CN100506792C - Substituted N-arylheterocycles, method for production and use thereof as medicaments - Google Patents

Substituted N-arylheterocycles, method for production and use thereof as medicaments Download PDF

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CN100506792C
CN100506792C CNB2004800098606A CN200480009860A CN100506792C CN 100506792 C CN100506792 C CN 100506792C CN B2004800098606 A CNB2004800098606 A CN B2004800098606A CN 200480009860 A CN200480009860 A CN 200480009860A CN 100506792 C CN100506792 C CN 100506792C
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alkyl
phenyl
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tetramethyleneimine
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CN1774418A (en
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L·施温克
S·施滕格林
M·戈塞尔
T·伯梅
G·黑斯勒
P·施塔尔
D·格雷策克
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Sanofi Aventis Deutschland GmbH
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention relates to N-arylheterocycles and the physiologically-acceptable salts and physiologically-functional derivatives thereof. Compounds of formula (I), where the groups have the given meanings, the N-oxides and the physiologically-acceptable salts and methods for production thereof are disclosed. The compounds are suitable as anorectics for example.

Description

The N-aryl-heterocyclic that replaces, they the preparation method and they are as the purposes of medicine
Salt that can tolerate on N-aryl-heterocyclic that the present invention relates to replace and their physiology and physiologic function derivative.
The compound with describing herein with pharmacological action has the N-aryl-heterocyclic of similar structures to be described in the prior art.For example, in WO 00/35454, addressed the Phenylpiperidine that replaces as the urea groups of pharmacological agent inflammatory and autoimmune disorders and-pyrrolidines.The Phenylpyrrolidine of the amido replacement that is used for the treatment of diabetes, obesity and disorders of lipid metabolism has then been described in WO02/042271.
The present invention aims to provide can be so that weight of mammal alleviates and is suitable for preventing and the compound of treatment of obesity and diabetes.
Therefore, the present invention relates to the salt that can tolerate on the N-oxide compound of formula I compound and they and the physiology
Figure C200480009860D00151
Wherein:
R1, R2 independently are H, (C each other 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, aryloxy-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8)-alkynyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO-aryloxy-(C 1-C 4)-alkyl, CO-(C 2-C 8)-alkenyl, CO-(C 2-C 8)-alkynyl, COCH=CH (R13), COCC (R14), CO-(C 1-C 4)-alkyl-S (O) p-(C 1-C 4)-alkyl, CO (C (R15) (R16)) qN (R17) (R18), CO (C (R19) (R20)) rCON (R21) (R22), CO (C (R23) (R24)) sO (R25); Or R1 forms 4-10 unit monocycle, dicyclo or a volution with the nitrogen-atoms that R2 is connected with them, except nitrogen-atoms, above-mentioned ring can comprise 0-4 other be selected from following heteroatoms: oxygen, nitrogen and sulphur, wherein the heterocycle ring system can further be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, COO (R29), N (R30) CO (C 1-C 6)-alkyl, N (R31) are (R32) or SO 2CH 3
O is 0,1,2,3,4,5,6;
P is 0,1,2
Q, r, s independently are 0,1,2,3,4 each other;
R13, R14 are 5-10 unit aromatics ring system independently of one another, and described ring system also comprises 0-2 and is selected from following heteroatoms: nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl, CO (R33);
Perhaps
R17 and R18, R21 and R22, R27 and R28, R31 and R32 are independently of one another, choose wantonly with the nitrogen-atoms that they connected and form 5-6 unit ring, and described ring also can comprise 0-1 heteroatoms that is selected from following groups: N-(C except nitrogen-atoms 1-C 6)-alkyl, oxygen and sulphur;
R33 is a 5-10 unit aromatics ring system, and described ring system can comprise 0-2 heteroatoms that further is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R12 is OH, O-(C 1-C 6)-alkyl, O (C 0-C 8)-alkylidene group-aryl, CN, S-(C 1-C 6)-alkyl, COO (R80), CON (R81) (R93), N (R82) (R83), 3-12 unit monocycle, dicyclo or volution, above-mentioned ring can comprise one or more and be selected from following heteroatoms: N, O and S, and the first ring of above-mentioned 3-12 also can comprise following substituting group, for example F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, O-(C 0-C 8)-alkylidene group-aryl, N (R34) (R35), COCH=CH (R36), (C (R37) (R38)) t(R39), CO (C (R37) (R38)) t(R39), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40), S (O) u(R41) and COOH;
T is 0,1,2,3,4,5,6;
U is 0,1,2;
