 7.34 (m, 11 H), 6.43 (s; 1 H), 3.11 (m, 2H), 2.96 (m, 2H), 1.29 (s, 9H); MS
N-N
UHNI
The title compound was synthesized in a manner analogous to Example 37 utilizing Example T(0.15 g, 0.42 mmol) and 4-chlorophenylisocyanate (0.065 g, 0.42 mmol) to yield 1-{3-tert-butyl-l-[3-(2-Aminoethyl)phenyl]-IH-pyrazol-5-yl}-3-(4-chlorophenyl)urea as an off-white solid (20 mg). mp:125-127 ; 'H NMR (200MHz, CDC13): S 8.81 (s, IH), 8.66 (s, 1H), 7.36 - 7.13 (m, 8H), 6.54 (s, IH), 3.15 (brs, 2H), 2.97 (brs, 2H), 1.32 (s, 9H); MS
EXAMPLE U
N'N NHz 6"OCH3 In a 250 mL Erlenmeyer flask with a magnetic stir bar, m-anisidine (9.84 g, 0.052 mol) was added to 6 N HC1 (80 mL) and cooled with an ice bath to 0 C. A solution of NaNO2 (4.22 g, 0.0612 mo1,1.18 eq.) in water (10 mL) was added drop wise. After 30 min, SnC12-2HZ0 (104.0 g, 0.46 mol, 8.86 eq.) in 6 N HCl (200 mL) was added and the reaction mixture was allowed to stir for 3 h., and then subsequently transferred to a 1000 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (8.00 g, 0.064 mol) and EtOH (200 mL) were added and the mixture refluxed for 4 h, concentrated in vacuo and the residue recrystallized from CHZC12 to yield 3-tert-butyl-l-(3-methoxyphenyl)-1H-pyrazol-5-amine as the HCl salt (13.9 g).
The crude material from the previous reaction (4.65 g, 0.165 mol) was dissolved in 30 mL of CHZCIZ with Et3N (2.30 mL, 0.0165 mol, I eq.) and stirred for 30 min Extraction with water followed by drying of the organic phase with NaZSO4 and concentration in vacuo yielded a brown syrup that was the free base, 3-tert-butyl-l-(3-methoxyphenyl)-IH-pyrazol-5-amine (3.82 g, 94.5%), which was used without further purification.
N/ \ ~ \ I
'N H H
MeO b In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0 107 mol) was dissolved in CH2CIZ (5 mL, anhydrous) followed by the addition of 1-naphthylisocyanate (1.53 mL, 0.0107 mol, I eq.). The reaction was kept under Ar and stirred for 18 h. Evaporation of solvent followed by column chromatography with EtOAc/hexane/Et3N (7:2:0.5) as the eluent yielded 1-[3-tert-butyl-l-(3-methoxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (3.4g, 77%). HPLC: 97%;
mp: 78 - 80; 'H NMR (CDC13): S 7.9 - 6.8 (m, 15H), 6.4 (s, 1 H), 3.7 (s, 3H), 1.4 (s, 9H).
CI
N, N J~ N\ I N
H H
MeO \
The title compound was synthesized in a manner analogous to Example 39 utilizing Example U (3.82 g; 0.0156 mol) and p-chlorophenylisocyanate (2.39 g, 0.0156 mol, 1 eq.), purified by trituration with hexane/EtOAc (4:1) and filtered to yield 1-[3-tert-butyl-l-(3-methoxyphenyl)-1 H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (6.1 g, 98%). HPLC
purity: 95%; mp:
158 - 160 ;'H NMR (CDC13): S 7.7 (s, 1H); S 7.2 6.8 (m, 8H), 6.4 (s, 1H), 3.7 (s; 3H), 1.3 (s, 9H).
r N
N~
N H H
HO b In a 100 ml round bottom flask equipped with a magnetic stir bar, Example 39 (2.07 g) was dissolved in CHZC12 (20 mL) and cooled to 0 C with an ice bath. BBr3 (1 M
in CHZC12; 7.5 mL) was added slowly. The reaction mixture was allowed to warm warm to RT
overnight.
Additional BBr3 (1 M in CH2C12, 2 X I mL, 9.5 mmol total added) was added and the reaction was quenched by the addition of MeOH. Evaporation of solvent led to a crystalline material that was chromatographed on silica gel (30 g) using CH2C12/MeOH (9.6:0.4) as the eluent to yield 1-[3-tert-butyl-l-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalene-l-yl)urea (0.40g, 20%).
'H NMR (DMSO-d6): S 9.0 (s, IH), 8.8 (s, 1H), 8.1 - 6.8 (m, 11H), 6.4 (s, 1H), 1.3 (s, 9H). MS
(ESI) m/z: 401 (M+H+).
O CI
N, N N 'k N
H H
/
HO \
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 40 (2.00 g, 5 mmol) that resulted in a crystalline material that was filtered and washed with MeOH to yield 1-[3-tert-butyl-l-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (1.14 g, 60%). HPLC purity: 96%; mp: 214 - 216 ;'H NMR
(CDC13): S 8.4 (s, IH), 7.7 (s, 1 H), 7.4 - 6.6 (m, 9H), 1.3 (s, 9H).
EXAMPLE V
N, N NHZ
NH
The starting material, 1-[4-(aminomethyl)phenyl]-3-tert-butyl-N-nitroso-lH-pyrazol-5-amine, was synthesized in a manner analogous to Example A utilizing 4-aminobenzamide and 4,4-dimethyl-3-oxopentanenitrile.
A 1 L four-necked round bottom flask was equipped with a stir bar, a source of dry Ar, a heating mantle, and a reflux condenser. The flask was flushed with Ar and charged with the crude material from the previous reaction (12 g, 46.5 mmol; 258.1 g/mol) and anhydrous THF
(500 ml). This solution was treated cautiously with LiAlH4 (2.65 g, 69.8 mmol) and the reaction was stirred overnight. The reaction was heated to reflux and additional LiA1H4 was added complete (a total of 8.35 g added). The reaction was cooled to 0 and H20 (8.4 ml), 15% NaOH
(8.4 ml) and H20 (24 ml) were added sequentially; The mixture was stirred for 2h, the solids filtered through Celite, and washed extensively with THF, the solution was concentrated in vacuo to yield 1-(4-(aminomethyl-3-methoxy)phenyl)-3-tert-buty]-1H-pyrazol-5-amine (6.8 g) as an oil.
A 40 mL vial was equipped with a stir bar, a septum, and a source of Ar. The vial was charged with the crude material from the previous reaction (2 g, 8.2 mmol, 244.17 g/mol) and CHC13 (15 mL) were cooled to 0 under Ar and di-tert-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHC13 (5 mL) was added drop wise over a 2 min period. The mixture was treated with IN KOH (2 mL), added over a 2h period. The resulting emulsion was broken with the addition of saturated NaCI solution, the layers were separated and the aqueous phase extracted with CHZCIZ (2 x 1.5 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated in vacuo to yield tert-butyl (4-(3-tert-butyl-5-amino-1hT pyrazol-l-yl)-2-methoxybenzylcarbamate (2.23 g, 79%) as a light yellow solid. 'H NMR (CDC13):
S 7.4 (m, 5H), 5.6 (s, 114), 4.4 (d, 2H), 1.5 (s, 9H), 1.3 (s, 9H).
N/ /\
N H H
NH
A 40 mL vial was equipped with a septum, a stir bar and a source of Ar, and charged with Example V (2 g, 5.81 mmol), flushed with Ar and dissolved in CHC13 (20 mL).
The solution was treated with 2-naphthylisocyanate (984 mg, 5.81 mmol) in CHC13 (5 mL) and added over I min The reaction was stirred for 8h, and additional 1-naphthylisocyanate (81 mg) was added and the reaction stirred overnight. The solid was filtered and washed with CH2C12to yield tert-butyl4-(3-tert-butyl-5-(3-naphthalen-l-yl)ureido)-1H-pyrazol-l-yl]benzylcarbamate (1.2 g). HPLCpurity:
94.4 %; 'H NMR (DMSO-d6): S 9.1 (s, IH), 8.8 (s, 1 H), 8.0 (m, 3H), 7.6 (m, 9H), 6.4 (s, 1 H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
p ~ ci N~ \ I
H H
NH
O--,\O-<-The title compound was synthesized in a manner analogous to Example 43 utilizing Example V(2.0 g, 5.81 mmol) and p-chlorophenylisocyanate (892 mg) to yield tert-butyl 4-[3-tert-butyl-5-(3-(4-chloropnehyl)ureido)-1 H-pyrazol-l-ylJbenzylcarbamate (1.5 g). I-IPLC purity:
97%; 'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.4 (s, 1 H), 7.4 (m, 8H), 6.4 (s, 1 H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
/ CI
N
~ N~ N N\ ~
H H
NH
0-1\04 A 10 mL flask equipped with a stir bar was flushed with Ar and charged with Example 43 (770 mg, 1.5 mmol) and CH2C12 (1 ml) and 1:1 CH2C12:TFA (2.5 mL). After 1.5 h, reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (15 mL), washed with saturated NaHC03 (10 mL) and saturated NaCI (10 mL). The organic layers was dried, filtered and concentrated in vacuo to yield 1- { 3-tert-butyl-l-[4-(aminomethyl)phenyl]-1 H-pyrazol-5-yl }-3-(naphthalen-l-yl)urea (710 mg). 'H NMR (DMSO-d6): S 7.4 (m, l l H), 6.4 (s, l H), 3.7 (s, 2H), 1.3 (s, 9H).
/ CI
N~ ~ ~ \ ~
~N N N
H H
The title compound was synthesized in a manner analogous to Example 45 utilizing Example44 (1.5g, 1.5mmol)toyield 1-{3-tert-butyl-l-[4-(aminomethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.0 g). HPLC purity: 93.6%; mp: 100 - 102 ;'HNMR
(CDC13): S
8.6 (s, 1 H), 7.3 (m, 8H), 6.3 (s, IH), 3.7 (brs, 2H), 1.3 (s, 9H).
N -~
\N H H
N
~SOZ
A 10 ml vial was charged with Example 45 (260 mg, 63 mmol) and absolute EtOH
(3 mL) under Ar. Divinylsulfone (63 uL, 74 mg, .63 mmol) was added drop wise over 3 min and the reaction was stirred at RT for 1.5 h. and concentrated in vacuo to yield a yellow solid, which was purified via preparative TLC, developed in 5% MeOH:CHZCIZ. The predominant band was cut and eluted off the silica with 1:1 EtOAc:MeOH, filtered and concentrated in vacuo to yield 1-{3-tert-butyl-l-[4-(1,1-dioxothiomorpholin-4-yl)methylphenyl]-1H-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (150 mg). HPLC purity: 96%; 'H NMR (DMSO-d6): S 9.1 (s, IH), 9.0 (s, 111), 7.9 (m, 3H), 7.5 (m, 8H), 6.4 (s, 1 H), 3.1 (brs, 4H), 2.9 (brs, 4H), 1.3 (s, 9H).
~ ci I
N'N N N \
H H
N"') ~~S02 The title compound was synthesized in a manner analogous to Example 47 utilizing Example 46 (260mg, 0.66 mmol) to yield 1-{3-tert-butyl-l-[4-(1,1-dioxothiomorpholin-4-yi)methylphenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (180 mg). HPLC
purity: 93%; mp:
136 - 138 ;'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.5 (s, 1H), 7.4 (m, 9H), 6.4 (s, 1H), 3.1 (brs, 4H), 3.0 (brs, 4H), 1.3 (s, 9H).
O
N/ NN
N H H
O ~ I
II O~ ,O
NxNs, O \
G H
To a stirring solution of chlorosulfonyl isocyanate (0.35g, 5 mmol) in CH2C12 (20 mL) at 0 C was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5 C. After stirring for 2h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylmine (0.46 g, 9 mmol) in CHZC12 (20 mL) was added. When the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCI (10 mL) saturated with NaC1 , the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (IVTa2SO4) and concentrated in vacuo, purified by preparative HPLC to yield (pyrrolidine-l-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-1-yl]phenyl ester (40 mg). 'H NMR
(CDC13): S 9.12 (brs, 1H), 8.61 (brs, IH), 7.85 - 7.80 (m, 3H), 7.65 (d, J =
8.0 Hz, 2H), 7.53 -7.51 (m, 1H), 7.45 - 7.25 (m, 5H), 6.89 (s, 4H), 3.36 - 3.34 (brs, 1H), 3.14 -3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H+).
O / CI
/\ ~ I
N~N N N \
H H
~ O\ O '~ I
~N N'S' O ~
H
The title compound was synthesized in a manner analogous to Example 49 utilizing Example 42 to yield (pyrrolidine- I-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(4-chlorophenyl-l-yl-ureido)pyrazol-l-yl]phenyl ester. MS (ESI) m/z: 561 (M+H').
EXAMPLE W
N,N NH2 OMe Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight.
The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 'H NMR (DMSO-d6): S
7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, IH), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
O OMe N, N
H H
OMe To a solution of 1-isocyanato-4-methoxy-naphthalene (996 mg) in anhydrous CHZC12 (20 mL) of was added Example W (1.23 g). The reaction solution was stirred for 3 h, the resulting white precipitate filtered, treated with 10% HCI and recrystallized from MeOH, and dried in vacuo toyield 1-[3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl]-3-(1-methoxynaphthalen-4-yl-urea as white crystals (900 mg, 40%). HPLC purity: 96%; mp: 143 - 144 ;'H
NMR
(DMSO-d6): S 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (d, IH), 8.0 (d, IH), 7.6 (m, 5H), 7.1 (d, 2H), 7.0 (d, IH), 6.3 (s, IH), 4.0 (s, 3H), 3.9 (s, 3H); 1.3 (s, 9H).
O / Br I
N, N N N ~
H H
OMe The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and p-bromophenylisocyanate (990mg) to yield 1-{3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)urea as off-white crystals (1.5g, 68%).
HPLC purity: 98%; mp: 200 - 201 ;'H NMR (DMSO-d6): S 9.3 (s, 1 H), 8.3 (s, l H), 7.4 (m, 6H), 7.0 (d, 2H), 6.3 (s, 1 H), 3.8 (s, 3H), 1.3 (s, 9H).
/ /I
.
N N N N \
H H
OMe The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and p-chlorophenylisocyanate (768 mg) into yield 1-{3-tert-butyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (1.3g, 65%). HPLC
purity: 98%; mp: 209 - 210 ;'H NMR (DMSO-d6): S 9.1 (s,.1H), 8.3 (s, 1H), 7.4 (m, 4H), 7.3 (d, 2H), 7.1 (d, 211), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).
, \
N N N N \
H H
OH
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 53 (500 mg) to yield 1-{3-tert-butyl-I-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (300 mg, 62%). HPLC purity: 94%; mp: 144 -145 ; 'H
NMR (DMSO-d6): S 9.7 (s, IH), 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (d, 2H), 7.3 (m, 4H); 6.9 (d, 2H), 6.3 (s, 1 H), 1.3 (s, 9H) sr N N N
H H
OH
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 52 (550 mg) to yield 1-{3-tert-butyl-l-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)urea as a white crystalline solid (400 mg, 70%). HPLC purity: 93%;
mp: 198 200 ;'H NMR (DMSO-d6): S 9.7 (s, 1H), 9.2 (s, 1H), 8.3 (s, 1H), 7.4 (d, 4H), 7.2 (m, 2H), 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H).
EXAMPLE X
I
N, N NHZ
CO2Me Methyl 4-(3-tert-butyl-5-amino-lH-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).
O
N, NO
N H
C02Me A 500mL round bottom flask was equipped with a magnetic stir bar and an ice bath. The flask was charged with Example X(1 g) and this was dissolved in CH2C12 (100 mL). Saturated sodium bicarbonate (100 mL) was added and the rriixture rapidly stirred, cooled in an ice bath and treated with diphosgene (1.45 g) and the heterogeneous mixture stirred for I h. The layers were separated and the CH2C12 layer treated with tert-butanol (1.07 g) and the solution stirred overnight at RT. The solution was washed with H20 (2 x 150 mL), dried (Na2SO4), filtered, concentrated in vacuo, and purified by flash chromatography using 1:2 ethyl acetate: hexane as the eluent to yield tert-buthyl 1-(4-(methoxycarbonyl)phenyl)-3-tert-butyl-lH-pyrazol-5-ylcarbamate (100 mg) as an off-white solid. 'H NMR (DMSO-d6): S 9.2 (s, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 6.3 (s, 1 H), 3.3 (s, 3H), 1.3 (s, 18H).
CI
N
, N N N a H H
COZMe The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.37 g) andp-chlorophenylisocyanate (768 mg) to yield methyl4-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-l-yl}benzoate as white crystals (1.4 g 66%).
HPLC purity:
98%; mp: 160 - 161 ;'H NMR (DMSO-d6): S 9.2 (s, ]H), 8.6 (s, 1H), 8.1 (d, 2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (d, 2H), 6.4 (s, 1 H), 3.9 (s, 3H), 1.3 (s, 9H).
O OMe N. N H H\
CO2Me The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.27 g) and 1-isocyanato-4-methoxy-naphthalene (996 mg) to yield methyl4-{3-tert-butyl-5-[3-(1-methoxynaphthalen-4-yl)ureido]-1H-pyrazol-1-yl}benzoate as white crystals (845 mg, 36%). HPLC purity: 98%; mp: 278 280 ; 'H NMR (DMSO-d6): S 8.76 (s, 1H), 8.73 (s, IH), 8.1 (m, 3H), 7.9 (d, IH), 7.7 (d, 2H), 7.6 (m, 3H), 7.0 (d, IH), 7.0 (d, IH), 6.3 (s, 1 H), 4.0 (s, 3H), 3.9 (s, 3H),1.3 (s, 9H).
Br N/ O / I
\
N N ~ N\
H H
CO2Me ~
The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.37 g) and p-bromophenylisocyanate (990 mg) to yield methyl 4-{3-tert-butyl-5-[3-(4-bromophenyl)ureido]-1H-pyrazol=l -yl}benzoate as white crystals (1.4 g, 59%). HPLC purity:
94%; mp: 270 272 ; 'H NMR (DMSO-d6): 8 9.2 (s, 1 H), 8.6 (s, 1 H), 8.1 (d, 2H), 7.7 (d, 2H), 7.4 (d, 4H), 6.4 (s, 1 H), 3.9 (s, 3H), 1.3 (s, 9H).