R34, R35, R37, R38 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R34 forms a 5-6 unit ring with the optional nitrogen-atoms that is connected with them of R35, and described ring also can comprise 0-1 and be selected from following heteroatoms: N-(C except nitrogen-atoms 1-C 6)-alkyl, oxygen and sulphur, and can choose wantonly by 1-2 oxo group replacement;
R36, R39 are (C independently of one another 3-C 8)-cycloalkyl, 5-10 unit aromatics ring system, described ring system also can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R41 is (C 1-C 6)-alkyl, 5-10 unit aromatics ring system, described ring system also can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl;
R80, R81 and R93 are H, (C independently of one another 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R82, R83 are H, (C independently of one another 1-C 6)-alkyl;
Perhaps
The optional nitrogen-atoms that connects with them of R82 and R83 forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, and can choose wantonly by 1-2 oxo group replacement;
R3 is H, (C 1-C 6)-alkyl;
R4, R5 are H, (C independently of one another 1-C 6)-alkyl, OH, O-(C 1-C 6)-alkyl, O-CO (C 1-C 6)-alkyl, S-(C 1-C 6)-alkyl;
R6, R7, R8, R9 independently are H, (C each other 1-C 8)-alkyl;
Perhaps
R6 and R7, R8 and R9 are optional independently of one another to be oxo;
N, m are 0,1,2 independently of one another;
A, B, D, G are N, C (R42) independently of one another;
Perhaps
Group A and B or group D and G are C (R42), and form 5-or 6 yuan of carbocyclic rings or heterocyclic group together, thereby form the second cycle line system;
R42 is H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R43) (R44), SO 2-CH 3, COOH, COO-(C 1-C 6)-alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2(R50), CO (R51) ,-(CR84R85) x-O (R86);
R43, R44, R45, R46, R47, R49 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R43 and R44, R45 and R46 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring also can comprise 0-1 and be selected from N-(C except nitrogen-atoms 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R48, R50, R51 are H, (C independently of one another 1-C 8)-alkyl, aryl;
R84, R85 are H, (C independently of one another 1-C 8)-alkyl;
R86 is H, (C 1-C 6)-alkyl, aryl;
X is 1,2,3,4,5,6;
R10 is H, (C 1-C 8)-alkyl, (C 3-C 6)-alkenyl, (C 3-C 6)-alkynyl;
X be N (R52), O, key, C=C, C (R53) (R54), C (R55) (R56) O, CO, C ≡ C, formula-(CR87R88) y-group, wherein one or more-(CR87R88)-group can replace by Y, obtains a chemically feasible group;
Y is O, S, N (R89);
R52, R53, R54, R55, R56 are H, (C independently of one another 1-C 8)-alkyl;
R87, R88 are H, (C independently of one another 1-C 4)-alkyl, wherein R87 and the R88 in the y group can have identical or different implication in all cases;
Y is 2,3,4,5,6;
R89 is H, (C 1-C 8)-alkyl;
E is selected from N, O and heteroatomic 3-14 unit's divalence carbocyclic ring of S or heterocyclic ring structure for having 0-4, can choose the substituting group with the following groups of being selected from: H, F, Cl, Br, I, OH, CF wantonly 3, NO 2, CN, OCF 3, oxo, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R57) (R58), SO 2-CH 3, COOH, COO-(C 1-C 6)-alkyl, CON (R59) (R60), N (R61) CO (R62), N (R63) SO 2(R64), CO (R65), and can be monocycle or dicyclo;
R57, R58, R59, R60, R61, R63 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R57 and R58, R59 and R60 are independently of one another, and the optional nitrogen-atoms that connects with their forms a 5-6 unit ring, and described ring also can comprise 0-1 and other be selected from following heteroatoms except nitrogen-atoms: N-(C 1-C 6)-alkyl, oxygen and sulphur;
R62, R64, R65 are H, (C independently of one another 1-C 8)-alkyl, aryl;
K is key, O, OCH 2, CH 2O, S, SO, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C ≡ C, C=C, formula-(CR90R91) z-group, wherein one or more-(CR90R91)-group can replace by Z, obtains a chemically feasible group;
V is 1,2,3,4;
R66, R67, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
Z is O, S, N (R92), CO, SO, SO 2
R90, R91 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, hydroxyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, wherein R90 in the z group and R91 all can have identical or different implication in all cases;
Z is 2,3,4,5,6;
R92 is H, (C 1-C 8)-alkyl;
R11 is H, (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8The monocycle of)-alkynyl, a 3-10 unit, dicyclo or volution, above-mentioned ring can comprise 0-4 heteroatoms that is selected from oxygen, nitrogen and sulphur, and wherein ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, hydroxyl-(C 1-C 4)-alkyl, COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3, SCF 3
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl; Perhaps
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur; Perhaps
E, K and R11 form three-loop system together, and described ring can be saturated, fractional saturation or undersaturated independently of one another, and all can comprise 3-8 annular atoms.