O
'k / Br N/ ~ I
N NN
H H
OH
To asolution of Example 59 (700mg) in 30 mL of toluene at -78 C, was added dropwise a solution of diisobutylaluminum hydride in toluene (1M in toluene, 7.5 mL) over 10 min. The reaction mixture was stirred for 30 min at -78 C, and then 30 min at 0 C. The reaction mixture was concentrated in vacuo to dryness and treated with H20. The solid was filtered and treated with acetonitrile. The solution was evaporated to dryness and the residue was dissolved in ethyl acetate, and precipitated by hexanes to afford yellow solid which was dried under vacuum to give 1-[3-tert-butyl-l-(4-hydroxymethyl)phenyl)-1H-pyrazol-5-y1]urea (400 mg, 61%). HPLC
purity: 95%;'HNMR (DMSO-d6): S 9.2 (s,1H), 8.4 (s,1H), 7.5 (m, 8H), 6.4 (s,1H), 5.3 (t,1H), 4.6 (d, 2H), 1.3 (s, 9H).
Example 1 Example 2 N \ O ~~ C~ N \ 0 NN~
~N N~N ~N N),N
H H H H
\ I \ I
D D
Example 3 Example 4 N O S
N\N H H~N NN NN~
H H H N
Y
\D Y--I D
Example 5 Example 6 N~ A, / I \ N a\\/) NH
N N N N N N N
H H H H
\ I
Y, D Y-1 D
Wherein Y is 0, S, NR6, -NR6SO2-, NR6CO-, alkylene, 0-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or Y is a direct bond; D is taken from the groups identified in Chart I:
Chart I
O
Ra R4 0 NRa S NRa p NR4 S N ON\ ~p O~S~,NRa ~ ~ O O ~0 N ' /~O I /N~g>=O
NS~ /N~N~ / ~N N ~N >r0 Q-1 R Rs 4R0 R4 Q-2 Q-3 a Q-4 Q-NRa R4 R4 O o 0 p a /Z)R4 I /A\ 0 NRe Ra R
aN/S\N~R N
N H I H
iv" Ra Q-8 Q-9 Q-10 , Q-I1 O 0 ~~ Re~ O Ra\N RaN lj~ NH Ra\N~NH R,\N OR6 ~ I OR6 y~0 2yL0 I O Rs Re ''~ Rs RS p Q-12 Rs O OH SH
R4 R4 0 ~ 0 CO H O ~ 0 N Rs ~O N CO ~ HOW N W" W W ' W
p H3C CH3 II
H3C H3C -c-L-O O O N R 0 H H ZRa pN~s NRa~
HNNlS/Z,Ra S_0 O /n1 8 N~ pO
H R4 H SO3H p O
W'A~ W
I/\\W I/\\W
rCOZRa SO3R6 O O ~
N COZRd Ra I N , n O
SOzN(Ra)2 Ra OR O~ 0 N R4 N J
GZ.Ra I ~ I \ I \ I \ O
I \ I \ 8 n Example 7 Example 8 O ~ O NN
N/ \ /~ CI N /k '~
~ ,, N N H N H N N N
H H
\ I \ I
~_S
N ~S
O
ON O N
H H
Example 9 Example 10 O S
N\ N H Nl' H N H N
N N N N
~ H H-\\
N
NS LNS
>=o O
O N N
H H
Example 11 Example 12 N~ ~ ~ / I \ N~ ~ ll ~ / NH
N N NN
N H H N N H H
\ I \ I
NS LN~S
>==o ~
O N O N
H H
Example 13 Example 14 O
~ CI \ O N1~;,-N
N" N N~N N,~ N NxN
H H H H
N~N CHs >==o N
~
O" SN I >==o ~S
O H O~II
Example 15 Example 16 O
~ 0 S
N\N H H H N\N N N~
H H N
I / I I /
N~N CH3 I >=O N'N
O.S~N 1 >=0 O H 0"~~ N
Example 17 Example 18 O
N Nl~N N NH
N H H N N N N
H H
\ I \
CHa CH3 N 'N NN
>==o I >=O
N H 0~lb, N
0 p Example 19 Example 20 r CI \
N, NJ~NII ~~ N N~N
N H H N H H
' \ \
NN-S\
NH
H3C H3C-~ /NH
H3C C H3C/ ~O
Example 21 Exarimple 22 O
\i \ ~ S
NN H H N N N N~
H N H H N
S~ 0 00 N' \NH N-S
H3C 0 H3C ~O
Example 23 Example 24 / / \ O
~ l \ l~ ~ NH
N ~ N N N N N /
N H H N N H H
\ I \ I
.N
NH NH
N
HH < H3C ~ /
Example 25 Example 26 ~ CI
NN N~N ~~ N~ N N~N
H H H H
\0 0 0 ~ p N N
Example 27 Example 28 N~ A, //~~ / \ CII S
N H HN N NI~N~\
~S CH3 00 \\ 'C 0 O~H~ N/ ONN/CH3 Example 29 Example 30 N ~ NH
N N NN NN N N H H H H
\ I \ I
/S"I CH3 II NNCH3 0 H N 0 H i Example 31 Example 32 O O
6N~ CI N N
N N~N N~N N~N
H H H H
\ \ I
N OH N OH
N OH N OH
i Example 33 Example 34 N O S
N/ N\ N~N~N N/ N~N~ {
H H H N H H
O O
N OH N OH
N OH OH
O O
Example 35 Example 36 x O O
NH
N N~N ~N ~ N N N
N H H H H
\ I \
O.
N OH N OH
N OH N OH
0 i O
Example 37 Example 38 CI N N
\ II
N, N\ N~N N N N/~N
H H H H
H t ON HN_ON
Example 39 Example 40 O
N,, N NA, N~ \/ / \ O S I
H H H NN N~N
H H N
HN~ ON
O HN t_,(/
ample 41 Example 42 Ex ~ O / \ O
N J /
N /
N N N N \
N H H N N NH
HNfto N HN~ //O N .
O~"
Example 43 Example 44 O N OI, NN
N
CE
N NN \ / N H H
H H
/ I I
N
N lI ~SO
vs ~O \O
\O
Example 45 Example 46 S
N \ ~ti. \ f f \ J. {
~N N N N NN N N~
H H H H H
N N
S~~O S\ O
~O \O
Example 47 Example 48 l~ / \ O
N/ N N N"N N~H /
N H H H
\ ~ ~ I
N/~1 N, 1 SZZ--O SIyO
\\O ~\O
Example 49 Example 50 O O N~N
~ CI
N" N\ N~N \~ N*~ N x N
H H N H H
O N CH3 0 N~ CH3 H H
Example 51 Example 52 N \ O S
N H H H N~N N~N 10:
H H N ~~/~ o ~S \ s/
O H CH3 O N~ ~CH3 H
Example 53 . Example 54 O / \ O
N ~ ~ ~ / NH
,N N
N N H H N N H H /
\
O \ ~ O
'V/
O HN ~S~CH3 O H~ CH3 Example 55 Example 56 N \ ~ N N~ N~~'/
H H N H H
\ I \ I
O NI-I''CONHCH3 O N~\CONHCH3 CONHCH3 L~",CONHCH3 Example 57 Example 58 6 Nf \ N \/ \ O S
~N N NJN N N~N~
H H H N H H
\ \
O NCONHCH3 O N-,-,~CONHCH3 Example 59 Example 60 NH
N~
N N~N
H H N H H
N
\ \
O CONHCH3 O N/~CONHCH3 ~'CONHCH3 CONHCH3 Example 61 Example 62 O ~ \ O
CI NN
. NN N NN N N N~N ~
H H H H
SO2NHPh SO2NHPh Example 63 Example 64 O
NI \ II \ II S
~N H~H N N~ N~N~ ~
H N H H N
\ I \ I /
SO2NHPh SOZNHPh Example 65 Example 66 NI ~ ll / I \ NI ~ ~ ~ / NH
N N~N N N N N
H H H H
SOzNHPh SOZNHPh Example 67 Example 68 X O
~ CI N N
N N N N,N H H
H H
\ I ~ I
\ OEt O~\ OEt O \NH NH
Example 69 Example 70 S
\ ~ ~ \ / N/
N
N N N N ,,N N N~
H H H H H N ~
\ I \ I /.
~,OEt -OEt O NH NH
Example 71 Example 72 / =~ O ~
O NH
N~N N~N ~N N H H
H H
/
\ I \ I
_,OEt _,OEt / NH
~ O
O NH
Example 73 Example 74 N ~ N Ou N \ X\ ~ \ ~ / 1 X\N, O=
N~ N N
N H H N H H
\ I \
Y--p Y-p Example 75 Example 76 X
H / I I\ / N\ 0 X
N I\
l N ~
N H N \ /N N N N \ /N
H H
\ I \ .
Y-p Y'D
Example 77 Example 78 / X I ~N X
N N\ NN \ N \ '' / I N
H H I ~N N N
/ I \ H H
Y--p Y~p wherein X or Y is 0, S, NR6, -NR6SO2-, NR6CO-, alkylene, O-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or X
or Y is a direct bond; D is taken from the groups identified in Chart I:
Chart I
R4 R4 Rq ~ 0 NRq 0 ~ 0 O~N S~N 0 0 N SN ~S O O i-N~O
0 jl' I
N\S~ N\S~ N\. >~O ~NN O ~N ~N~N
D-1 3 Ra D-4Ra D-5R R4 D-2 D- D-6 0 O N R4~ O R4 R~ 0 \ \SO ~N /N R4 0 NR4 NR4 ~ Z H ~~ H/ \1/
RS 0 o 0 D-10 D-11 0 0 0 R4, ~~
Ra\ R+~ N NH N NH i ORe N ~ ORa p /N
OR6 ~ ORa Rs OR6 RS R5 p ~ O
RS 'nn R4~N R4 0 / 0 CpzH O ~ O
R5 ~ 0 N C H0/ N W ~ W W ~ W
/ ?? 0 H3C CH3 0 r I I
O~ i H3C CHa H3C CHa /
3C ~~%
0 0 0 p 0 ~O N R 0 t1uN~SZRa pNN ~ HN' N~\S,Z~R4 JS_O 0 S a II 0~%0 H Rq H S03H N'~/ 0np 0 W W W W W~W I I
"o, D-24 D.25 D-27 D-28 COZR4 = O 0 S03Ra ~ 0 N~
NH RB
0 NCOZRa SOzN(R4h 0 N R9 I~O~ 0 N ~ N J
I \ I ~ I \ N
N / I \ I \ I \
~~-NH
i, '4, Specific examples of the present invention are illustrated by their structural formulae below:
Example 79 Example 80 0 O O~~N N/
' ~"/
N~N N N H
H H I H
\ ~ \ ( O Q
'S S~
N >=
0/N p N
H
Example 81 Example 82 Nl \ O /( I N NJ ~ ~ /( O I\
O
NN N N N
N H H N H H
~s ~s j ~o j >=o p~=N N
H H
Example 83 Example 84 \ ~
N,N H H N N N~N \ I I/
H H
\ I ~ ~
N~S --S
O~ ~ H o ~~ NO
Fi Example 85 Example 86 0 / O / O\/~N
II a N ~ /II~.
NN NN 'N H H\
H H
N'-N i ~-N
/)c0 ~O
Example 87 Exainple 88 J ~ i N ~~
~
N N N N NN N N ~/ N
H H H H
\ I ~ \ ( N~N N
~ >=O I >==O
0'N 0;: ISI N
O H O H
Example 89 Example 90 O ON O
N ~ ~
~N H H\ ~ NN N
H H
\~ \I
NN\ CH3 ' >=o N~N
~ >=o 011'N GS~ N
0 H O ~p H
Example 91 Example 92 0 N/', OI' / O\/\\ N N I ~ ~ I ~\O \ J~ ~/
N
NN N N N H H ~ H
H H
O N S!
O O
N ~S\ \
NH
~ H3C
Example 93 Example 94 O O
N N\ NN T{I~~/'1N N~ N\ NN I N
H H H H
\ I ~ \ I
~
Of0 OO
N''S NiS\
I NH NH
H3C-~ H3C
Example 95 Example 96 O
N \ N ~ N ~ I I / ~ ~ / \h1/~~
N H H NN N N
H H
\ I \ ~
O p O O
N
~ 'NH NH
H3C-~~ H3C ~
Example 9?
Example 98 O
NN a~\N/, N! N~ M~N /
H H 'y/ H H
a N S N~CH3 aANN,.CHg ~J( 4H C, H3 H CH3 Example 99 Example 100 0 d N N~N N N N~ NN \( N
H H H H ~
/ ~ \ fr a ~ Q Sr .'CHg Op % O
O M N O/'N"g\NCH3 Example 101 Example 102 N N' NN ( Nf \
O O rlD
H H N \ N N"
\ ~ H H
a~ 'N~,S" NI,CH3 ~ 0 aS~//~a ICH
~ ,J+., 3 H ~H3 O H ~H
Example 103 Example 104 O / O~\N \ N O O
~ ll I \ o x I N ~
H \H H \
NN N~N \ N
I \
N OH N OH
N OH ~N OH
Example 105 Example 106 O O / O N~ \ N~N I I% NN\ O H H N~N N
H H
i OH N OH
~N OH N OH
i Example 107 Example 108 N N NN \ I I/ N \
H H N N N~
H H
\ \
O
I OH N OH
/N N OH
Example'109 Example 110 O O\~\N I \ O / I O\/\N' N
N~ N\ N~N I ~ ,N H H
H
\
~I \
HN~fO N
H3C HNt N
f O CH3 H3C CH3 Exem ple 111 Example 112 N~ N NN \\y/N
N~ \ NN N
O O O
H H I H H
\~ \ \~
HN~f/O N HN~//O N
OT Oi Example 113 Example 114 O N O / N
N N\ NI~N / N \ I I/
H H N N N
H H
\ I \ ~
HN~f/O N HN O N
OT
CH O
Example 115 Example 116 ~~ N OII O~~N' ' , /~ ~/ .
N N\ N~N N H H \
H H
\ ~ \ I
S O' S O
\
O O
Example 117 Example 118 o ~ ~
N N NN N N
N NN \ I I/N
H H H H
N
Qo \\O
Example 119 Example 120 OII N
NN\ NN \ I I/ N O
H H N N N
H H
N
O oo VSp o Example 121 Example 122 O O / O
~~\N O
N N \ I v0 NN\ N~N ~ I v N H H ~ H H
\ I \ I 00 0 0 'V/
O N ~S \
O N~
H H
Example 123 Example 124 O
II
\ N /~N N N~ N \ I 1 N
N H H N\ N H H
,~ O 0 0 N/ O H I\
H ~
Example 125 Example 126 O O '~'N 0 / O N
~
NN NN I ~/ N NJ~.N \ I I/
H ~ N H H
\
O N~ \ O N/
H I / .
Example 127 Example 128 N ~ N N
N N N }~ H
H H \ I ' I
0 N CONHCH3 0 NII~~ CONHCH3 ~CONHCH3 LCONHCH3 Example 129 Example 130 O O~~i~~~ \ O O\\///~
N \ NN N NN NN N
N H H H H
0 CONHCH3 O N-,,~CONHCH3 CONHCH3 CONHCHa Example 131 Example 132 \ O 0 / N
H
N NH N~ NN~
H H
\ ~ ~ I
N~-ICONHCH3 O Nl-~~CONHCH3 Example 133 Example 134 \ 0 O~~N O O / I O~~N' ~=
N N/~N NN NJ~N- /
N H H H H
\ I \
S02NHPh S02NHPh Example 135 Example 136 N ~ N~N / N N~ N~N \ I \\V/// N
\\/// /N
N O O O O
H H H H
\ I \ \ I
S02NHPh S02NHPh Example 137 Example 138 NN N~N ~ N \ ~ \ I /
~ O ~ O I N 0 / ~N
H H N N N
\ ~ H H
\ I \ I
S02NHPh S02NHPh Example 139 Exampie 140 N O O\~~N~ O O~~~N
N NN NN H H
H H
I \
~OEt iOEt Oo~,~\NH O N H
Example 141 Example 142 N \ ~ / I O I N N/
N N N N N
N H H N H H
OEt s~OEt 0% \\
NH NH
Example 143 Example 144 ~
N ~
N~ H H N
N N'kN
H H
_--OEt \ ~OEt O \NH 0NH
Example Y
NHNH2.HCI
OEt To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CHZC12 (200 mL) was added (triphenyl-15-phosphanylidene)-acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) dropwise at 0 C, which was stirred for 2 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 %) 'H-NMR (400MHz, CDC13): 8.42 (s, 1 H), 8.23 (d, J= 8.0 Hz, 1 H), 7.82 (d, J= 7.6 Hz, 1 H), 7.72 (d, J =
16.0 Hz, 1 H), 7.58 (t, J= 8.0 Hz, 1H), 6.56 (d, J= 16.0 Hz, 1H), 4.29 (q, J= 7.2 Hz, 2H), 1.36 (t, J
6.8 Hz, 3H).
A mixture of 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi of H2 at RT for 2 h then filtered over celite. After removal the solvent, 14 g of 3-(3-amino-phenyl)-propionic acid ethyl ester was obtained and used directly without further purification. 'H-NMR (400 MHz, CDC13): 7.11 (t, J= 5.6 Hz, 1H), 6.67 (d, J= 7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13 (q, J=7.2 Hz,' 2H), 2.87 (t, J= 8.0 Hz, 2H), 2.59 (t, J= 7.6 Hz, 2H), 1.34 (t, J= 6.8 Hz, 3H).
To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g, 72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution (10 mL) of NaNO2 (5 g, 72.5 mmol) at 0 C and the resulting mixture was stirred for I h. A solution of SnC12.2H20 (33 g, 145 mmol) in concentrated HCI (150 mL) was then added at 0 C.
The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid, which was used without further purification.