Therefore, in another embodiment, the present invention relates to the salt that can tolerate on formula I compound and their physiology:
Figure C200480009860D00201
Wherein:
R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CH 2) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, aryloxy-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8)-alkynyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO-aryloxy-(C 1-C 4)-alkyl, CO-(C 2-C 8)-alkenyl, CO-(C 2-C 8)-alkynyl, COCH=CH (R13), COCC (R14), CO-(C 1-C 4)-alkyl-S (O) p-(C 1-C 4)-alkyl, CO (C (R15) (R16)) qN (R17) (R18), CO (C (R19) (R20)) rCON (R21) (R22), CO (C (R23) (R24)) sO (R25);
Perhaps R1 forms 4-10 unit monocycle, dicyclo or a volution with the nitrogen-atoms that R2 is connected with them, above-mentioned ring is except nitrogen-atoms, also can comprise 0-4 the other heteroatoms that is selected from oxygen, nitrogen and sulphur, described heteroaryl ring system also can be replaced by following groups: F, Cl, Br, CF3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, COO (R29), N (R30) CO (C 1-C 6)-alkyl, N (R31) are (R32) or SO 2CH 3
O is 0,1,2,3,4,5,6;
P is 0,1,2;
Q, r, s are 0,1,2,3,4 independently of one another;
R13, R14 are a 5-10 unit aromatics ring system independently of one another, and described ring system also can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl, CO (R33);
R17 and R18, R21 and R22, R27 and R28, R31 and R32 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 in addition 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R33 is a 5-10 unit aromatics ring system, can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur in addition, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R12 is OH, 3-12 unit's monocycle, dicyclo or volution, and described ring can comprise one or more heteroatoms that is selected from N, O and S, and 3-12 unit ring can comprise following substituting group in addition: for example F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, O-(C 0-C 8)-alkylidene group-aryl, N (R34) (R35), COCH=CH (R36), (C (R37) (R38)) t(R39), CO (C (R37) (R38)) t(R39), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40), S (O) u(R41) and COOH;
T is 0,1,2,3,4,5,6;
U is 0,1,2;
R34, R35, R37, R38 are H, (C independently of one another 1-C 8)-alkyl;
R34 forms a 5-6 unit ring with the optional nitrogen-atoms that is connected with them of R35, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 in addition 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, and above-mentioned ring can be chosen wantonly by 1-2 oxo group replacement;
R36, R39 are (C independently of one another 3-C 8)-cycloalkyl, 5-10 unit aromatics ring system, above-mentioned aromatics ring system can further comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups:
F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R41 is (C 1-C 6)-alkyl, 5-10 unit aromatics ring system, this aromatics ring system can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur in addition, and can be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R3 is H, (C 1-C 6)-alkyl;
R4, R5 are H, (C independently of one another 1-C 6)-alkyl, OH, O-(C 1-C 6)-alkyl, O-CO (C 1-C 6)-alkyl, S-(C 1-C 6)-alkyl;
R6, R7, R8, R9 are H, (C independently of one another 1-C 8)-alkyl;
R6 and R7, R8 and R9 are optional independently of one another to be oxo;
N, m are 0,1,2 independently of one another;
A, B, D, G are N, C (R42) independently of one another;
R42 is H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R43) (R44), SO 2-CH 3, COOH, COO-(C 1-C 6)-alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2(R50), CO (R51);
R43, R44, R45, R46, R47, R49 are H, (C independently of one another 1-C 8)-alkyl;
R43 and R44, R45 and R46 are independently of one another, and the optional nitrogen-atoms that connects with their forms a 5-6 unit ring, and described ring also can comprise 0-1 the other N-(C that is selected from except nitrogen-atoms 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R48, R50, R51 are H, (C independently of one another 1-C 8)-alkyl, aryl;
R10 is H, (C 1-C 8)-alkyl, (C 3-C 6)-alkenyl, (C 3-C 6)-alkynyl;
X be N (R52), O, key, C=C, C (R53) (R54), (R56) O of C (R55);
R52, R53, R54, R55, R56 are H, (C independently of one another 1-C 8)-alkyl;
E is selected from N, O and heteroatomic 3-8 unit's divalence carbocyclic ring of S or heterocycle structure for having 0-4, and above-mentioned ring can be chosen wantonly to have and be selected from following substituting group: H, F, CI, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 3-C 8)-cycloalkyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, O-(C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R57) (R58), SO 2-CH 3, COOH, COO-(C 1-C 6)-alkyl, CON (R59) (R60), N (R61) CO (R62), N (R63) SO 2(R64), CO (R65), and can be monocycle or dicyclo;
R57, R58, R59, R60, R61, R63 are H, (C independently of one another 1-C 8)-alkyl;
R57 and R58, R59 and R60 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R62, R64, R65 are H, (C independently of one another 1-C 8)-alkyl, aryl;
K is key, O, OCH 2, CH 2O, S, SO, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C ≡ C;
V is 1,2,3,4;
R66, R67, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
R11 is H, (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8)-alkynyl, 3-10 unit monocycle, dicyclo or volution, and this ring can comprise 0-4 heteroatoms that is selected from oxygen, nitrogen and sulphur, and described ring system can further be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring further is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur; Perhaps
E, K and R11 form three-loop system together, and wherein ring can be saturated, fractional saturation or unsaturated independently of one another, and all can comprise 3-8 annular atoms.
The present invention relates to the racemoid of formula I compound, mixture and pure enantiomer and their diastereomer and composition thereof of enantiomer enrichment.
Substituent R 1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, alkyl among R92 and the R93, alkenyl and alkynyl group can be straight chain, side chain or optional by halogenation.
Term " aryl " is meant particularly phenyl or naphthyl group.
" three ring systems " is meant the structure with 3 rings by linking together more than a key.The example of this class ring system be have 3 the ring condense ring system and with a ring system condensed volution.
When the nitrogen-atoms that is connected with them as R1 and R2 formed a ring, this ring can be replaced by one or more described substituting group.
Divalence carbocyclic ring or heterocyclic ring structure E comprise such structure, and this structure is connected with X with two adjacent group K by an identical atom.
Because its solvability in water is than its original shape or basic cpd height, so pharmacy acceptable salt more especially is suitable for medicinal application.These salt must have a pharmaceutically acceptable negatively charged ion or positively charged ion.The suitable pharmaceutically-acceptable acid addition of The compounds of this invention is an inorganic acid salt, for example hydrochloride, hydrobromate, phosphoric acid salt, metaphosphate, nitrate, sulfonate and vitriol, and organic acid salt for example acetate, benzene sulfonate, benzoate, Citrate trianion, esilate, fumarate, gluconate, oxyacetate, isethionate, lactic acid salt, Lactobionate, maleate, malate, mesylate, succinate, p-tosylate, tartrate and trifluoroacetate.The preferred especially hydrochloride that can be used as pharmaceutical use that uses.Suitable pharmaceutically acceptable basic salt is ammonium salt, an alkali metal salt (for example sodium and sylvite), alkaline earth salt (for example magnesium and calcium salt).
Have a pharmaceutically unacceptable anionic salt and also belong to scope of the present invention, they can be used as useful as intermediates and are used for preparation or purifying pharmacy acceptable salt and/or be used for non-therepic use, for example in external use.
Term " physiologic function derivative " is meant the derivative that can tolerate on any physiology of formula I compound of the present invention as used herein, for example a kind of ester, when giving Mammals such as man-hour, this ester can form (directly or indirectly) formula I compound or their active metabolite.
The physiologic function derivative comprises the prodrug of The compounds of this invention.This type of prodrug metabolism in vivo is a The compounds of this invention.These prodrugs itself can be for active or inactive.
The compounds of this invention also can exist with various forms, for example exists with amorphous and multiple crystal habit form.The polymorphic form of all The compounds of this invention all is contained in the present invention and constitutes others of the present invention.