Example Z
\
N, >NNH2 A mixture of Example Y(13 g, 53.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester (14.3 g, 45.4 mmol) as a white solid. 'H NMR (DMSO-d6): 7.39-7.32 (m, 3H), 7.11 (d, J = 6.8 Hz, IH), 5.34 (s, 1 H), 5.16 (s, 2H), 4.03 (q, J =
7.2 Hz, 2H), 2.88 (t, J =7.6 Hz, 2H), 2.63 (t, J =7.6 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J 7.2 Hz, 3H).
Example 145 O
N~ \ XN
N H
O
A solution of 4-fluoro-phenylamine (111 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then added to a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT
overnight then added to water (50 mL). The reaction mixture was extracted with ethyl acetate (3x50 mL) and the combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester (150 mg, 33%). 'H-NMR
(CDC13):
7.91 (s, 1 H), 7.42 (d, J= 4.8 Hz, 1 H), 7.37-7.34 (m, 2H), 7.28 (s, 1 H), 7.17-7.16 (m, 2H), 6.98 (t, J 8.8 Hz, 2H), 6.59 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.03 (t, J=
7.2 Hz, 2H), 2.77 (t, J= 7.2 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J= 7.2 Hz, 3H); MS (ESI) m/z:
(M+H+).
Example 146 F
O
- -- N/ ' N H
N H
b OH
O
A solution of Example 145 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, extracted with ethyl acetate (3x20 mL), the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[3- (4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid, (37 mg, 90%). 'H
NMR (CD3OD): 7.63-7.62 (m, 2H), 7.56 (s, 1 H), 7.53-7.48 (m, 1 H), 7.41-7.38 (m, 2H), 7.04 (t, J= 8.8 Hz, 2H), 5.49 (s, 1 H), 3.07 (t, J= 7.6 Hz, 2H), 2.72 (t, J
7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 415 (M+H).
Example 147 OMe O ~ I
N~ 1 l~ N11 N
N H H
OEt O
A mixture of 4-methoxy-phenylamine (123 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was. then added a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT
overnight then quenched with of water (50 mL). The reaction mixture was extracted with ethyl acetate (3x50 mL) and the combined organic extracts were washed with brine, dried (NaSOA filtered, concentrated under reduced presume to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (210 mg, 45%). 1H-NMR
(CD3OD): 7.46 (t, J= 7.6 Hz, 114), 7.3 8 (s, 1 H), 7.34 (d, J= 7.6 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.38 (s, IH), 4.09 (q, J= 7.2 Hz, 2H), 3.75 (s, 3H), 3.00 (t, J= 7.6 Hz, 2H), 2.68 (t, J 7.6 Hz, 2H), 1.33 (s, 9H), 1.20 (t, J 7.6 Hz, 3H);
MS (ESI) m/z: 465 (M+H+).
Example 148 OMe O ~ 1 N~ NXN ~
N H H
OH
Utilizing the same synthetic procedure as for Example 61 and starting with Example 147, 3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid is synthesized.
Example 149 O
N, N Hj N
b--A solution of isoquinoline-l-carboxylic acid (346 mg, 2.0 mmol), Example Z
(315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), and NMM
(1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3- { 3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-l-yl } -phenyl)-propionic acid ethyl ester, (380 mg, 80%). 1H-NMR (DMSO-d6): 8.83 (d, J= 8.4 Hz, IH), 8.85 (d, J= 5.2 Hz, 1 H), 8.09 (s, 1 H), 8.07 (d, J= 8.4 Hz, 1 H), 7.82 (t, J= 8.0 Hz, 1 H), 7.72 (t, J
= 8.0 Hz, 1 H), 7.52 (s, 1 H), 7.44 (d, J= 8.0 Hz, 1 H), 7.3 9(t, J= 5.2 Hz, 1 H), 7.22 (d, J=
8.0 Hz, 1 H), 6.57 (s, I H), 3.98 (q, J= 7.2 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 2.57 (t, J=
7.6 Hz,.2H), 1.32 (s, 9H), 1.10 (t, J 7.6 Hz, 1 H); MS (ESI) m/z: 471 (M+H+) Example 150 O
N~
, N H N
b-- OH
O
A solution of Example 149u (47 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH
(3 mL) was stirred at RT. overnight. The reaction mixture was neutralized to pH = 4, extracted with ethyl acetate (3x20 mL), and the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (39 mg, 87%). 'H-NMR (DMSO-d6): 10.77 (s, 1 H), 9.68 (d, J 7.6 Hz, 1 H), 8.44 (d, J=
5.2 Hz, IH), 7.89-7.44 (m, 2H), 7.78-7.74 (m, 2H), 7.49-7.47 (m, 3H), 7.30-7.27 (m, 3H), 6.95 (s, 1 H), 3.05 (t, J 7.2 Hz, 2H), 2.75 (t, J 7.6 Hz, 2H), 1.42 (s, 9H); MS
(ESI) m/z: 443 (M+H+).
Example 151 O
N~ \ N ' ' N H
A solution of pyridine-2-carboxylic acid (246 mg, 2.0 mmol), Example Z (315mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (300 mg, 70%). 1H-NMR (CDCL3): 8.53 (d, J = 4.4 Hz, 1 H), 8.26 (d, J 7.2 Hz, 1 H), 7.90 (t, J= 8.0 Hz, 1 H), 7.48-7.43 (m, 4H), 7.27 (s, 1 H), 6.87 (s, IH), 4.13.(q, J= 7.2 Hz, 2H), 3.04 (t, J= 7.6 Hz, 2H), 2.71 (t, J= 7.6 Hz, 2H), 1.39 (s, 9H), 1.24 (t, J 7.2 Hz, 3H); MS__(ESI)_mlz_ 421 (M+H+).
Example 152 N~
, H 1 /
b A solution of Example Z (315 mg, 1.0 mmol) and Barton's base (0.5 mL) in anhydrous CH2C12 (5 mL) under N2 was stirred at RT for 30 min, and then added to a solution of naphthalene-l-carbonyl fluoride (348 mg, 0.2 mmol) in anhydrous CH2CI2 (5 mL). The resulting mixture was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-l-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester, (350 mg, 74%). 'H-NMR (CDCL3): 8.29 (d, J= 8.0 Hz, 1H), 7.98 (d, J
= 7.2 Hz, 2H),'7.89 (d, J = 7.2 Hz, 1H), 7.62-7.57 (m, 3H), 7.49-7.28 (m, 4H), 7.03 (s, 1 H), 3.94 (q, J= 7.2 Hz, 2H), 2.96 (t, J= 7.2 Hz, 2H), 2.58 (t, .1 7.2 Hz, 2H), 1.45 (s, 9H), 1.13 (t, J= 7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Example 153 o 'N,N H 1 /
b OH
O
A solution of Example 152 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-l-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (38 mg, 86%). 'H NMR (DMSO-d6): 7.99 (d, J= 8.0 Hz, IH), 7.90 (m, 2H), 7.62 (m, 1H), 7.54-7.42 (m, 6H), 7.3 5(m, 1 H), 6.54 (s, 1 H), 2.94 (t, J 7.6 Hz, 2H), 2.57 (t, J
7.2 Hz, 2H), 1.38 (s, 9H); MS (ESI) m/z: 443 (M+H+).
Example 154 N~N
/ H.
A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCIZ (10 mL) was heated to reflux for 2 h. After concentration under reduced pressure, the residue was dissolved into CH2CI2 (5 mL) and was dropped into a solution of Example Z(315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0 C, and was then stirred at RT overnight.
After quenching with water (50 mL), the reaction mixture was extracted with CHZCIz (3x 100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified. by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino)-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (180 mg, 38%). 'H-NMR (CDCL3): 8.24 (s, 1 H), 8.21 (s, 1 H), 7.91 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 1 H), 7.73 (d, J= 8.4 Hz, IH), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J= 7.2 Hz, 2H), 3.04 (t, J= 7.6 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 1.43 (s, 9H), 1.17 (t, J 7.2 Hz, 3H);
MS (ESI) m/z: 470 (M+H+).
Example 155 O
N \
'N H
OH
O
A solution of Example 154 (47 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH-=
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-2-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid, (37 mg, 84%). 'H-NMR (CDCL3): 8.25 (s, 1 H), 8.18 (s, 1 H), 7.91-7.86 (m, 3H), 7.75 (d, J= 8.0 Hz, 1 H), 7.59-7.55 (m, 2H), 7.48-7.39 (m, 3H), 7.28 (s, 1 H), 6.81 (s, IH), 3.02 (t, J= 7.6 Hz, 2H), 2.69 (t, J 7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Example 156 O
N~ \ \ ~
N H N
A solution of isoquinoline-3-carboxylic acid (346 mg, 2.0 mmol), example Z
(315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), and NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts we're washed with-brine, -dried-(NaSO4)-and-filtered-After-concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-l- yl}-phenyl)-propionic acid ethyl ester (250 mg, 54%). 1 H-NMR (CD3OD): 9.24 (s, 1 H), 8.63 (s, 1 H), 8.17 (d, J= 8.0 Hz, IH), 8.11 (d, J= 8.0 Hz, 1 H), 7.88 (t, J= 7.6 Hz, 1 H), 7.81 (t, J= 7.6 Hz, IH), 7.50 (s, 1 H), 7.48 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 7.6 Hz, 2H), 7.36 (d, J= 7.6 Hz, 1 H), 6.75 (s, 1 H), 4.04 (q, J= 7.6 Hz, 2H), 3.01 (t, J= 7.6 Hz, 214), 2.69 (t, J= 7.6 Hz, 2H), 1.39 (s, 9H), 1.14 (t, J 7.6 Hz, 3H); MS (ESI) m/z: 471 (M+H+).
Example 157 O
N%~
N N
/ H
\ I OH
O
A solution of Example 156 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (39 mg, 88%). 'H NMR (CDCL3): 10.49 (s, 1 H), 9.16 (s, 1 H), 8.69 (s, 1 H), 8.03 (d, J= 7.6 Hz, 2H), 7.81 (t, J= 7.2 Hz, 1H), 7.73 (t, J= 7.2. Hz, 1H), 7.48-7.39 (m, 3H), 7.28 (br s, 1H), 6.94 (s, 1 H), 3.02 (t, J= 7.6 Hz, 2H), 2.79 (t, J= 7.6 Hz, 2H), 1.42 (s, 9H);
MS (ESI) m/z: 442 (M+H}) .Example 158 O
N/
'N h~ , / CI
b A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOC12 (10 mL) was heated to reflux for 2 h. After removal of the solvent, the residue was dissolved into CHZCIZ (5 mL) and was dropped into a solution of Example Z (315 rng, 1.0 mmol) in CH2C12 (10 mL) at 0 C, was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2C12 (3x100 mL). The combined organic extracts were washed with brine, dried (NaSO4) arid filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]- phenyl}-propionic acid ethyl ester (290 mg, 64%). 'H-NMR (CDCL3): 8.02 (s, IH), 7.67 (d, J = 8.4 Hz, 2H), 7.46 (t, J =
7.6 Hz, 1 H), 7.44 (d, J=-8.4 Hz, 2H), 7.36 (t, J= 8.4 Hz, 3H), 6.87 (s, 1 H), 4.06 (q, J=
7.6 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=
7.6 Hz, 3H); MS (ESI) m/z: 454 (M+H+).
Example 159 N~
'N H , / CI
b OH
O
A solution of Example 158 (45 mg, 0. 1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-{3-[3-t-butyl-5- (4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid, (38.5 mg, 87%).
'H NMR (DMSO-d6): 10.38 (s, IH), 7.85 (d, J 8.4 Hz, IH), 7.56 (d, .I = 8.4 Hz, 2H), 7.3 9(s, 1 H), 7.32 (d, J= 4.8 Hz, 2H), 7.15 (t, J= 4.8 Hz, 1 H), 6.3 8 (s, 1 H), 2.80 (t, J=
7.6 Hz, 2H), 2.44 (t, J 7.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 426 (M+H)+.
Example AA -NHZ
N
EtO2C
To a solution of m-aminobenzoic acid (200.0 g, 1.46 mmol) in concentrated HCI
(200 mL) was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mmol) at and the reaction mixture was stirred for 1 h. A solution of SnC12.2H20 (662 g, 2.92 mmol) in concentrated HCl (2000 mL) was then added at 0 C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-hydrazino-benzoic acid hydrochloride as a white solid, which was used for the next reaction without further purification. 'H NMR (DMSO-d6):
10.85 (s, 3 H), 8.46 (s, 1 H), 7.53 (s, I H), 7.48 (d, J = 7.6 Hz, 1 H), 7.37 (m, J 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, I H).
A mixture of 3-hydrazino-benzoic acid hydrochloride (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-l-yl)- benzoic acid (93 g, 36%). 3- (5-amino-3-t-butyl-pyrazol-l-yl)-benzoic acid and ethyl ester: 'H NMR (DMSO-d6): 8.09 (s, 1 H), 8.05 (brd, J= 8.0 Hz, 1 H), 7.87 (br d, J= 8.0 Hz, 1 H), 7.71 (t, J= 8.0 Hz, 1 H), 5.64 (s, I H), 4.3 5(q, J 7.2 Hz, 2 H), 1.34 ---(t;-J-= 7.2 Hz, 3 H), 1.28 (s, 9H).
Example BB
N, N NH2 \
HO I /
To a stirred solution of Example AA (19.5 g, 68.0 mmol) in THF (200 mL) was added LiAlH4 powder (5.30 g, 0.136 mol) at -10 C under N2. The mixture was stirred for 2 h at RT and excess LiAlH4 was destroyed by slow addition of ice. The reaction mixture was acidified to pH = 7 with diluted HCI, the solution concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic extracts were concentrated to give [3 -(5 -amino-3-t-butyl-pyrazol- 1 -yl)-phenyl] -methanol (16.35 g, 98%) as a white powder. 'H NMR (DMSO-d6): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, I H), 6.41 (s, 1H), 4.60 (s, 2 H), 1.28 (s, 9 H);
MS (ESI) m/z:
415 (M+H+).
Example CC
CI I /
A solution of Example BB (13.8 g, 56.00 mmol) and SOC12 (8.27 mL, 0.11 mol) in THF (200 mL) was refluxed for 3 h and concentrated under reduced pressure to yield 5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-ylamine (14.5 g, 98%) as white powder which was used without further purification. 'H NMR (DMSO-d6), 57.62 (s, 1 H), 7.53 (d, J= 8.0 Hz, 1 H), 7.43 (t, J= 8.0 Hz, 1 H), 7.31 (d, J= 7.2 Hz, l H), 5.3 8(s, I
H), 5.23 (br s, 2 H), 4.80 (s, 2H), 1.19 (s, 9 H). MS (ESI) m/z: 264 (M+H+).
Example DD
ON O
N"
I \ 1 NH
Me0 ~ ~J
O
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 rnmol) in (20 mL) at 0 C was added 2-methyl-propan-2-ol (0.74 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of glycine ethyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in CHZCl2 (20 mL) was added at such a rate that the reaction temperature didn't rise above C. When the addition was completed, the solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCl and extracted with CH2C12.
The organic layer was washed with saturated NaCI, dried (Mg2SO4) and filtered.
After removal of the solvent, the crude product was washed with CH2C12 to afford ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85 %). 1H-NMR(DMSO):- S
10.85 (s, 1 H), 8.04 (t, J 6.0 Hz, I H), 4.07 (q, J = 5.6 Hz, 2H); 3.77 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J= 7.2 Hz, 3H).
To a solution of (4-methoxyphenyl)-methanol (1.4 ga 8.5 mmol) and triphenyl-phosphane (2.6 g, 8.5 mol) in dry THF was added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0 C under N2 atmosphere. The mixture was stirred at 0 C for 2 h, warmed to RT and stirred overnight. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford ethyl2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate (2.3 g, 69%) as a white solid. 'H-NMR(CDC13): S 7.32 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.71 (m, IH), 4.76 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.80 (s; 3H), 3.55 (d, J 5.2 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J= 7.2 Hz,3H).
To a solution of HCl in methanol (2 M) was added ethyl 2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (2.0 g, 5.0 mmol) in portions at RT and the mixture was stirred for 3 h. After the solvent was removed in vacuo, the residue was washed with diethyl ether to afford ethyl2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate (1.0 g, 70%). 'H-NMR (DMSO-d6): S
7.43 (t, J= 6.0 Hz, l H), 7.287 (t, J= 6.4 Hz, 1 H), 7.21 (d, J= 8.4 Hz, 2H), 6.86 (d, J= 8.4 Hz, 2H), 3.94 (d, J= 4.8 Hz, 2H), 3.71 (s, 3H), 3.64 (d, J= 6.0 Hz, 2H), 3.62 (s, 3H), To a solution of ethyl 2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (1.0 g, 3.47 mmol) in DMF (50 mL) was added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 atmosphere at RT. The mixture was stirred overnight then quenched with HCI/ methanol (2 M). After the solvent was removed in vacuo, the residue was washed with water to afford 2-(4-methoxy-benzyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one (480 mg, 54 %). 'H-NMR(CDCl3): S 7.36 (d, J= 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.87 (m, 1 H), 4.68 (s, 2H), 4.03 (d, J 7.2 Hz, 2H), 3.80 (s, 3H).
Example EE
OMe ~ ~
O~~O -HN ~N
O
IA
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 nunol) in (20 mL) at 0 C was added benzyl alcohol (1.08 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After stirring for 1.5 h, a solution of L-alanine methyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in (20 mL) was added at such a rate that the reaction temperature didn't rise above 5 C.
When the addition was completed, the reaction solution was allowed to warm up to RT
and stirred overnight. The reaction mixture was poured into 10% HCI, extracted with CHZC12, the organic extracts washed with saturated NaCl, dried (Mg2SO4), and filtered.
After removal of the solvent, the crude product was recrystallized in PE/EA
(10:1) to afford the desired product (2.5 g, 79 %), which was used directly in the next step. 'H-NMR(DMSO): S 11.31 (s, IH), 8.43 (d, J= 8.0 Hz, IH), 7.37-7.32 (m, 5H), 5.11 (s, 2H), 4.03 (m, 1 H), 3.57 (s, 3H), 1.23 (d, J= 7.2 Hz, 3H).
A mixture of material from the previous reaction (2.5 g, 12 mmol) and Pd/C (10 %, 250 mg) in methanol was stirred for 4 h at 50 C under H2 atmosphere (55 psi). After the catalyst was removed by suction, the filtrate was evaporated to afford the desired compound (1.37 g, 92%) as a white solid, which was used directly in the next step. jH-2l7 NMR (CDC13): 6 5.51 (d, J= 5.6 Hz, 1 H), 4.94 (br, 2H), 4.18 (m, 1 H), 3.78 (s, 3H), 1.46 (d, J = 7.2 Hz, 3H).
To a solution of 2.0 N of NaOMe in methanol (20 mL) was added a solution of compound form the previous reaction (1.2 g, 6.1 mmol) in methanol and the resulting mixture was heated to reflux overnight. After cooling down, a solution of HC1 in methanol was added to acidify to pH 7. The resulted salt was filtered off and the filtrate was evaporated to dryness to afford a light yellow solid which was used directly in the next step (600 mg, 66%). 'H-NMR (DMSO-d6): 8 6.04 (d, J 4.8 Hz, 1 H), 3.60 (m, 1 H), 1.11 (d, J= 7.2 Hz, 3H).
A mixture of compound from the previous step (500 mg, 3.33 , mmol) and 1-chloromethyl-4-methoxybenzene (156 mg, 1.0 mmol) in acetonitrile was heated to reflux overnight together with K2C03 (207 mg, 1.5 mmol) and KI (250 mg, 1.5 mmol) under N2 atmosphere. After cooling, the salt was filtered off and the filtrate was purified by column to afford 2-(4-methoxybenzyl)-(S)-4-methyl-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one as a white solid (200 mg), which was used without further purification.
Example 160.
N~
H N H H
O N ~ ~~ \ \
~
NOI~
---. . _ ~,.. _ -- ---- --- To a solution of Example EE (100 mg, 0.37 mmol) in.
anhydrous DMF (3 mL) was added NaH (18 mg, 0.44 mmol) at 0 C. After stirring for 0.5h at 0 C, a solution of Example E (160 mg, 0.37 mmol) in anhydrous DMF (3 mL) was added to the reaction mixture,.which was_stirred overnight at RT and subsequently concentrated under reduced pressure to yield a-crude solid which was used- without further purification.
A solution of the crude material from the previous reaction (60 mg, 0.090 mmol ) in trifluoroacetic acid (3 mL ) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative HPLC to afford 1-{5-t-butyl-2-[3-((S)-3-methyl-1, 1,4-trioxo- 1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3 -yl } -3-naphthal-en-1-yl-urea as white power (45 mg). 'H NMR (DMSO-d6): 9.04 (s, 1H), 8.87 (s, 1H), 8.02 (d, J= 8.0 Hz, 1 H), 7.89 (d, J= 7.2 Hz, 2 H), 7.62 (d, J= 8.0 Hz, 2 H), 7.41-7.52 (m, 6 H), 6.40 (s, I H), 4.31-4.49 (dd, J= 8.0 Hz, 2 H), 4.03 (q, J= 6.8 Hz, I
H), 1.27 (s, 9 H), 1.17 (d, J= 8'.0 Hz, 3 H). MS (ESI) m/z: 547 (M+H+).
Example FF
HN'S N \ / OMe )-0 2-(4-methoxy-benzyl)-(R)-4-methyl-1,1-dioxo-1 X6-[ 1,2,5]thiadiazolidin-3-one was prepared from D-alanine ethyl ester using the same procedure as Example EE.
Example 161 O
N ~ N~N
N O ~N H H
O
O
To a solution of Example FF (60 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added NaH (11mg, 0.27 mmol) at 0 C. After stirring for 0.5h at 0 C, a solution of Example D (100 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added to the.reaction mixture, which was stirred overnight at RT. The crude reaction mixture was concentrated unjder reduced pressure and the residue by purified through preparative HPLC
to yield 1-(5-t-butyl-2- { 3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1 k 6-[
1,2,5]-thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-y1)-3-naphthalene-l-yl-urea (20 mg ).
'H NMR (DMSO-d6): 8.98 (s, 1H), 8.81 (s, IH), 8.00 (d, J = 8.0 Hz, 1 H), 7.90 (d, J
7.2 Hz,2 H), 7.62(s, 2 H), 7.51-7.55 (m, 6H), 7.44 (d, J= 7.6 Hz, 2 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.86 (d, J= 8.8 Hz, 2 H), 6.40 (s, 1H), 4.57-4.62 (dd, J= 8.0 Hz, 4 H), 4.53 (q;
J= 7.6 Hz, I H), 3.71 (s, 3H), 1.30 (d, J= 8.0 Hz, 3 H), 1.27 (s, 9 H). MS
(ESI) m/z: 653 (M+H+).
A solution of 1-(5-t-Butyl-2-{3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1X6-[1,2,5]- thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea (20 mg, 0.030 mmol) in trifluoroacetic acid (2 mL) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative-HPLC to afford 1-{5-t-butyl-2-[3-((R)-3-methyl-1,1,4-trioxo-1,6-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3- naphthalen-1-yl-urea 'as a white power (6 mg). 1H NMR (D1vISO-d6):
8.99 (s, 1 H), 8.80 (s, 1 H), 8.00 (d, J= 7.2 Hz, I H), 7.90 (d, J= 7.2 Hz, 2 H), 7.60-7.64 (m, 2 H), 7.44-7.54 (m, 7 H), 6.41 (s, I H), 4.31-4.49 (dd, J= 8.0 Hz, 2 H), 4.03 (q, J=
7.6 Hz, 1 H), 1.27 (s, 9 H), 1.19 (d, J 8.0 Hz, 3 H). MS (ESI) m/z: 533 (M+H).
Example 162 O
~ F
'k I
O N~N H H ~
HN~ ~
O S1 N I ~
O
To a solution of Example CC (0.263 g, 1.0 mmol) in THF (2.0 mL) was added a solution of 1-fluoro-4-isocyanato-benzene (0.114 mL, 1.10 mrnol) in THF (5.0 mL) at 0 C. The mixture was stirred at RT for 1 h then heated until all solids were dissolved. The mixture was stirred at RT for 3 h and poured into water (20 mL). The resulting precipitate was filtered, washed with diluted HCI and H20, dried under reduced pressure to yield 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-urea (400 mg) as a white power. 'H NMR (DMSO-d6): 8.99 (s, 1H), 8.38 (s, 1H), 7.59 (s, IH), 7.44-7.51 (m, 3H), 7.38-7.40 (m, 2H), 7.08 (t, J= 8.8 Hz, 2H), 6.34 (s, IH), 4.83 -(s; 2H),-1:26-(s5-9H): MS-(ESI)-m/z: .401-(M_+..I-T+-).
To a solution of 2-(4-methoxy-benzyl)-1,1=diox6-lX6=[17,2;5]thiadiazolidin-3-one (64 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added NaH (11mg, 0.27 mmol) at C. After stirred for 0.5h at 0 C, a solution of 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3- (4-fluoro-phenyl)-urea from the previous reaxtion (100 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added to the reaction mixture, then was stirred ovemight at RT. The crude was purified through prepared-HPLC to yield 1-(5-t-butyl-2-{ 3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3-(4-fluoro- phenyl)-urea (45 mg ). 1H NMR (DMSO-d6): 8.95 (s, IH), 8.37 (s, IH), 7.50-7.54 (m, 3H), 7.36-7.41 (m, 3H), 7.25 (d, J= 8.8 Hz, 2H), 7.07 (t, J
8.8 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 6.35 (s, 1H), 4.64 (s, 2H), 4.47 (s, 2H), 4.19 (s, 2H), 3.75 (s, 3H), 1.26 (s, 9H). _MS (ESI) m/z: 515 (M+H*).
ioxo-l~6-A solution of 1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-tr [1,2,5]thiadia- zolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea (40 mg, 0.060 mmol) in trifluoroacetic acid (3 mL ) was stirred at 50 C for 4h. After the solvent was removed, the residue was purified by preparative HPLC to afford 1-{ 5-t-butyl-2-[3-(3-(R)-methyl-1,1,4-trioxo-1 k 6-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea as a white power (12 mg). IH NMR (DMSO-d6):
8.98 (s, I H), 8.39 (s, 1 H), 7.37-7.51 (m, 6 H), 7.07 (t, J= 8.8 Hz, 2 H), 6.35 (s, I H), 4.21 (s, 2 H), 3.88 (s, 2 H), 1.26 (s, 9 H). MS (ESI) m/z: 501 (M+H+).
Example GG
N'~~CI
To a stirred suspension of K2CO3 (5.5 g, 40 nunol) and 1-bromo-3-chloro-propane (3.78 g, 24 mmol) in acetonitrile (lOmL) was added a solution of N-methyl piperazine (2.0 g, 20 mmol) in acetonitrile (lOmL) dropwise at RT. After the addition was completed, the reaction mixture was stirred for 3 h then filtered. The filtrate was concentrated and dissolved in -CHZC12, washed with brine, dried (NaSO4) and filtered.
After removal of the solvent; -the -residue 'was dissolved in ether. To the above solution was added the solution of HCl and filtered to afford the desired product (2.3g, 65.7%). 1H
NMR (D20): 3.61 (t, J = 6.0 Hz, 2H), 3.59 (br, 8H), 3.31 (t, J= 8.0 Hz, 2H), 2.92 (s, 3H), 2.15 (m, 2H).
Example 163 O
N/ N
N H H
N
To a solution of Example 41 (100 mg, 0.25 mmol) in acetonitrile (lOmL) was added Example GG (75 mg, 0.30 mmol) and K2C03 (172 mg, 1.25 mmol). The resulting mixture was stirred at 45 C for 3 h before filtered. After the filtrate was concentrated, the residue was purified by preparative TLC to afford 1-(5-t-Butyl-2-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl }-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea (31mg, 23 %). 'H-NMR (CD3OD): 7.93 (m, 1H), 7.88 (m, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.66 (d, J
= 7.6 Hz, 1 H), 7.43-7.50 (m, 4H), 7.14 (m, 2H), 7.05 (m, 1 H), 6.43 (s, 1 H), 4.10 (t, J =
6.0 Hz, 2H), 3.09-3.15 (br, 4H), 2.74-2.86(br, 6H), 2.72 (s, 3H), 1.99 (t, J=
6.8 Hz, 2H), 1.35 (s, 9H). MS (ESI) m/z: 541 (M+H+).
Example HH
O NH
>r--kA OEt Intermediate HH was synthesized according to literature procedures starting from 4,4-dimethyl-3-oxo-pentanenitrile (10 mmole) in absolute ethanol and HCl in quantitative afford.
Example II
O
O N O
~ ~ .
OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2Cl2 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 1-napthylchloroformate is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for I h.
The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-naphthalen-l-yl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 164 \ II I
N, N NJ~,O
H I
O
OEt Example II (10 mmol) is dissolved in absolute EtOH (50 mL) at RT and Example Y (10.5 nimol) is added dropwise over 5 min. The reaction mixture is stirred for 30 min at RT, poured in water (100 mL) and ethyl acetate (100 mL). After shaking, the organic layer is washed with 5% HCI, water, dried (MgSO4) and concentrated 'to afford naphthyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 165 N O
H
O
OH
A solution of Example 164 (0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) is stirred at RT overnight. The reaction mixture is neutralized to pH = 4, extracted with ethyl acetate (3x20 mL), the combined organic extracts are washed with bri ne, dried (NaSO4) and filtered. The filtrate is concentrated to afford 1-napthyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example JJ
O
O N)~ O
OEt Example JJ is synthesized utilizing Example HH and 2-napthylchloroformate according to the procedure described for Example II to afford (Z)-naphthalen-2-y1-1-ethoxy-4,4-dimethyl-3 -oxopentyli denecarbamate.
Example 166 O
N, N H 0 /
O
yfl \
OEt Example 166 is synthesized utilizing Example Y and Example JJ according to the procedure described for Example 79 to afford 2-naphthyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 167 N,N NO
H
OH
Example 167 is synthesized utilizing Example 166 according to the procedure described for Example 165 to afford 2-napthyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example KK
cl 0 ~ \
~
OEt Example KK is synthesized utilizing Example HH and p-chlorophenylchloroformate according to the procedure described for Example II
to afford (Z)-4-chlorophenyl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 168 CI
N/
N H O
O
OEt Example 168 is synthesized utilizing Example Y and Example KK according to the procedure described for Example 164 to afford 4-chlorophenyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 169 CI
N/ ~ O~ I
\ N H
Y~6 O
OH
Example 169 is synthesized utilizing Example 168 according to the procedure described for Example 165 to afford 4-chlorophenyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example LL
OMe OEt Example LL is synthesized utilizing Example HH and p-methoxyphenylchloroformate according to the procedure described for Example II
to afford (Z)-4-methoxyphenyl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.
Example 170 COMe N H
OEt Example 170 -is synthesized utilizing Example Y and Example LL according to the procedure described for Example 164 to afford 4-methoxyphenyl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 171 OMe O
N~ a ~ ~ ~ N H 0 O
OH
Example 171. is synthesized utilizing Example 170 according to the procedure described for Example 165 to afford 4-methoxyphenyl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example MM
O p 0 N O
N
OEt Example MM is synthesized utilizing Example HH and quinolin-8-yl-chloroformate according to the procedure described for Example II to afford (Z)-quinolin-8-yl 1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate Example 172 N/ N J~
O
H
N
O
OEt Example 172 is synthesized utilizing Example Y and Example MM according to the procedure described for Example 164 to afford quinolin-8-yl 1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 173 o H
N
OH
Example 173 is synthesized utilizing Example 172 according to the procedure described for Example 165 to afford quinolin-8-yl 1-(3-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 174 OMe N/ \ N~H
N H
OEt Example 174 is synthesized utilizing a mixture of 4-methoxy-l-naphthylamine and Example Z according to the procedure described for Example 147 to afford 3-(3-{3-t-butyl-5-[3-(4-methoxy-l-naphthyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester.
Example 175 OMe N/ N~ H
N H
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 174, 3-(3-{3-t-butyl-5-[3-(4-methoxy-l-naphthtyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid is synthesized.
Example 176 O N/ N N N
H
OEt O
Example 176 is synthesized utilizing a mixture of indoline and Example Z
according to the procedure described for Example 147 to afford ethyl 3-(3-(3-t-butyl-5-(indoline-l-carboxamido)-1 H-pyrazol-l-yl)phenyl)propanoate.
Example 177 O
N/ \ N
N N
H
b OH
O
Utilizing the same synthetic procedure as for Example 146 and starting with Example 173, .3-(3-(3-t-butyl-5-(indoline-l-carboxamido)-1 H-pyrazol-1-yl)phenyl) propionic acid is synthesized.
Example NN
NHNH2.HCI
OEt O
Utilizing the same synthetic procedure as for Example Y and starting with: p-bromo nitrobenzene, 3-(4-hydrazino-phenyl)-propionic acid ethyl ester is synthesized.
Example 178 ~ \ \ I
N" N ~ O
H
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example II (10 mmol) and Example NN (10.5 mmol) are combined to afford 1-naphthyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3 -t-butyl- I H-pyrazol-5-ylcarbamate.
Example 179 N/ )~
\N O
H
Example 179 is synthesized utilizing Example 178 according to the procedure described for Example 165 to afford 1-napthyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 180 p / I \
N NO
H
Et0 O
Utilizing the same synthetic procedure as for Example 164, Example JJ (10 mmol) and Example NN (10.5 mmol) are combined to afford 2-naphthyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 181 O r I \
N, N N~O
H
HO O
Example 181 is synthesized utilizing Example 180 according to the procedure described for Example 165 to afford 2-napthyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 182 232.
cl N/ \ l~ \ I
~N H
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example KK (10 mmol) and Example NN (10.5 mmol) are combined to afford p-chlorophenyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 183 cl N \
N J,O\ I
H
~
HO O
Example 183 is synthesized utilizing Example 182 according to the procedure described for Example 165 to afford 4-chlorophenyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 184 OMe N, \ ~ ~ I
, N H O
EtO 0 Utilizing the same synthetic procedure as for Example 164, Example LL (10 mmol) and Example NN (10.5 mmol) are combined to afford p-methoxyphenyl 1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 185 OMe N/ ~ ~
.N H O
Example 185 is synthesized utilizing Example 184 according to the procedure described for Example 165 to afford p-methoxyphenyl 1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.
Example 00 . ~
O
O
OEt Ethyl bromoacetate is reacted with meta-nitrophenol under standard conditions to afford ethyl 2-(3-nitrophenoxy)acetate, which is elaborated to ethyl 2-(3-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Example PP
O
O N N
OEt Example HH and 1-naphthylisocyanate are combined utilizing the same synthetic procedure as for Example II to afford (Z)-1-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-3-(naphthalen-l-yl)urea.
Example 186 O
N, N NN
" "
O \
~ /
O- - -OEt Utilizing the same synthetic procedure as for Example 164, Example PP (10 mmol) and Example 00 (10.5 mmol) are combined to afford 3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid ethyl ester.
Example 187 N/ \ ~ \ I
\N H H
O
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 186, 3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid is synthesized.
Example QQ
cl O
O N N
H
OEt Example HH and 4-chlorophenylisocyanate are combined utilizing the same synthetic procedure as for Example II to afford (Z)-1-(4-chlorophenyl)-3-(1-ethoxy-4,4-dimethyl-3 -oxopentyl idene)urea Example 188 cl N~ ~ O
N N"'r \N H
H
Oi - - ~
OEt Utilizing the same synthetic procedure as for Example 164, Example QQ (10 mmol) and Example 00 (10.5 nunol) are combined to afford 3-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 189 CI
N H H \ I
O
O
OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 188, 3-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-acetic acid is synthesized.