All " formula (I) compounds " of mentioning are meant formula as noted before (I) compound hereinafter, and their salt, solvate and physiologic function derivative as described here.
If group or substituting group occur more than once in formula I compound, they all have implication independent of each other and can be identical or different.
The present invention relates to formula I compound at one more in the particularly preferred embodiment, wherein: R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CH2) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, COCH=CH (R13), COCC (R14), CO-(C 1-C 4)-alkyl-S (O) p-(C 1-C 4)-alkyl, CO (C (R15) (R16)) qN (R17) (R18), CO (C (R19) (R20)) rCON (R21) (R22), CO (C (R23) (R24)) sO (R25); Or the nitrogen-atoms that R1 and R2 connect with their forms 4-10 unit monocycle, dicyclo or a volution, above-mentioned ring is except nitrogen-atoms, also can comprise 0-2 the other heteroatoms that is selected from oxygen, nitrogen and sulphur, described heterocycle ring system can further be replaced by following groups: F, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, COO (R29), N (R30) CO (C 1-C 6)-alkyl, N (R31) are (R32) or SO 2CH 3, wherein R1 and R2 preferably are not H simultaneously, and R1 and R2 preferably are not the morpholino group with nitrogen-atoms;
O is 0,1,2,3,4;
P is 0,1,2;
Q, r, s are 0,1,2,3 independently of one another, preferred q, s be independently of one another 1,2,3 and r be 0,1,2,3;
R13, R14 are a 5-10 unit aromatics ring system independently of one another, and this ring also can comprise the heteroatoms that another one is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl, CO (R33);
R17 and R18, R21 and R22, R27 and R28, R31 and R32 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur,
R33 is a 5-10 unit aromatics ring system, and this ring also can comprise the heteroatoms that another one is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R12 is OH, 3-12 unit monocycle, dicyclo or volution, and described ring can comprise one or more heteroatoms that is selected from N, O and S, and the first ring of above-mentioned 3-12 also can comprise other substituting group, for example F, Cl, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, N (R34) (R35), COCH=CH (R36), (C (R37) (R38)) t(R39), CO (C (R37) (R38)) t(R39), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40) and S (O) u(R41), wherein in a preferred embodiment when 3-12 unit ring during for phenyl, substituting group is not O-(C 1-C 6)-alkyl;
T is 0,1,2,3,4;
U is 0,1,2;
R34, R35, R37, R38 are H, (C independently of one another 1-C 8)-alkyl;
R34 forms a 5-6 unit ring with the optional nitrogen-atoms that is connected with them of R35, and described ring further is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, and can choose wantonly by 1-2 oxo group replacement;
R36, R39 are (C independently of one another 3-C 8)-cycloalkyl, 5-10 unit aromatics ring system can comprise a heteroatoms that further is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R41 is (C1-C6)-alkyl, 5-10 unit aromatics ring system, can comprise 0-2 heteroatoms that further is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R3H, (C 1-C 6)-alkyl;
R4, R5 are H, (C independently of one another 1-C 6)-alkyl, OH, O-(C 1-C 6)-alkyl, O-CO (C 1-C 6)-alkyl;
R6, R7, R8, R9 are H, (C independently of one another 1-C 8)-alkyl;
R6 and R7, R8 and R9 are optional independently of one another to be oxo;
N, m are 0,1,2 independently of one another, preferred m be 0,1,2 and n be 1;
A, B, D, G are N, C (R42) independently of one another;
R42 is H, F, Cl, Br, CF 3, CN, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 3-C 8)-cycloalkyl, (C 0-C 2)-alkylidene group-aryl, O-(C 0-C 2)-alkylidene group-aryl, (N (R43) (R44), SO 2-CH 3, COO-(C 1-C 6)-alkyl, CON (R45) (R46), N (R47) CO (R48), N (R49) SO 2(R50), CO (R51)
R43, R44, R45, R46, R47, R49 are H, (C independently of one another 1-C 8)-alkyl;
R43 and R44, R45 and R46 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R48, R50, R51 are H, (C independently of one another 1-C 8)-alkyl, aryl;
R10 is H, (C 1-C 8)-alkyl;
X be N (R52), O, key, C=C, C (R53) (R54), (R56) O of C (R55);
R52, R53, R54, R55, R56 are H, (C independently of one another 1-C 8)-alkyl
E is 3-8 unit divalence carbocyclic ring or heterocyclic ring structure, and this ring has 0-4 heteroatoms that is selected from N, O and S, and can choose wantonly by following groups and replace: H, F, Cl, CF 3, NO 2, OH, CN, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, (N (R57) (R58), SO 2-CH 3, COO-(C 1-C 6)-alkyl, CON (R59) (R60), N (R61) CO (R62), N (R63) SO 2(R64), CO (R65), above-mentioned ring can be monocycle or dicyclo, preferred group E is not replaced by following groups at the ortho position of X tie point: (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl and N (R57) (R58), wherein R57 and R58 form 5-6 unit ring with nitrogen-atoms; More preferred E is a monocycle;
R57, R58, R59, R60, R61, R63 are H, (C independently of one another 1-C 8)-alkyl; R57 and R58, R59 and R60 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, wherein R59 and R60 preferably are not H simultaneously;
R62, R64, R65 are H, (C independently of one another 1-C 8)-alkyl, aryl;
K is key, O, CH 2O, N (R66), (C (R69) (R70)) v, C ≡ C, OCH 2, CON (R68), be preferably key, O, CH 2O, ((CR69) (R70)) v, C ≡ C, N (R66);
V is 1,2;
R66, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
R11 is H, (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, 3-10 unit monocycle, dicyclo or volution, this ring can comprise 0-4 heteroatoms that is selected from oxygen, nitrogen and sulphur, and described ring system can further be replaced by following groups: F, Cl, Br, CF 3, NO 2, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3, preferred R11 is not COO (R74);
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur.
More particularly preferred formula I compound is such compound, wherein
A, B, D, G are N or C (R42) independently of one another, and the quantity of total nitrogen-atoms is 0-2 in the ring, preferred 0 or 1.
More special preferred formula I compound is such compound, wherein
N be 1 and
M is 1 or 2.
Particularly preferred formula I compound is such compound, wherein
A, B, D, G are N or C (R42) independently of one another, and the total quantity of ring nitrogen is 0-2, preferred 0 or 1;
N is 1, and
M is 1 or 2.
In the another one embodiment preferred, the present invention relates to the salt that can tolerate on formula I compound or its N-oxide compound and its physiology, wherein:
R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO-aryloxy-(C 1-C 4)-alkyl, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R19) (R20)) rCON (R21) (R22), CO (C (R23) (R24)) sO (R25); Perhaps R1 forms 4-10 unit monocycle, dicyclo or a volution with the nitrogen-atoms that R2 is connected with them, and this ring also can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, COO (R29), N (R30) CO (C 1-C 6)-alkyl, N (R31) are (R32) or SO 2CH 3
Preferred above-mentioned R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) sO (R25); Perhaps R1 forms 4-10 unit's monocycle or dicyclo with the nitrogen-atoms that R2 is connected with them, and this ring also can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur except nitrogen-atoms, and described heterocycle ring system can further be replaced by following groups: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R26), hydroxyl, N (R31) are (R32) or SO 2CH 3More preferred R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO (C (R15) (R16)) qN (R17) (R18); Perhaps R1 forms 4-10 unit's monocycle or dicyclo with the nitrogen-atoms that R2 is connected with them, and this ring also can comprise 0-2 heteroatoms that is selected from oxygen and nitrogen in addition except nitrogen-atoms, and wherein the heterocycle ring system can further be replaced by following groups: F, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, oxo, CO (R26), hydroxyl, N (R31) are (R32);
O is 0,1,2,3,4,5,6; Preferred 0,1,2,3,4; Preferred more especially 0,1,2,3;
Q, r are 1,2,3 independently of one another; Preferred q is 1 or 2;
S is 0,1,2,3,4; Preferred 0,1,2,3; Preferred more especially 0,1,2;
R13, R14 are the phenyl ring that comprises the 0-1 nitrogen-atoms independently of one another;
R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl, CO (R33); Be preferably H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl; More special the H, (C of being preferably 1-C 6)-alkyl;
Perhaps