Example RR
~ OEt O---~O
Ethyl bromoacetate is reacted with para-nitrophenol under standard conditions to afford ethyl 2-(4-nitrophenoxy)acetate, which is elaborated . to ethyl 2-(4-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Example 190 N/ \ ~ \ I
\N H H
O
O OEt Utilizing the same synthetic procedure as for Example 164, Example PP (10 mmol) and Example RR (10.5 mmol) are combined to afford 4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 191 N
" N H H
\ \ -O
~
O OH
Utilizing the same synthetic procedure as for Example 146 and starting with Example 190, 4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid is synthesized.
Example 192 cl N \
N J, H\ I
\
H
O
O OEt )--, Utilizing the same synthetic procedure as for Example 164, Example QQ (10 mmol) and Example RR (10.5 mmol) are combined to afford 4-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid ethyl ester.
Example 193 cl N/ \ , \ ( ~N H H
O
O OH
)--Utilizing the same synthetic procedure as for Example 146 and starting with Example 192, 4-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-l-yl}-phenoxy)-acetic acid is synthesized.
Example DD
~OSO
N 'NH
O~J
To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 mmol) in (20 mL) at 0 C was. added 2-methyl-propan-2-ol (0.74 g, 10.0 mmol) at such a rate that the reaction solution temperature did not rise above 5 C. After being stirred for 1.5 h, a solution of glycine ethyl ester (1.45 g, 12.0 mmol) and Et3N (3.2 mL, 25.0 mmol) in CH2C12 (20 mL) was added at such a rate that the reaction temperature didn't rise above C. When the addition was completed, the solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCl and extracted with CH2C12.
The organic layer was washed with saturated NaCI, dried (Mg2SO4) and filtered.
After removal of the solvent, the crude product was washed with CH2ClZ to afford ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85 %). IH-NMR(DMSO): S 10.85 (s, 1 H), 8.04 (t, J= 6.0 Hz, 1 H), 4.07 (q, J= 5.6 Hz, 2H), 3.77 (d, J= 6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J 7.2 Hz, 3H).
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amirio)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF
dropwise at 0 C under N2 atmosphere. The mixture is stirred at 0 C for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
To a solution of HCl in methanol (2 M) is added ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate from the previous step (5.0 mmol) in portions at RT
and the mixture is stirred for 3 h. After the solvent is removed in vacuo, the residue is washed with diethyl ether to afford ethyl 2-((N-methylsulfamoyl)amino)acetate To a solution of ethyl 2-((N-methylsulfamoyl)amino)acetate from the previous step (3.5 mmol) in DMF (50 mL) is added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 at RT. The mixture is stirred overnight then quenched with HCl/
methanol (2 M). After the solvent is removed in vacuo, the residue is washed with water to afford 2-methyl-l,l-dioxo-lk6-[1,2,5]thiadiazolidin-3-one (480 mg, 54 %). 'H-NMR(CDC13): S
7.36 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.87 (m, 1 H), 4.68 (s, 2H), 4.03 (d, J=
7.2 Hz, 2H), 3.80 (s, 3H).
Example 194 'J~
N- S'O
N
Example E and Example 00 are combined utilizing the procedure for Example 160 to afford 1-(5-t-butyl-2-{3-[5-methyl-1,1,4-trioxo-lX 6-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3-naphthyl-urea.
Example 195 O
N~ \ N XN
N H
H
CO2Et To a solution of Example X (2.9 g, 10 mmol) in THF (50 mL) was added a solution of 1-naphthyl isocyanate (1.7 g, 10 mmol) in THF (20 mL) at 0 C. The mixture was stirred at RT for 1 h and heated until all solids dissolved. The mixture was then stirred at RT for 3 h and poured into water (200 mL). The precipitate was filtered, washed with diluted HCI and H20, dried under vacuum to give 4.3 g of 4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol- 1-yl]-benzoic acid ethyl ester, which was used without further purification.
Example 196 O
N~ N XN' N H
H
OH
To a solution of Example B (228 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 solution and aqueous HCl solution (10%), extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent removed iri vacuo and the residue purified by column chromatography to afford 1-{5-t-butyl-2-[3-(1-hydroxy-l-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea (150 mg, 67 %). 'H NMR
(DMSO-d6): 9.00 (s, 114), 8.75 (s, I H), 7.98 (d, J = 7.6 Hz, I H), 7.92-7.89 (m, 2 H), 7.65-7.62 (m, 2 H), 7.52-7.44 (m, 5 H), 7.37 (d, J= 6.8 Hz, 1 H), 6.39 (s, I
H), 5.13 (s, 1 H), 1.45 (s, 6 H), 1.27 (s, 9 H); MS (ESI) m/z: 443 (M+H+).
Example 197 CI
O
N/ N H
N H
I \ -.
OH
To a solution of Example C (220 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for I h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 and aqueous HCl solution (10 %), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography to afford 1-{5-t-butyl-2-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]- 2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea (174 mg, 81 %). IH
NMR (DMSO-d6): 9.11 (s, 1 H), 8.34 (s, I H), 7.59 (s, 1H), 7.46 (t, J = 8.8 Hz, 1 H), 7.43-7.40 (m, 3 H), 7.31-7.28 (m, 3 H), 6.34 (s, I H), 5.13 (s, 1 H), 1.42 (s, 6H), 1.27 (s, 9 H); MS (ESI) m/z: 428 (M+H+).
Example 198 O ~ I
N/ N H
N H
HO
To a solution of Example 195 (228 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methylmagnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4C1 and aqueous HCl solution (10%), extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent was removed in vacuo and the residue purified by column chromatography to afford 1-{5-t-butyl-2-[4-(1-hydroxy-l-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea (180 mg, 81 %). 'H NMR
(DMSO-d6): 9.06 (s, 1 H), 8.83 (s, 1 H), 7.99 (d, J 8.0 Hz, 1 H),. 7.92 (t, J
= 8.0 Hz, 2H), 7.64-7.61'(m, 3H), 7.55-7.43 (m, 5H), 6.40 (s, 1H), 5.13 (s, IH), 1.47 (s, 6H), 1.27 (s, 9 H); MS (ESI) mJz: 443 (M+H+).
Example 199 CI
o N/ H
N H
HO
To a solution of Example 57 (220 mg, 0.5 mmol) in dry THF (20 mL) was added dropwise a solution of methyl magnesium bromide in toluene/THF (3.6 mL, 5.0 mmol) at -78 C under N2. After stirring for 1 h, the mixture was allowed to rise to RT
and stirred for another 2 h. The reaction mixture was quenched with saturated NH4Cl and aqueous HCl solution (10 %), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the solvent removed in vacuo and the residue was purified by column chromatography to afford 1-{5-t-butyl-2-[4-(1-hydroxy-l-methyl-ethyl)-phenyl]- 2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea (187 mg, 87 %). 'H-_NMR (CDC13): 9.14 (s, 1 H), 8.42 (s, 1 H), 7.58 (d, J= 8.4 Hz, 2 H), 7.42 (d, J= 5.6 Hz, 2 H), 7.40 (d, J= 4.8 Hz, 2 H), 7.29 (d, J= 8.8 Hz, H), 6.34 (s, 1 H), 5.11 (s, 1 H), 1.44 (s, 6 H), 1.25 (s, 9 H); MS (ESI) m/z: 427 (M+H+).
Example PP
~ Br To a solution of 3-bromo-phenylamine (17 g, 0.1 mol) in concentrated HCl (200 mL) was added an aqueous solution (20 mL) of NaNO2 (7 g, 0.1 mol) at 0 C and the resulting mixture was stirred for 1 h. A solution of SnC1Z.2HZ0 (45 g, 0.2 mmol) in concentrated HCI (500 mL) was then added at 0 C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give (3-bromo-phenyl)-hydrazine as a white solid, which was used for the next reaction without further purification Example QQ
t-Bu ~
N
Br A mixture of Example PP (22.2 g, 0.1 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (18.7 g, 0.15 mol) in ethanol (250 mL) was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue purified by column chromatography to afford 2-(3-bromo-phenyl)-5-t-butyl-2H-pyrazol-3-ylamine as a white solid. 'H NMR (DMSO-d6): 7.85 (s, 1H), 7.68 (d, J =7.6 Hz, 1H), 7.62 (d, J
=7.2 Hz, IH), 7.50 (t, J =8.0 Hz, 1 H), 5.62 (s, 1 H), 1.27 (s, 9H).
---Example-RR--t-Bu /~
N~ NH2 N
( \ -/ COOEt To a mixture of Example QQ (2.94 g, 10 mmol), Pd(OAc)2 (1 mmol), PPh3 (20 mmol), and K2CO3 ( 20 mmol) in MeCN (50 mL) was added 2-methyl-acrylic acid ethyl ester (20 mmol). The resulting mixture was heated to reflux overnight, filtered, concentrated, and the residue was purified by column chromatography to afford 1.2 g of 3-[3-(5-Amino-3-t-butyl-pyrazol-1-yl)-phenyl]- 2-methyl-acrylic acid ethyl ester. 'H
NMR (CDC13): 7.41 (s, IH), 7.40-7.36 (m, 2H), 7.15 (d, J = 6.8 Hz, 1 H), 6.24 (s, 1H), 5.51 (s, 1H), 4.27 (q, J= 7.2 Hz, 2H), 2.12 (s, 3H), 1.33 (s, 9H), 1.27 (t, J
7.2 Hz, 3H).
Example SS
t-Bu N~
6 COOEt A mixture of Example RR (1.2 g,) and Pd / C (120 mg, 10 %) in methanol (50 mL) was stirred under 40 psi of H2 at RT overnight, filtered. And concentrated to afford 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-2-methyl-propionic acid ethyl ester as a racemate (1.1 g), which was used for the next reaction without further purification.
Example 200 .t-Bu O
N \ NXN
N H
I \
~ COOEt To a solution of Example SS (100 mg, 0.3 mmol) and Et3N (60 mg, 0.6 mmol) in CH2CI2 (10 mL) was added 1-isocyanato-naphthalene (77 mg, 0.45 mmol). The resulting mixture was stirred at RT overnight, added to water (50 mL), extracted with (3x30 mL) and the combined organic extracted were washed with brine, dried (Na2SO4), and filtered. After concentration under reduced pressure, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-l-yl}-phenyl)-propionic acid ethyl ester as a racemate (50 mg, 33 %). IH-NMR
(CDC13): 7.99 (s, 1 H), 7.91 (d, J= 8.4 Hz, 1 H), 7.84 (t, J= 7.2 Hz, 2H), 7.67 (d, J= 8.4 Hz, 1 H), 7.49=
7.41 (m, 3H), 7.35-7.33 (m, 3H), 7.21 (s, 1H), 7.14-7.13 (m, IH), 6.65 (s, IH), 3.98 (q, J
= 6.0 Hz, 2H), 2.92-2.88 (m, 3H), 1.36 (s, 9H), 1.24 (d, J 6.0 Hz, 3H), 1.08 (t, J 7.2 Hz, 3H); MS (ESI) m/z: 499 (M+H~.
Example 201 t-Bu 0 ~LO..
N H
A solution of Example 200 (17 mg, mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT over night. The reaction mixture was adjusted to pH = 4, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After the filtrate was concentrated, the residue was purified by preparative-TLC to afford 3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-l-yl]-phenyl}-2-methyl-propionic acid as a racemate (15 mg, 92 %). 'H
NMR
(DMSO): 11.81 (br s, 1 H), 9.58 (s, 1 H), 8.56 (s, 1 H), 7.95 (d, J= 7.6 Hz, 1 H), 7.82 (d, J
= 8.4 Hz, IH), 7.55 (d, J= 7.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.28 (d, J= 8.0 Hz, 1H), 7.14 .(t, J= 7.6 Hz, 1 H), 6.52 (s, 1 H), 3.77 (m, 1 H), 2.65 (m, 1 H), 2.36 (m, 1 H), 1.27 (s, 9H), 1.00 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 471 (M+H+).
Example 202 CI
t-Bu H H
COOEt To a solution of Example SS (100 mg, 0.3 mmol) and Et3N (60 mg, 0.6 mmol) in CH2C12 (10 mL) was added 1-chloro-4-isocyanato-benzene (77 mg, 0.45 mmol). The resulting mixture was stirred at RT overnight, and then added to water (50 mL). The solution was extracted with CH2C12 (3x30 mL) and the combined organic extracts were washed with brine, dried (Na2SO4),and filtered. After concentration under reduced pressure, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl }-phenyl)-2-methyl- propionic acid ethyl ester as a racemate (51 mg, 35 %). 'H-NMR (CDC13): 8.20 (s, 1 H), 7.39 (d, J= 4.4 Hz, 2H), 7.37 (d, J= 8.8 Hz, 2H), 7.21 (t, J= 8.4 Hz, 2H), 7.14-7.11 (m, 2H), 6.59 (s, 1 H), 4.04-3.99 (m, 2H), 3.00 (m, 1 H), 2.93 (m, 1 H), 2.83 (m, 1 H), 1.34 (s, 9H), 1.17 (d, J
6.4 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 483 (M+H+).
Example 203 CI
t-Bu rN H
N' H
A solution of Example 202 (15 mg, mmol) and 2N LiOH (3 rnL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was adjusted to pH = 4, extracted with ethyl acetate (3x20 mL), the combined organic extracts were washed with brine, dried (NaZSO4),and filtered. After the filtrate was concentrated, the residue was purified by preparative-TLC to afford 3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)- uxeido]-pyrazol-l-yl}-phenyl)-2-methyl-propionic acid as a racemate (13 mg, 90%). 'H NMR (DMSO):
12.48 (br s, IH), 9.35 (br s, 1 H), 7.55 (d, J= 8.8 Hz, IH), 7.34-7.32 (m, 2H), 7.26 (d, J=
8.4 Hz, 1 H); 7.24 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1 H), 6.45 (s, 1 H), 2.74 (m, 1 H), 2.65 (m, 1 H), 2.31 (m, 2H), 1.26 (s, 9H), 0.99 (d, J= 6.8 Hz, 3H); MS
(ESI) m/z:
455 (M+H+).
Example 204 O ~ I
N~ N N
N H
HO
To a stirred solution of Example 195 (500 mg, 0.83 mmol) iri THF (10 mL) was added LiAlH4 powder (65 mg, 1.66 mmol) in portion at 0 C under N2. The mixture was stirred for 2 h at RT, excess LiA1H4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH = 7 with dilute HCI. After the solvent was removed, the residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After concentration in vacuo, the crude product was purified by preparative-TLC to afford 1-[2-(4-hydroxymethyl-phenyl)- 5-isopropyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (415 mg, 92 %). 'H NMR (DMSO-d6): 9.04 (s, 1 H), 8.78 (s, 1 H), 7.98 (d, J= 8.0 Hz, I H), 7.90 (d, J= 7.2 Hz, 2H), 7.63 (d, J= 8.4 Hz, I H), 7.55-7.42 (m, 7 H), 6.39 (s, 1 H), 5.30 (t, J 5.6 Hz, 1 H), 4.56 (d, J 5.6 Hz, 2 H), 1.27 (s, 9 H); MS (ESI) m/z: 415 (M+H+).
Example 205 >o=
N/ /~_ N
N H H
O
To a solution of Example 204 (200 mg) in CH2C12 (50 mL) was added Mn02 (450 mg) at RT. The suspension was stirred for 2 h then filtered through celite.
The filtrate was concentrated under reduced pressure to afford 150 mg of 1-[5-t-butyl-2-(4-formyl=
phenyl)-2H-pyrazol-3-yl]-3-naphthalen-1-yl- urea, which was used without further purification.
Example 206 O
N/ N H
N H
\ .
To a solution of (trifluoromethyl)trimethylsilane (77 mg) and TBAF (10 mg) in THF (10 mL) was added Example 205 (150 mg) in THF (10 mL) under N2 atmosphere in ice-bath. The resulting mixture was stirred at 0 C for 1 h and then warmed to RT for an additional hour. To the reaction was then added 0.5 mL of 3 N HCL, which was then stirred at RT overnight. After removal the solvent, the residue was dissolved in CHZCIZ
(50 mL). The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by preparative-TLC to afford the final product 1-{5-t-Butyl-2-[4-(2,2,2-trifluoro-l-hydroxy- ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea ( 110 mg, 63 %). 'H NMR (DMSO-d6): 9.07 (s, IH), 8.89 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.90 (d, J 7.6 Hz, 2H), 7.67-7.62 (m, 5H), 7.55-7.51 (m, 2H), 7.44 (t, J= 8.0 Hz, 1 H), 6.95 (d, J 6.0 Hz, 1 H), 6.42 (s, 1 H), 5.27 (m, 1 H), 1.28 (s, 9H). MS (ESI) m/z: 483 (M+H+).
Example 207 CI
O
N/ \ N~ N
N H
H
HO
To a stirred solution of Example 57 (500 mg, 1.1 mmol) in THF (10 inL) was added LiA1H4 powder (65 mg, 1.66 mmol) in portion at 0 C under N2. The mixture was stirred for 2 h at RT, excess LiA1H4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH = 7 with diluted HCI. After the solvent removal, the residue was extracted with ethyl acetate, and the combined organic extracts were washed with brine, d dried (Na2SO4), and filtered, After solvent removal, the crude product was purified by preparative TLC to 1-[5-t-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea (380 mg, 92%) as a white powder. 'H-NMR (CDC13):
8.17 (br s, I H), 7.22 (s, 4 H), 7.17 (d, J= 8.0 Hz, 2 H), 7.09 (d, J= 8.0 Hz, 2 H), 7.04 (s, H), 6.38 (s, 1 H), 4.51 (s, 1 H), 1.22 (s, 9 H); MS (ESI) m/z: 399 (M+H+).
Example 208 CI
O
N/ N H
N H
O
To a solution of Example 207 (200 mg) in CH2C12 (50 mL) was added Mn02 (450 mg) at RT. The suspension was stirred for 2 h, then filtered through celite.
The filtrate was concentrated to afford 160 mg of 1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea, which was used without further purification.