R17 and R18, R21 and R22, R27 and R28, R31 and R32 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring also can comprise 0-1 and be selected from N-(C except nitrogen-atoms 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur; Preferred ring is tetramethyleneimine, piperidines, N methyl piperazine, morpholine;
R33 is a 5-10 unit aromatics ring system, also can comprise a heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R12 is OH, O-(C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, CN, S-(C 1-C 6)-alkyl, COO (R80), CON (R81) (R82), 3-12 unit monocycle, dicyclo or volution, this ring can comprise one or more heteroatoms that is selected from N, O and S, and above-mentioned 3-12 unit ring also can comprise other substituting group, for example F, Cl, Br, OH, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, (C 0-C 8)-alkylidene group-aryl, N (R34) (R35), COCH=CH (R36), (C (R37) (R38)) t(R39), CO (C (R37) (R38)) t(R39), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40), S (O) u(R41);
Be preferably OH, O-(C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, CN, 3-10 unit's monocycle or dicyclo, this ring can comprise 1-3 heteroatoms that is selected from N, O and S, and above-mentioned 3-10 unit ring can comprise other substituting group for example F, Cl, Br, OH, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 1-C 6)-alkyl, (C 0-C 2)-alkylidene group-aryl, N (R34) (R35), CO (C 1-C 6)-alkyl;
More special OH, the O-(C of being preferably 1-C 6)-alkyl, 3-10 unit's monocycle or dicyclo ring, this ring can comprise 1-2 heteroatoms that is selected from N, O and S, and the first ring of above-mentioned 3-10 can comprise other substituting group for example F, OH, oxo, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl;
T is 0,1,2,3,4,5,6;
U is 0,1,2; Be preferably 0 or 2; Be preferably 2 more especially;
R34, R35, R37, R38 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R34 forms a 5-6 unit ring with the optional nitrogen-atoms that is connected with them of R35, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, and can choose wantonly by 1-2 oxo group replacement;
R36, R39 are (C independently of one another 3-C 8)-cycloalkyl, 5-10 unit aromatics ring system, above-mentioned aromatic ring can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R41 is (C1-C6)-alkyl, 5-10 unit aromatics ring system, and this aromatic ring can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl;
R80, R81 are H, (C independently of one another 1-C 8)-alkyl;
R3 is H, (C 1-C 6)-alkyl; Preferred H;
R4, R5 are H, (C independently of one another 1-C 6)-alkyl, OH, O-(C 1-C 6)-alkyl, O-CO-(C 1-C 6)-alkyl, S-(C 1-C 6)-alkyl; Preferred is H, (C independently of one another 1-C 6)-alkyl, OH, O-(C 1-C 6)-alkyl, O-CO-(C 1-C 6)-alkyl; More preferred is H, OH, O-(C independently of one another 1-C 6)-alkyl;
R6, R7, R8, R9 are H;
Perhaps
R6 and R7, R8 and R9 are optional independently of one another to be oxo;
Preferred R6, R7, R8, R9 are H;
N is 1
M is 1 or 2; Be preferably 1;
A, B, D, G are N, C (R42) independently of one another;
Perhaps group A and B or D and G are C (R42), and can form a neighbour-phenylene unit together, form one 1 then, the dibasic naphthalene of 4-system; Preferred B is N, C (R42); And A, D, G are C (R42); More preferred A, B, D, G are C (R42);
R42 is H, F, Cl, Br, CF 3, CN, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, (N (R43) (R44), SO 2-CH 3, CON (R45) (R46), N (R47) CO (R48), CO (R51) ,-(CR84R85) x-O (R86); Preferred H, F, Cl, Br, CF 3, CN, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, SO 2-CH 3, CON (R45) (R46), N (R47) CO (R48), CO (R51) ,-(CR84R85) x-O (R86); More preferred H, F, Cl, CF 3, CN, (C 1-C 6)-alkyl ,-(CR84R85) x-O (R86);
R43, R44, R45, R46, R47 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R43 and R44, R45 and R46 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur;
R48, R50, R51 are H, (C independently of one another 1-C 8)-alkyl, aryl; Preferred is H, (C independently of one another 1-C 8)-alkyl;
R84, R85 are H;
R86 is H, (C 1-C 6)-alkyl;
X is 0,1,2; Preferred 0,1; Preferred more especially 1;
R10 is H, (C 1-C 8)-alkyl;
X be N (R52), key, C=C, C (R53) (R54), C (R55) (R56) O, C ≡ C, CH 2-CH 2, YCH 2Preferred N (R52), key, C=C, C (R53) (R54), CH 2-CH 2A preferred more especially key, C=C, C (R53) (R54), CH 2-CH 2
Y is O, S, N (R89);
R89 is H, (C 1-C 8)-alkyl;