Example 209 CI
O
N/ \ NX N
N H
H
To a solution of (trifluoromethyl)trimethylsilane (86 mg) and TBAF (10 mg) in THF (10 mL) was added Example 208 (160 mg) in THF (20 mL) under N2 atmosphere in ice-bath. The resulting mixture was stirred at 0 C for 1 h and then warmed to RT for an additional hour. To the reaction was added 0.5 mL of 3 N HCI, which was then stirred at RT overnight. After removal of the solvent, the residue was dissolved in CH2CI2 (100 mL). The organic extracts were washed with saturated NaHCO3 and brine, dried (Na2SO4), and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by preparative-TLC to afford the final product 1-{5-t-butyl-2-[4-(2,2,2-trifluoro-l- hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea ( 120 mg, 64 %). 'H-NMR (DMSO-d6): 9.15(s, 1H), 8.50 (s, IH), 7.61 (d, J = 8.4 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 8.8 Hz, 2 H), 7.28 (d, J= 8.8 Hz, 2 H), 6.91 (d, J= 5.6 Hz, 1 H), 6.36 (s, 1 H), 5.25 (m, IH), 1.26 (s, 9 H); MS (ESI) m/z: 467 (M+H+).
Example 210 O
N~
N
H
OH
O
A solution of Example 151 (42 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT over night. The reaction mixture was neutralized to pH =
4, and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-l-yl}-phenyl)-propionic acid (30 mg, 76%). 8.45 (d, 4.0 Hz, 1 H), 8.24 (d, 8.0 Hz, 1 H), 7.92 (s, 1 H), 7.88 (t, 7.6 Hz, 1 H), 7.67 (d, 8.0 Hz, I H), 7.36 (t, 5.6 Hz, 1 H), 7.23 (t, 7.6 Hz, 1 H), 6.96 (d, 6.8 Hz, 1 H), 6.67 (s , 111), 2.77 (t, 7.6 Hz; 2H), 2.22 (t, 7.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z:
393 (M+H+).
Example 211 J, N H H I
OyNH
C;) Example I is reacted with CDI and N-methyl piperazine using the procedure for Example 145 to afford the title compound.
Example 212 ' CI
H ~
N\
N H \
OyNH
CN) N
Example J is reacted with CDI and N-methyl piperazine using the procedure for Example 145 to afford the title.compound.
Example 213 N~ ~ J1, 1 N H H
OyNH
N
Example I is reacted with CDI and piperdine using the procedure for Example 145 to afford the title compound.
Example 214 N
\N H H
\ \
. ~ /
Oy NH
CN
O
Example I is 'reacted with CDI and morpholine using the procedure for Example 145 to afford the title compound.
Example 215 N/ ~
\N H N H
Oy NH
U
Example I is reacted with CDI and pyrrolidine using the procedure for Example 145 to afford the title compound.
Example 216 N~, ~ J~ \ 4 N H H
Oy NH
Example I is reacted with CDI and dimethylamine using the, procedure for Example 145 to afford the title compound.
Example 217 O /
H CI
N/ \ J~ \ I
N H
O\ /NH
~N"
Example J is reacted with CDI and piperdine using the procedure for Example 145 to afford the title compound.
Example 218 O / CI
N\~ J~ ~~
N H H
Oy NH
CN
O
Example J is reacted with CDI and morpholine using the procedure for Example 145 to afford the title compound.
Example 219 CI
N H H
Oy NH
U
Example J is reacted with CDI and pyrrolidine using the procedure for Example 145 to afford the title compound.
Example 220 / CI
O
N \ J~ \ I.
\N H H
O\ /NH
Example J is reacted with CDI and dimethylamine using the. procedure for Example 145 to afford the title compound.
Example 221 O N/
~
N,N H 1 /
O
~..
Isoquinoline-8-carboxylic acid and Example Z are reacted using the procedure for Example 149 to afford ethyl 3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)-1H-pyrazol-l-, yl)phenyl)propanoate.
Example 222 N/
N/
.N H
/ I
~ OH
O
Example 222 is reacted using the procedure for Example 150 to afford 3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)- I H-pyrazol-1-yl)phenyl)propanoic acid.
Example 223 O
N N~N
H H I
OEt Example E is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 224 N ~ I
.N ~ NN
H H
O
p OH
Example 224 is reacted using the procedure for Example 150 to afford 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-l-yl)benzyl)-2-methylpropanoic acid Example 225 / CI
\ I
N H N H
O
OEt Example G is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 226 CI
N/ \ 'J~ \ I
N H H N
p O
OH
Example 226 is reacted using the procedure for Example 150 to afford 2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-1-yl)benzyl)-2-methylpropanoic acid.
Example TT
O
N~ ~ XN
N H H ' /
CI
Example 204 is reacted using the procedure for Example E to afford 1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea Example UU
CI
O
NN H H
CI
Example 122 is reacted using the procedure for Example G to afford 1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 227 /
N ~ J, I
'N H H
I / .
O OEt Example TT is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(4-(3-t-butyl-5-(3-(naphthalen=1-yl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate.
Example 228 O
N \
~N N~N
H H
OH
Example 227 is reacted using the procedure for Example 150 to afford 2-(4-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol- I -yl)benzyl)-2-methylpropanoic acid.
Example 229 CI
N
~ N ~ H<) H
OEt Example UU is reacted with (1-ethoxy-2-methylprop-l-enyloxy)trimethylsilane under literature conditions to afford ethyl 2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)benzyl)-2-methylpropanoate Example 230 O / CI
N/ ~ I
\N H H
OH
Example 144 is reacted using the procedure for Example 150 to afford 2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-l-yl)benzyl)-2-methylpropanoic acid.
Example VV
~ ~/CI
N
NJ
N-methyl piperazine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-methylpiperazine hydrochloride.
Example WW
~ ~/CI
r N
OJ
Morpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 4-(2-chloroethyl)morpholine ~..
Example XX
NCI
OJ
Morpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 4-(3-chloropropyl)morpholine.
Example Yl' ~~CI
OH
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-methylpiperidin-4-ol.
Example ZZ
CI
OH
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 1-(3-chloropropyl)-4-methylpiperidin-4-ol.
Example AAA
N
O =SJ
A solution of 4,4-dioxothiomorpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 4-(2-chloroethyl)-4,4-dioxo-4-thiomorpholine.
Example BBB
O =S
A solution of 4,4-dioxothiomorpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 4-(3-chloropropyll)-4,4-dioxo-4-thiomorpholine.
Example CCC
~~CI
OH
A solution of 4-(trifluoromethyl)piperidin-4-ol and 1-bromo-2-chloroethane are reacted using the procedure for Example 00 to afford 1-(2-chloroethyl)-4-(trifluoromethyl)piperidin-4-ol.
Example DDD
N--~CI
OH
A solution of 4-(trifluoromethyl)piperidin-4-oI and 1-bromo-3-chloropropane are reacted using the procedure for Example 00 to afford 1-(3-chloropropyll)-4-(tri fluoromethyl)piperidin-4-ol.
Example 231 N/ \ J~ \ ( \N H H
I \
O ~
N
Example 4.1 and Example WW are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-morpholinoethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen- I -yl)urea.
Example 232 N/ \ ~ \ I
,N H H
O
O
Example 41 and Example XX are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-morpholinopropoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-(naphthalen-l-yl)urea.
Example 233 N H H
\
~ /
O
(N) N
Example 41 and Example VV are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3 -(naphthalen-l-yl)urea.
Example 234 O
N H I \ \
/
N O
ONH
Example CC, 2-naphthoic acid chloride and Example DD were combined utilizing the same general approach for Example 162 to yield N-(3-tert-butyl-l-(3-([5-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]phenyl)-1 H-pyrazol-5-yl)-naphthamide. 'H-NMR (DMSO-d6): 10.50 (s, 1H), 8.45 (s, 1H), 8.15-8.05 (m, 3H), 7.90 (s, 1 H), 7.60 (t, J= 7.2 Hz, 3H), 7.45 (s, 1 H), 7.3 8(t, J= 8.0 Hz, 1 H), 7.27 (d, J= 7.2 Hz, 1 H), 6.44 (s, 1 H), 4.05 (s, 2H), 1.31 (s, 9H). MS (ESI) m/z: 518 (M+H+).
Example 235 N H H
Ob N
C~
oso Example 41 and Example AAA are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)ethoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 236 ~ \ ~ \I
N
\N H H
O \
~ /
~ O
O
Example 41 and Example BBB are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)propoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3 -(naphthalen-1-yl)urea.
Example 237 N H H
O ~
~ /
N
OH
Example 41 and Example YY are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-methylpiperidin-4-ol)ethoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 238 N H H
O
OH
Example 41 and Example ZZ are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-(4-methylpiperidin-4-ol-)propoxy)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 239 II
N NN
H H
~ \
O /
Example 41 and Example CCC are reacted according to the procedure for Example 194 to afford 1-(1-(3-(2-(4-(trifluoromethyl)piperidin-4-ol)ethoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 240 r \ O
N~N N'J~N
H H
\
~ j O
v _N
OH
Example 41 and Example DDD are reacted according to the procedure for Example 194 to afford 1-(1-(3-(3-(4-(trifluoromethyl)piperidin-4-ol)propoxy)phenyl)-3-t-butyl-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 241 t-Bu 0 N \ XN
N H H
Example D is reacted using the procedure for Example 205 to afford 1-(3-t-butyl-1-(3-formylphenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 242 N/ \ ~ ~ I
~N H H I
OH
Example 242 is reacted using the procedure for Example 206 to afford 1-(3=t-butyl-l-(3-(2,2,2-trifluoro-l-hydroxyethyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 243 CI
t-Bu 0 ~
N/ \
N N~ N
H H
Example F is reacted using the procedure for Example 208 to afford 1-(3-t-butyl-1-(3-formylphenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 244 N \ ~C!
~ ~
\N H H
b Y
OH
Example 244 is reacted using the procedure for Example 209 to afford 1-(3-t-butyl-l-(3-(2,2,2-trifluoro-l-hydroxyethyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea Example 245 N~ O
, N N~N
H H
F I ~
F
OH
Example B is saponified using the procedure for Example 150. The resulting acid is reacted with trifluorotriazine in pyridine to afford the acid fluoride which is directly reacted with CsF and TBAF according to literature procedures (see J. Org.
Chem. USSR
(Engl. Transl.), 11, 1975, 315-317) to afford 1-(3-t-butyl-l-(3-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 246 icI
N H H
~ \
F /
F
OH
Example C is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-l-(3-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 247 O
~
N~N NN
H H
F OH
F
Example 205 is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-l-(4-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3 -(naphthalen-l-yl)urea.
Example 248 cl N H H \ I
F OH
F
Example 57 is reacted according to the procedure for Example 245 to afford 1-(3-t-butyl-1 -(4-(difluoro(hydroxy)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example EEE
. I \
N
Boc Example EEE (tert-butyl 7-hydrazinyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate) was synthesized according to literature procedures.
Example 249 O
N N~N
H H
Boc,N
Utilizing the same synthetic procedure as for Example 164, Example EEE (10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl 7-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)-3,4-dihydroisoquinoline-2( I H)-carboxylate.
Example 250 CI
N/ \ J~
N H H \ I
P
Boc~N
Utilizing the same synthetic procedure as for Example 164, Example EEE (10 mmol) and Example QQ (10.5 mmol) are combined to afford t-butyl7-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1 H-pyrazol-l-yl)-3,4-dihydroisoquinoline-2( I H)-carboxylate Example 251 N H H
HN
Example 249 is reacted with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 252 CI
N H H \ I
HN
Example 250 is reacted with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea:
Example 253 N H H
O~N
HN,~ i0 S'O
/N\
Example 251 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[1-N-[[(1-dimethylaminolsulphonyl)amino] carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 254 O / CI
\ I
N H H
O\/N
H~N", i0 S
Example 252 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[1-N-[[(1-dimethylaminolsulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-pyrazol-5-yl)- 3-(4-chloropheny))urea.
Example 255 /. I CI
O
N, N N~N \
H H
O\ /N
H~N",, i0 s 1'O
Example 252, CDI, and methanesulfonamide are reacted under standard conditions to yield 1-(3-t-butyl-l-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1 H-pyrazol-5-yl)- 3-(4-chlorophenyl)urea.
Example 256 N/ J, \N H H
' \ \
O\ /N
O
H~N", //O
s 1'O
Example 251, CDI, and methanesulfonamide are reacted under standard conditions to yield 1-(3-t-butyl-l-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)- 3-(1-naphthyl)urea.
Example FFF
I ~ Boc N
Commercially available 3-nitrobenzoic acid is reacted with methylamine and EDC under standard conditions to afford N-methyl-3-nitrobenzamide, which is reduced with LAH under standard conditions to afford N-methyl(3-nitrophenyl)methanamine, which is protected with benzylchloroformate under standard conditions to yield t-butyl 3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced to yield t-butyl 3-hydrzazinobenzylmethylcarbamate.
Example 257 N~ \ O
N NJN
H H
Boc Utilizing the same synthetic procedure.as for Example 164, Example FFF (10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl 3-(3-t-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)benzylmethylcarbamate.
Example 258 N/ \ J~ \ I
N H H
,NH
Example 257 is deprotected with trifluoroacetic acid under standard conditions to afford 1-(3-t-butyl-l-(3-((methylamino)methyl)phenyl)-IH-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 259 N/ \ ~ \ I
\N H H
H
N, S, N D
p p ~\O
Example 258 is reacted with chlorosulfonyl isocyanate then piperdine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinylsulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 260 N. \ O ~ I
N NJN
H H
H
jN,,(Nll S/N
O O \O
Example 258 is reacted with chlorosulfonyl isocyanate then morpholine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-morpholinyl=
sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-I -yl)urea.
Example 261 N/ J~
.N H H
H
N N~ ~N
~ p~0 Example 258 is reacted -with chlorosulfonyl isocyanate then pyrrolidine according to the procedure for Example 7 to afford 1-(3-t-butyl-1-[[3-[[(1-pipeidinyl-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 262 N H H
H
N~N-~ S/N\
Example 258 is reacted with chlorosulfonyl isocyanate then dimethylamine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-dimethylamino-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 263 O
N H H
\. \
H
Ny N,,S~NH2 Example 258 is reacted with chlorosulfonyl isocyanate then ammonia according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-aminosulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-(naphthalen-l-yl)urea.
Example 264 I~
N NN
H H
~ CN
N N'S/hI 00 Example 258 is reacted with chiorosulfonyl isocyanate then N-methyl piperzine according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(N-methylpiperzinyl)sulphonyl)amino] carbonyl]-((methylamino)methyl)phenyl)-114-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 265 N J
N H H
I \ S~O \
H
N,~rNl~ ,N
Example 258 is - reacted-with chlorosulfonyl- isocyanate then- -4,4-dioxo-4-thiomorpholine according to the procedure for Example 7 to afford 1-(3-t-butyl-l.-[[3-[[(1-(4,4-dioxo-4-thiomorpholinyl)sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1 H-pyraiol-5-yl)-3-(naphthalen-l-yl)urea.
Example 266 H H
\
/
H
N
Cchlorosulfonyl isocyanate, piperdine, then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinylcarbonyl)amino] sulphonyll]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 267 OII
N NN
H H
H O
,-IN~"N~NJ
O Ol 0 Chlorosulfonyl isocyanate, morpholine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-morpholinyl-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 268 N~ \ \ I
N H N ~H
H
,N,S_NyNO
O~~l -Chlorosulfonyl isocyanate, pyrrolidine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-piperdinyl-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 269 N H N H ( \
~ /
H
N
,-IO, S' Ny 'O( 0 --Chlorosulfonyl isocyanate, dimethylamine, -then--Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-dimethylamino-carbonyl)amino] sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 270 N ~
\N ~ H H
rbH
NNyNHZ
Chlorosulfonyl isocyanate, ammonia and then Example 258 are reacted according to the procedure for Example 7 to afford 1-_(3-t-butyl-l-[[3-[[(1-aminocarbonyl)amino]sulphony]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 271 O
N NN
H H
\
~ / N
H
N ~N~N~
O, II
Chlorosulfonyl isocyanate, N-methyl piperzine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(N-methylpiperzinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 272 N \ ~
\N N N
O
S'O
N" g~N INJ
o~ Il y Chlorosulfonyl isocyanate, 4,4-dioxo-4-thiomorpholine and then Example 258 are reacted according to the procedure for Example 7 to afford 1-(3-t-butyl-l-[[3-[[(1-(4,4-dioxo=4-thiomorpholinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-pyrazol-5-yl)-3-(naphthal en- 1 -yl)urea.
Example GGG
O
I NH
N-i O
Commercially available 3-nitrobenzamide is reduced .with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with 4-methoxybenzylisocyanate to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)urea.
This material is subsequently reacted with oxalyl chloride to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione whose nitro group is reduced and oxidized to -afford-l-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione.
This material is deprotected with TFA under standard conditions to afford the title compound 1-(3-hydrazinylbenzyl)imidazolidine-2,4,5-trione.
Example 273 o N, N N~N
H H I
O N~O
NH
O
Utilizing the same synthetic procedure as for Example 164, Example GGG (10 mmol) and Example PP (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea Example 274 CI
N/ \ J~ \ I
\N H H
O N~O
NH
O
Utilizing the same synthetic procedure as for Example 164, Example GGG (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example HHH
\ O -~~rA
I NH
O
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with N-4-methoxybenzylsulfamic acid and EDC to afford 1-(4-methoxybenzyl)-3-benzylsulfonylurea. This material is reacted with oxalyl chloride to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione whose nitro group is reduced and oxidized to afford 1-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione. This material is deprotected with TFA under standard conditions to afford the title compound 1-(3-hydrazinyl benzyl )imi dazoli dine-2,2-dioxo-2-thi o-4, 5-trione.
Example 275 N/ \ , O N~~O
NHO
O
Utilizing the same synthetic procedure as for Example 164, Example HHH (10 mmol) and Example PP (10.5 nunol) are combined to afford 1-(3-t-butyl-l-(3-((2,2-dioxo-2-thio-4,5--diioxoimidazolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
Example 276 CI
O
N NN
H H
O N%~~O
NHO
O
Utilizing the same synthetic procedure as for Example 164, Example HHH (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-1-(3-((2,2-dioxo-2-thio-4,5-diioxoimidazolidin-1 -yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 277 OMe N H H
N
O ~
NH
Example CC, 4-methoxy-l-aminonaphthalene and Example E are reacted using the procedure for Example 162 to afford 1-(5-t-butyl-2-{3-[1,1,4-trioxo-lk 6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-methoxynaphth-1-yl)-urea:
Example III
H2N, NH
N -O
O
//~~NH
O
A solution of 1-(chloromethyl)-3-nitrobenzene and Example DD are combined using the procedure for Example 77 to yield 2-(4-methoxybenzyl)-5-(3-nitrophenylmethyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one. This material is reduced under standard condition to yield 2-(4-methoxybenzyl)-5-(3-aminophenylmethyl)-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-3-one, which was nitrosated and acidified to yield 5-(3-hydrazinophenylmethyl)- 1, 1 -dioxo- 1 %6-[ 1,2,5]thiadiazolidin-3-one.
Example JJJ
O
O i OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2C12 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 2-naphthoic acid chlorideis added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for 1 h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-2-naphthamide.
Example KKK
O OP, o i OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2C12 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and 1-naphthoic acid chloride is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for I h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-1-naphthamide Example LLL
O
O N
N
OEt Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH2CI2 (25 mL) and cooled in an ice bath. The suspension is stirred for 5 min and isoquinoloic acid chloride is added dropwise over 5 min. The reaction mixture is stirred an additional 5 min at 0 C, and the reaction is warmed and stirred at RT for 1 h. The reaction is pour into ethyl acetate (100 mL) and water (100 ml). After shaking, the aqueous layer is removed, the organic layer washed with water, dried (MgSO4) and concentrated to afford (Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)isoquinoline-3-carboxamide.
Example 278 (I
NIN, N NQ
H
NO
O
NH
Utilizing the same synthetic procedure as for Example 164, Example III (10 mmol) and Example 11 (10.5 mmol) are combined to afford 1-naphtyl 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3 -(naphthalen-l-yl)carbmate.
Example 279 / \ O
N H I \ \
N~~rl "O
NH
Utilizing the same synthetic procedure as for Example 164, Example III (10 mmol) and Example JJJ (10.5 mmol) are combined to afford 1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-2-naphthamide.
Example 280 / O
N
~N H I
/ .
\
NO
O NH
Utilizing the same synthetic procedure as for Example 164 Example III (10 mrnol) and Example KKK (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-1-naphthamide.
Example 281 O
\
N H N
N~'O
NH
O
Utilizing the same synthetic procedure as for Example 149, Example III (10 mmol) and Example KKK (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)isoquinoline-3-carboxamide.
Example _MMM
O
(:Ao N
O
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with succinic anhydride under standard conditions to afford 1 -(3 -nitrobenzyl)pyrroli dine-2,5 -di one.
This material is reduced at the nitro group and oxidized to afford 1-(3-hydrazinobenzyl)pyrrolidine-2,5 -dione.
Example 282 ~. /
O
ll NN NH/\H
b 0=~ \J
Utilizing the same synthetic procedure as for Example 164, Example MMM (10 mmol) and Example PP (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.
Example 283 O CI
NN NH H
N O
Utilizing the same synthetic procedure as for Example 164, Example MMM (10 mmol) and Example QQ (10.5 mmol) are combined to afford 1-(3-t-butyl-l-(3-((2,5-dioxopyrrolidin-l-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
Example 284 ' CI
O
\
N"N N H
H
OH
O
Example C was reacted with LiOH utilizing the procedure for Example 146 to yield 3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-l-yl)benzoic acid in 90%
overall yield. 'H NMR (DMSO-d6): 9.00 (s, 1 H), 8.83 (s, 1 H), 8.25 - 7.42 (m, 11 H), 6.42 (s, 1 H), 1.26 (s, 9 H); MS(ESI): Expected: 412.88 Found: 413.00.
Example 285 O
N( \ N~H \ ~ 1 N H
O
OH
Example B was reacted with LiOH utilizing the procedure for Example 146 to yield 3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzoic acid in 90%
overall yield. 1 H NMR (DMSO- d6): S 9.11 (s, 1 H), 8.47 (s, 1 H), 8.06 (m, 1 H), 7.93 (d, J
= 7.6 Hz, 1 H), 7.81 (d, J= 8.0 Hz, 1 H), 7.65 (dd, J= 8.0, 7.6 Hz, 1 H), 7.43 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, 1 H), 1.27 (s, 9H); MS (ESI) Expected: 428.49 Found: 429.2 (M+1).
Example NNN
O~NH
N\S~O
To the solution of phenyl-urea (13.0 g, 95.48 mol) in THF (100 mL) was slowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT. The reaction mixture was refluxed overnight, the volatiles removed in vacuo yielded 2-phenyl-1,2,4-thiadiazolidine-3,5-dione as a white solid (4.0 g, 20%). 'H NMR (DMSO-d6): S
12.49 (s, IH), 7.51 (d, J= 8.0 Hz, 2H), 7.43 (t, J= 7.6 Hz, 2H), 7.27 (t, J= 7.2 Hz, 1 H).
Example 286 o N/ )-N
N H H
I \
/
O,l/ N rO
N-S
Example E and Example NNN were reacted together utilizing the same general approach as for Example 160 to afford 1-(3-t-butyl-l-(3-((3,5-dioxo-2-pheny1-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(naphthalen-l-yl)urea.
'H NMR
(DMSO- d6): 58.96 (s, 1 H), 8.01 - 7.21 (m, 16 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H); MS (ESI): Expected: 590.21, Found 591.26 (M+1).
Example 287 o N~ N)-N
N H
. I ~
/
p ~N
S
HN
Example CC, 1-naphthylisocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-lX6-[1,2,5]thiadia- zolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-naphthylurea.
'H NMR
(DMSO- d6): S 9.0 (s, IH), 8.81 (s, IH), 7.99 - 7.42 (m, 11H), 6.41 (s, 1H), 4.33 (s, 2H), 1.27 (s, 9H); MS (ESI).Exact Mass: 532.19 Found: = 533.24 Example 288 ci -- - - o N N H H
O
O
iN
HN
O
Example CC, p-chlorophenylisocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1 X6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl } -2H-pyrazol-3-yl)-3 -(4-chloro-phenyl)-urea. 'H NMR (DMSO- d6): 6 9.07 (s, 1H), 8.42 (s, 1H), 7.52 - 7.272 (m, 8H), 6.36 (s, 1 H), 4.60 (s, 2H), 1.26 (s, 9H); MS (ESI) Exact Mass: 516.13 Found:
= 517.1 Example 289 CI
O
- -- - ~ ~ ~
N NH
N H
I \
/
0,'/N~0 \N-S
Example G and Example NNN were reacted together utilizing the same general approach as for Example 160 to afford 1-(3-t-butyl-l-(3-((3,5-dioxo-2-phenyl-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.
IH NMR
(DMSO- d6): 59.02 (s, IH), 8.51 (s, 1H), 7.52 - 7.24 (m, 13H), 6.36 (s, 1 H), 4.90 (s, 2H), 1.27 (s, 9H); MS (ESI): Expected: 574.16 Found: 575.26 (M+l) Example 290 CI
N~ \ ~ \ I
'N H H
b CI
C\/
Example Z and 2,6-dichlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.46 - 7.26 (m, 7H), 6.3 5 (s, 1 H), 4.11 (q, J= 7.2Hz, 2H), 3.31 (t, J= 5.2 Hz, 2H), 2.68 (t, J= 5.6 Hz, 2H), 1.32 (s, 9H), 1.24 (t, J = 7.2Hz, 3H); MS(ESI): Expected::
502.15 Found: = 503.1 (M+1).
Example 291 CI
N/ ~ I
,N H H
Cl I / OH
Example 290 was reacted utilizing the same condition as for Example 146 to yield 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1 H-pyrazol-l-yl)phenyl)propanoic acid in >90% yield. 'H NMR (DMSO- d6): S 8.70 (s, IH), 8.60 (s, 1H) 7.50 - 7.24 (m, 7H), 6.26 (s, IH), 2.87 (t, J= 5.2 Hz, 2H), 2.57 (t, J= 5.6 Hz, 2H), 1.25 (s, 9H);
MS(ESI):
Expected: 474.12 Found: 475.18 (M+1).
Example 000 N/
,N NHz A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
A solution of the crude material from the previous reaction (1.5 g, 8.4 nunol) was dissolved in 6 N HCI (9 ml), cooled to 0 C, and vigorously stirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After lh, tin (II) chloride dihydrate (5 g) in 6 N HCI (10 ml) was added. The reaction mixture was stirred at 0 C for 3h. The pH was adjusted to pH 7 to yield ethyl3-(4-(3-t-butyl-5-amino-IH-pyrazol-l-yl)phenyl)propanoate.
Example 292 -CI
CI
H H
~~O O
Example 000 and 2,6-dichlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(4-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.45 - 7.24 (m, 711), 6.36 (s, 1 H), 4.10 (q, J 7.2Hz, 2H), 3.02 (t, J 5.2 Hz, 2H), 2.70 (t, J= 5.6 Hz, 2H), 1.33 (s, 9H), 1.22 (t, J 7.2Hz, 3H); MS(ESI): Expected::
502.15 Found: = 503.1 (M+1).
Example 293 CI
N H H
CI
V
Example 292 was reacted utilizing the same condition as for Example 146 to yield 3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1 H-pyrazol-1-yl)phenyl)propanoic acid in >90% yield. 'H NMR (DMSO- d6): S 8.66 (s, 1H), 8.58 (s, IH) 7.50 - 7.28 (m, 7H), 6.27 (s, 1H), 2.85 (t, J= 5.2 Hz, 2H), 2.48 (t, J= 5.6 Hz, 211), 1.24 (s, 9H);
MS(ESI):
Expected: 474.12 Found: 475.18 (M+1).
Example 294 CI
O
N/ N~N
.N H H
~~O 0 Example 000 and p-chlorophenylisocyanate were reacted utilizing. the same conditions as for Example 145 to yield ethyl 3-(4-(3-tert-butyl-5-(3-(4-chlorophenyI)ureido)-1 H-pyrazol-I -yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
7.34 - 7.19 (m, 9H), 6.36 (s, 1 H), 4.10(q, J= 7.2Hz, 2H), 2.92 (t, J= 5.2 Hz, 2H), 2.58 (t, J=
5.6 Hz, 2H), 1.32 (s, 9H), 1.25 (t, J 7.2Hz, 3H); MS(ESI): Exact Mass: 468.19 Found: = 469.21 (M+1).
Example 295 CI
O
N.N\ H H
----- I \
O
Example Z and p-chlorophenylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-tert-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): S
9.12 (s, I H), 8.37 (s, 1 H), 7.41 - 7.27 (m, 8H), 6.34 (s, 1 H), 5.73 (s, 1 H), 4.01 (q, J 7.2Hz, 2H), 2.90 (t, J= 5.2 Hz, 2H), 2.62 (t, J= 5.6 Hz, 2H), 1.25 (s, 9H), 1.125 (t, J= 7.2Hz, 3H); MS(ESI): Exact Mass: 468.19 Found: = 469.21 (M+1).
Example 296 N~ ~-N
N H H
~~O O
Example 000 and 1-naphthylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(4-(3-tert-butyl-5-(3-(naphthalen-l-yl)ureido)-1 H-pyrazol-l-yl)phenyl)propanoate. S 7.88 - 9.95 (m, 13H), 6.27 (s, 1 H), 4.04 (q, J = 7.2Hz, 2H), 2.75 (t, J = 5.2 Hz, 2H), 2.42 (t, J = 5.6 Hz, 2H), 1.27 (s, 9H), 1.20 (t, J= 7.2Hz, 3H); MS(ESI): Exact Mass: 484.25 Found: = 485.26 (M+1).
Example 297 O
N~ ~ ~N
N H H ~
Example Z and 1-naphthylisocyanate were reacted utilizing the same conditions as for Example 145 to yield ethyl 3-(3-(3-tert-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate. 'H NMR (DMSO- d6): 6 9.01 (s, 1H), 8.80 (s, IH), 8.0 -7.27 (m, 11 H), 6.41 (s, 1 H), 4.01 (q, J= 7.2Hz, 2H), 2.95 (t, J= 5.2 Hz, 2H), 2.72 (t, J
5.6 Hz, 2H), 1.27 (s, 9H), 1.15 (t, J = 7.2Hz, 3H); MS(ESI): Exact Mass:
484.25 Found: = 485.26 (M+1).
Example 298 OMe N/ \ ~ \ ( \N H H I
ONH
Example CC, 1-(4-methoxynaphthyl)isocyanate and Example DD were combined utilizing the same general approach for Example 162 to yield 1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1 ~ 6-[ 1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-(4-methoxynaphthyl)urea. 'H NMR (DMSO- d6): S 8.69 (s, 1H), 8.61 (s, 1H), 8.15 -6.90 (m, IOH), 6.36 (s, 1H), 4.37 (s, 2H), 3.93 (s, 3H), 1.22 (s, 9H); MS (ESI) Exact Mass:
562.20 Found: = 563.2.
Example PPP
N\
In a 250 mL Erlenmeyer flask with a magnetic stir bar, 3-phenoxyphenylamine (4.81 g, 0.026 mol) was added to 6 N HCI (40 mL) and cooled with an ice bath to 0 C.
A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop -wise:- After 30 min, SnC12'2H20 (52.0 g, 0.23 mol, 8.86 eq.) in 6 N HCI (100 mL) was added and the reaction mixture was allowed to stir for 3 h; and then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for 4h, concentrated in vacuo and the residue extracted with EtOAc (2 X 100 mL) and purified by column chromatography using hexane/EtOAc/Et3N (8:2:0.2) to yield 3-tert-butyl-l-(3-phenoxyphenyl)-1H-pyrazol-5-amine (1.40g, 17%). mp: 108 - 110 C; 'H NMR
(CDC13): S 7.3 (m, I OH), 5.7 (s, 1 H), 4.9 (brs, 2H ), 1.3 (s, 9H).
Example 299 a p ""
o In a dry vial with a magnetic stir bar, Example PPP (0.184 g; 0.60 mmol) was dissolved in 2 mL CH2C12 (anhydrous) followed by the addition of phenylisocyanate (0.0653 mL; 0.60 mmol; 1 eq.). The reaction was kept under Ar and stirred for 18h.
Evaporation of solvent gave a crystalline mass that was recrystallized from EtOAc/hexane and then filtered washing with hexane/EtOAc (4:1) to yield 1-[3-tert-butyl-l-(3-phenoxyphenyl)-1H-pyrazol-5-yl]=3-phenylurea (0.150 g, 50%). HPLC
purity:
96%; 'H NMR (CDC13): S 7.5 (m, 16H), 6.8 (s, IH), 6.5 (s, 1H), 1.4 (s, 9H).
Example QQQ
N~
N /
O~
[<,N
To a stirred solution of Example L (1.2 g, 3.5 mmol) in THF (6 ml) was added borane-methylsulfide (9 mmol). The mixture was heated to reflux for 90 min and cooled to RT, and 6 N HCI was added and heated to reflux for 10 min. The mixture was basified by adding sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-amine (0.78 g), which was used without further purification.
Example 300 Nr N /
15r HNO /
A mixture of Example QQQ (0.35 g, 1.07 mmol) and 1-naphthylisocyanate (0.18 g, 1.05 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using 5 % methanol in CH2C12 (with a small amount of TEA) as the eluent (0.18 g, off-white solid) to yield 1-{3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-naphthalen-1-yl)urea. mp: 88 - 90 C; IH NMR (200MHz, DMSO- d6): S 9.07 (s, 1H), 8.80 (s, IH), 8.06-7.92 (m, 3H), 7.69 - 7.44 (m, 7H), 7.40 - 7.29 (m, 114), 6.44 (s, IH), 3.57 - 3.55 (m, 4H), 3.33 - 3.11 (m, 4H), 2.40 - 2.38 (m, 4H), 1.32 (s, 9H);
MS
Example 301 N~
N /
/ O
~ HN~/
Ui~ \
HN O CI
The title compound was synthesized in a manner analogous to Example 23 utilizing Example QQQ (0.35 g, 1.07 mmol) and 4-chlorophenylisocyanate (0.165 g, 1.05 mmol) to yield 1-{3-tert-butyl-l-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea. mp: 82 - 84 C; 'H NMR (200MHz, DMSO- d6): S 9.18.(s, IH, s), 8.40 (s, 1H), 7.53 - 7.26 (m, 8H), 6.37 (s, 1H), 3.62 - 3.54 (m, 4H), 2.82-2.78 (m, 4H), 2.41-2.39 (m, 4H), 1.30 (s, 9H); MS
All of the references above identified are incorporated by reference herein.
In addition, two simultaneously applications are also incorporated by reference, namely Modulation of Protein Functionalities, S/N 10/746,545, filed December 24, 2003, and Anti-Cancer Medicaments, S/N 10/746,607, filed December 24, 2003.