R52, R53, R54, R55, R56 are H, (C independently of one another 1-C 8)-alkyl;
E is 3-8 unit's divalence carbocyclic ring or heterocyclic ring structure, and this ring has 0-4 heteroatoms that is selected from N, O and S, can choose wantonly to have to be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, (N (R57) (R58), SO 2-CH 3, N (R61) CO (R62), N (R63) SO 2(R64), CO (R65), and can be monocycle or dicyclo; Preferred 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure, this ring has 0-3 heteroatoms that is selected from N, O and S, can choose wantonly to have to be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, (N (R57) (R58), SO 2-CH 3, N (R61) CO (R62), CO (R65), and can be monocycle or dicyclo; More preferred 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure, this ring has 0-2 heteroatoms that is selected from N, O and S, can choose wantonly to have to be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (N (R57) (R58), SO 2-CH 3, CO (R65).For example E is selected from following groups:
Figure C200480009860D00342
With
Figure C200480009860D00343
Above-mentioned group can be chosen wantonly to have and be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
Preferably
Figure C200480009860D00344
Figure C200480009860D00345
With
Figure C200480009860D00346
Above-mentioned group can be chosen wantonly has substituting group mentioned above;
R57, R58, R61, R63 are H, (C independently of one another 1-C 8)-alkyl;
R62, R64, R65 are H, (C independently of one another 1-C 8)-alkyl, aryl; Preferred is H, (C independently of one another 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C=C, C ≡ C, SCH 2, SO 2CH 2Preferred key, O, OCH 2, CH 2O, N (R66), CON (R68), (C (R69) (R70)) v, CO, C ≡ C, SCH 2More preferred key, O, OCH 2, CH 2O, CON (R68), (C (R69) (R70)) v, CO, C ≡ C;
V is 1,2,3,4; Preferred 1,2,3; Preferred more especially 1,2;
R66, R67, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
R11 is H, (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8)-alkynyl, 3-10 unit monocycle, dicyclo, three ring or volutions, this ring can comprise 0-4 heteroatoms that is selected from oxygen, nitrogen and sulphur, and described ring system can further be replaced by following groups: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3Preferred (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, 3-10 unit monocycle, dicyclo, three ring or volutions, this ring can comprise 0-3 heteroatoms that is selected from oxygen, nitrogen and sulphur, and described ring system can further be replaced by following groups: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3More preferred (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, 3-10 unit's monocycle or dicyclo, described ring can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring system can further be replaced by following groups: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, oxo, CO (R71), CON (R72) (R73), N (R75) CO (C 1-C 6)-alkyl, or SO 2CH 3
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur.
In an other embodiment preferred, the A among the formula I, B, G and D be CH or:
If E is 1, the 4-phenylene, the definition of then preferred A, B, G and D further is cited in the following Table I:
Table I:
A B G D
N CH CH CH
CH N CH CH
C-Cl N CH CH
C-F CH C-F CH
CH CH C-F CH
CH C-F CH CH
CH CH CH CF
CH C-Br CH CH
CH CH C-Br CH
CH C-Cl CH CH
CH CH C-Cl CH
CH CH C-CN CH
CH CH CH C-CN
CH CH C-CH 3 CH
CH CH CH C-CH 3
CH CH C-CF 3 CH
CH CH CH C-CF 3
CH CH CH CH 2OH
CH C-F CH C-F
CH C-F C-F CH
CH CH C-F C-F
CH CH C-F C-Cl
CH CH C-Cl C-CN
CH C-CH 3 C-Cl CH
CH N CH C-CH 3
CH C-CH 3 CH N
CH N C-CH 3CH
CH CH
Figure C200480009860D00361
If E is
Figure C200480009860D00362
The definition of then preferred A, B, G and D further is cited in the following Table II:
Table II:
A B G D
CH C-CH 3 CH CH
CH C-F CH CH
CH CH C-CH 3 CH
CH CH C-F CH
CH N CH CH
CH CH CH N
C-F CH C-F CH
If E is
Figure C200480009860D00371
The definition of then preferred A, B, G and D further is cited among the following Table I H:
Table 1II:
A B G D
CH CH C-F CH
CH N CH CH
CH CH CH N
The combination of further preferred E and A, B, G and D as shown in Table IV.
Table IV:
E A B G D
Figure C200480009860D00372
CH C-F CH CH
Figure C200480009860D00373
CH CH C-F CH
Figure C200480009860D00374
CH C-F CH CH