Claims (83)
1. A compound having the formula wherein:
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h , where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or l;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and G is alkylene, N(R6), 0;
each Z is individually selected from the group consisting of -0- and -N(R4)-;
each ring of formula (IA) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;
except that:
when Q is Q-3 or Q-4, then the compound of formula (I) is not when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
when Q is Q-7, R5 is -OH, Y is -O-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, then the compound of formula (I) is not when Q is Q-8, then Y is not -CH2O-;
when Q is Q-8, the compound of formula (I) is not R10 = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-10, then the compound of formula (I) is not when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-11, then the compound of formula (I) is not when Q is Q-15, then the compound of formula (I) is not when Q is Q-16 and Y is -NH-, then of formula (I) is not biphenyl;
when Q is Q-16 and Y is -S-, then of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;
when Q is Q-16 and Y is -SO2NH-, then the compound of formula (I) is not when Q is Q-16 and Y is -CONH-, then of formula (I) is not imidazophenyl;
when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not when Q is Q- 16 and t is 0, then of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
when Q is Q-17, then the compound of formula (I) is not when Q is Q-21, then the compound of formula (I) is not when Q is Q-22, then the compound of formula (I) is selected from the group consisting of when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of but excluding when Q is Q-23, then the compound of formula (I) is not when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of wherein each W is individually selected from the group consisting of -CH- and -N-;
each G, is individually selected from the group consisting of -O-, -S-, and -N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
wherein each Z is individually selected from the group consisting of -O- and -N(R4)-;
when Q is Q-31, then the compound of formula (I) is not when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not when Q is Q-32, then is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
when Q is Q-32, Y is -CONH-, q is 0, m is 0, and of formula (I) is -CONH-, then A is not phenyl;
when Q is Q-32, q is 0, m is 0, and is -CONH-, then the compound of formula (I) is not when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone;
when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32 and Y is an ether linkage, then of formula (I) is not biphenyl or phenyloxazolyl;
when Q is Q-32 and Y is -CH=CH-, then of formula (I) is not phenylaminophenyl;
when Q is Q-32, then the compound of formula (I) is not b = 0-1 X1 = O, S
R56 = H, CF3, Cl, imidazolyl, amino, morpholino, phenylthio, cycloalkyl, benzyl, phenyl, phenoxy, thienyl, substituted alkyl, pyridylthio, pyrimidyl, benzylamino, N-benimidazolyl, pyridylcarbonylamino, ureido,N- thiourea, substituted alkanoylamino, phenylsulfonyl,substituted benzoyl, phenylalkenoyl, furanoyl, thienoyl, pyridinoyl, R57 = substituted phenyl, substituted biphenyl , or d = 0-2 R58 = substituted alkylaminocarbonyl, phenylaminocarbonyl R60 = H, alkyl R59 = H, Cl R61 = substituted phenyl, thienyl, Br R62 = H, alkyl, phenyl R63 = substituted phenyl when Q is Q-35 as shown wherein G is selected from the group consisting of -O-, -S-, -NR4-, and -CH2-, k is 0 or 1, and u is 1, 2, 3, or 4, then is selected from the group consisting of except that the compound of formula (I) is not
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h , where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or l;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and G is alkylene, N(R6), 0;
each Z is individually selected from the group consisting of -0- and -N(R4)-;
each ring of formula (IA) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;
except that:
when Q is Q-3 or Q-4, then the compound of formula (I) is not when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
when Q is Q-7, R5 is -OH, Y is -O-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, then the compound of formula (I) is not when Q is Q-8, then Y is not -CH2O-;
when Q is Q-8, the compound of formula (I) is not R10 = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-10, then the compound of formula (I) is not when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
when Q is Q-11, then the compound of formula (I) is not when Q is Q-15, then the compound of formula (I) is not when Q is Q-16 and Y is -NH-, then of formula (I) is not biphenyl;
when Q is Q-16 and Y is -S-, then of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;
when Q is Q-16 and Y is -SO2NH-, then the compound of formula (I) is not when Q is Q-16 and Y is -CONH-, then of formula (I) is not imidazophenyl;
when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not when Q is Q- 16 and t is 0, then of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
when Q is Q-17, then the compound of formula (I) is not when Q is Q-21, then the compound of formula (I) is not when Q is Q-22, then the compound of formula (I) is selected from the group consisting of when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of but excluding when Q is Q-23, then the compound of formula (I) is not when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of wherein each W is individually selected from the group consisting of -CH- and -N-;
each G, is individually selected from the group consisting of -O-, -S-, and -N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
wherein each Z is individually selected from the group consisting of -O- and -N(R4)-;
when Q is Q-31, then the compound of formula (I) is not when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not when Q is Q-32, then is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
when Q is Q-32, Y is -CONH-, q is 0, m is 0, and of formula (I) is -CONH-, then A is not phenyl;
when Q is Q-32, q is 0, m is 0, and is -CONH-, then the compound of formula (I) is not when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone;
when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32 and Y is an ether linkage, then of formula (I) is not biphenyl or phenyloxazolyl;
when Q is Q-32 and Y is -CH=CH-, then of formula (I) is not phenylaminophenyl;
when Q is Q-32, then the compound of formula (I) is not b = 0-1 X1 = O, S
R56 = H, CF3, Cl, imidazolyl, amino, morpholino, phenylthio, cycloalkyl, benzyl, phenyl, phenoxy, thienyl, substituted alkyl, pyridylthio, pyrimidyl, benzylamino, N-benimidazolyl, pyridylcarbonylamino, ureido,N- thiourea, substituted alkanoylamino, phenylsulfonyl,substituted benzoyl, phenylalkenoyl, furanoyl, thienoyl, pyridinoyl, R57 = substituted phenyl, substituted biphenyl , or d = 0-2 R58 = substituted alkylaminocarbonyl, phenylaminocarbonyl R60 = H, alkyl R59 = H, Cl R61 = substituted phenyl, thienyl, Br R62 = H, alkyl, phenyl R63 = substituted phenyl when Q is Q-35 as shown wherein G is selected from the group consisting of -O-, -S-, -NR4-, and -CH2-, k is 0 or 1, and u is 1, 2, 3, or 4, then is selected from the group consisting of except that the compound of formula (I) is not
2. The compound of claim 1, wherein Ri is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls.
3. The compound of claim 2, where R, is selected from the group consisting of each R2 is individually selected from the group consisting of -H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys; and each R3 is individually selected from the group consisting of -H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R4NHSO2-, and -NHSO2R4.
4. The compound of claim 1, wherein A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and where each W, is individually selected from the group consisting of -CH- and -N-.
5. A method of modulating the activation state of p38 .alpha.-kinase comprising the step of contacting said kinase with a molecule having the formula wherein:
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene, N(R6), O;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (II) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls, and thereby causing modulation of said activation state.
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene, N(R6), O;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (II) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls, and thereby causing modulation of said activation state.
6. The method of claim 5, said contacting step occurring at the region of a switch control pocket of said kinase.
7. The method of claim 6, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (II) molecule.
8. The method of claim 6, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
9. The method of claim 8, said region being selected from the group consisting of the .alpha.-C helix, the .alpha.-D helix, the catalytic loop, the switch control ligand sequence, the C-lobe residues, the glycine rich loop residues, and combinations thereof.
10. The method of claim 9, said .alpha.-C helix including SEQ ID NO. 2.
11. The method of claim 9, said catalytic loop including SEQ ID NO. 3.
12. The method of claim 9, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
13. The method of claim 9, said C-lobe residues including SEQ ID NO. 6.
14. The method of claim 9, said glycine rich loop residues including SEQ ID
NO. 7.
NO. 7.
15. The method of claim 5, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
16. The method of claim 5, said activation state being selected from the group consisting of the upregulated and downregulated states.
17. The method of claim 5, said molecule being an antagonist of the on switch control pocket for said kinase.
18. The method of claim 5, said molecule being an agonist of the off switch control pocket for said kinase.
19. The method of claim 5, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
20. The method of claim 19, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
21. The method of claim 5, said molecule having the structure of the compound of claim 1.
22. An adduct comprising a molecule binding with a kinase, said molecule having the formula wherein:
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h , where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, -aminoalkyls,-alkoxyalkyls,-aryls,-aralkyls,-heterocyclyls,-and-heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene, N(R6), O;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (III) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
R1 is selected from the group consisting of aryls and heteroaryls;
each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h , where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of each R4 group is individually selected from the group consisting of -H, alkyls, -aminoalkyls,-alkoxyalkyls,-aryls,-aralkyls,-heterocyclyls,-and-heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros;
each R6 is individually selected from the group consisting of -H, alkyls, allyls, and .beta.-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene, N(R6), O;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (III) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
23. The adduct of claim 22, said molecule binding at the region of a switch control pocket of said kinase.
24. The adduct of claim- 23, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (III) molecule.
25. The adduct of claim 23, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
26. The adduct of claim 25, said region being selected from the group consisting of the .alpha.-C helix, the .alpha.-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
27. The adduct of claim 26, said .alpha.-C helix including SEQ ID NO. 2.
28. The adduct of claim 26, said catalytic loop including SEQ ID NO. 3.
29. The adduct of claim 26, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
30. The adduct of claim 26, said C-lobe residues selected from SEQ ID NO. 6.
31. The adduct of claim 26, said glycine rich loop residues taken from SEQ ID
NO.
7.
NO.
7.
32. The adduct of claim 22, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
33. The adduct of claim 22, said molecule having the structure of the compound of claim 1.
34. A compound having the formula A-T-(L )n-(NH)p-D-(E )q-(Y)t-Q
(IB) wherein:
Y is selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl,.
benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and where each W1 is individually selected form the group consisting of -CH- and -N-.
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
T is NR6, O, alkylene, -O(CH2)h-, or -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, or T is absent wherein A
is directly bonded to -(L)n(NH)p -D-(E)q -(Y)t -Q;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
v is 1,2, or 3;-x is 1 or 2;
Q is selected from the group consisting of formulae Q36 - Q59 , inclusive, each R4 group is individually selected from the group consisting of -H, alkyls , aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R6 is individually selected from the group consisting of -H, alkyls , allyls, and B-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, phenyl, naphthyl, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R9, group is individually selected from the group consisting of-F, and alkyls, wherein when two R9, groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R10 is alkyl or perfluoroalkyl;
G is alkylene, N(R6), 0;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (I) optionally includes one or more of R7, where R7, is a substituent individually selected from the group consisting of -H, alkyls , aryls , heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, perfluoroalkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, perfluoroalkyls; aminooxaloylamino; alkylaminooxaloylamino;
dialkylaminooxaloylamino; morpholinooxaloylamino; piperazinooxaloylamino;
alkoxycarbonylamino; heterocyclyloxycarbonylamino;
heterocyclylalkyloxycarbonylamino; heterocyclylcarbonylamino;
heterocyclylalkylcarbonylamino; aminoalkyloxycarbonylamino;
alkylaminoalkyloxycarbonylamino; or dialkylaminoalkyloxycarbonylamino, said Q36-Q59 groups being
(IB) wherein:
Y is selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h , one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl,.
benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and where each W1 is individually selected form the group consisting of -CH- and -N-.
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of -C(O)- and -S(O)2-;
T is NR6, O, alkylene, -O(CH2)h-, or -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, or T is absent wherein A
is directly bonded to -(L)n(NH)p -D-(E)q -(Y)t -Q;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
v is 1,2, or 3;-x is 1 or 2;
Q is selected from the group consisting of formulae Q36 - Q59 , inclusive, each R4 group is individually selected from the group consisting of -H, alkyls , aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R6 is individually selected from the group consisting of -H, alkyls , allyls, and B-trimethylsilylethyl;
each R8 is individually selected from the group consisting of alkyls, phenyl, naphthyl, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R9, group is individually selected from the group consisting of-F, and alkyls, wherein when two R9, groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R10 is alkyl or perfluoroalkyl;
G is alkylene, N(R6), 0;
each Z is individually selected from the group consisting of -O- and -N(R4)-;
and each ring of formula (I) optionally includes one or more of R7, where R7, is a substituent individually selected from the group consisting of -H, alkyls , aryls , heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, perfluoroalkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, perfluoroalkyls; aminooxaloylamino; alkylaminooxaloylamino;
dialkylaminooxaloylamino; morpholinooxaloylamino; piperazinooxaloylamino;
alkoxycarbonylamino; heterocyclyloxycarbonylamino;
heterocyclylalkyloxycarbonylamino; heterocyclylcarbonylamino;
heterocyclylalkylcarbonylamino; aminoalkyloxycarbonylamino;
alkylaminoalkyloxycarbonylamino; or dialkylaminoalkyloxycarbonylamino, said Q36-Q59 groups being
35. A method of modulating the activation state of p38 a-kinase comprising the step of contacting said kinase with a molecule having the formula of claim 34.
36. The method of claim 35, said contacting step occurring at the region of a switch control pocket of said kinase.
37. The method of claim 36, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (IB) molecule.
38. The method of claim 36, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
39. The method of claim 38, said region being selected from the group consisting of the .alpha.-C helix, the .alpha.-D helix, the catalytic loop, the switch control ligand sequence, the C-lobe residues, the glycine rich loop residues, and combinations thereof.
40. The method of claim 39, said .alpha.-C helix including SEQ ID NO. 2.
41. The method of claim 39, said catalytic loop including SEQ ID NO. 3.
42. The method of claim 39, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
43. The method of claim 39, said C-lobe residues including SEQ ID NO. 6.
44. The method of claim 39, said glycine rich loop residues including SEQ ID
NO. 7.
NO. 7.
45. The method of claim 35, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
46. The method of claim 35, said activation state being selected from the group consisting of the upregulated and downregulated states.
47. The method of claim 35, said molecule being an antagonist of the on switch control pocket for said kinase.
48. The method of claim 35, said molecule being an agonist of the off switch control pocket for said kinase.
49. The method of claim 35, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
50. The method of claim 49, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
51. An adduct comprising a molecule binding with a p 38-alpha kinase, said molecule having the formula of claim 34.
52. The adduct of claim 51, said molecule binding at the region of a switch control pocket of said kinase.
53. The adduct of claim 52, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said molecule.
54. The adduct of claim 52, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
55. The adduct of claim 52, said region being selected from the group consisting of the .alpha.-C helix, the .alpha.-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
56. The adduct of claim 55, said .alpha.-C helix including SEQ ID NO. 2.
57. The adduct of claim 55, said catalytic loop including SEQ ID NO. 3.
58. The adduct of claim 55, said switch control sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
59. The adduct of claim 55, said C-lobe residues selected from the group consisting of SEQ ID NO. 6.
60. The adduct of claim 55, said glycine rich loop residues including SEQ ID
NO. 7.
NO. 7.
61. The adduct of claim 51, said kinase selected from the group consisting of the consensus wild type P 38-alpha kinase sequence and disease polymorphs thereof.
62. A kinase-modulator adduct comprising a p38-alpha kinase having a switch control pocket with a non-naturally occurring molecule bound to the kinase at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein.
63. The adduct of claim 62, said molecule serving to induce a conformation change in said kinase.
64. The adduct of claim 62, said molecule serving to restrict a conformation change in said kinase.
65. The adduct of claim 62, said region of the switch control pocket being selected from the group consisting of the .alpha.-C helix, the .alpha.-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
66. The adduct of claim 65, said .alpha.-C helix including SEQ ID NO. 2.
67. The adduct of claim 65, said catalytic loop including SEQ ID NO. 3.
68. The adduct of claim 65, said switch control sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
69. The adduct of claim 65, said C-lobe residues selected from the group consisting of SEQ ID NO. 6.
70. The adduct of claim 65, said glycine rich loop residues including SEQ ID
NO. 7.
NO. 7.
71. The adduct of claim 62, said kinase also having a switch control ligand, said ligand interacting in vivo with said pocket to regulate the conformation and biological activity of said kinase such that the kinase will assume a first conformation and a first biological activity upon said ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of said ligand-pocket interaction.
72. The adduct of claim 62, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an agonist.
73. The adduct of claim 62, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an antagonist.
74. The adduct of claim 62, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an agonist.
75. The adduct of claim 62, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an antagonist.
76. A method of altering the biological activity of a p38 kinase comprising the steps of:
providing a p38-alpha kinase having a switch control pocket;
contacting said kinase with a non-naturally occurring molecule modulator; and causing said modulator to bind with said kinase at the region of said pocket in order to at least partially regulate the biological activity of the kinase by inducing or restricting the conformation of the kinase.
providing a p38-alpha kinase having a switch control pocket;
contacting said kinase with a non-naturally occurring molecule modulator; and causing said modulator to bind with said kinase at the region of said pocket in order to at least partially regulate the biological activity of the kinase by inducing or restricting the conformation of the kinase.
77. The method of claim 76, said molecule serving to induce a conformation change in said kinase.
78. The method of claim 76, said molecule serving to restrict a conformation change in said kinase.
79. The method of claim 76, said kinase also having a switch control ligand, said ligand interacting in vivo with said pocket to regulate the conformation and biological activity of said kinase such that the kinase will assume a first conformation and a first biological activity upon said ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of said ligand-pocket interaction.
80. The method of claim 76, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an agonist.
81. The method of claim 76, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an antagonist.
82. The method of claim 76, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an agonist.
83. The method of claim 76, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an antagonist.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/886,329 | 2004-07-06 | ||
| US10/886,329 US7202257B2 (en) | 2003-12-24 | 2004-07-06 | Anti-inflammatory medicaments |
| PCT/US2005/023100 WO2006014290A2 (en) | 2004-07-06 | 2005-06-30 | Anti-inflammatory medicaments |
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| Publication Number | Publication Date |
|---|---|
| CA2573124A1 true CA2573124A1 (en) | 2006-02-09 |
Family
ID=35787557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002573124A Abandoned CA2573124A1 (en) | 2004-07-06 | 2005-06-30 | Anti-inflammatory medicaments |
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| Country | Link |
|---|---|
| US (4) | US7202257B2 (en) |
| EP (1) | EP1773784A2 (en) |
| JP (1) | JP2008505900A (en) |
| AU (1) | AU2005270132A1 (en) |
| CA (1) | CA2573124A1 (en) |
| WO (1) | WO2006014290A2 (en) |
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- 2005-06-30 AU AU2005270132A patent/AU2005270132A1/en not_active Abandoned
- 2005-06-30 WO PCT/US2005/023100 patent/WO2006014290A2/en active Application Filing
- 2005-06-30 EP EP05768204A patent/EP1773784A2/en not_active Withdrawn
-
2006
- 2006-01-20 US US11/336,708 patent/US7531566B2/en not_active Expired - Fee Related
- 2006-06-09 US US11/450,840 patent/US7342037B2/en not_active Expired - Fee Related
- 2006-06-09 US US11/450,853 patent/US20080132506A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US7342037B2 (en) | 2008-03-11 |
| JP2008505900A (en) | 2008-02-28 |
| US7202257B2 (en) | 2007-04-10 |
| US20080064688A1 (en) | 2008-03-13 |
| WO2006014290A2 (en) | 2006-02-09 |
| WO2006014290A3 (en) | 2006-04-27 |
| AU2005270132A1 (en) | 2006-02-09 |
| US20080132506A1 (en) | 2008-06-05 |
| US20070037808A1 (en) | 2007-02-15 |
| US7531566B2 (en) | 2009-05-12 |
| US20050288286A1 (en) | 2005-12-29 |
| EP1773784A2 (en) | 2007-04-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |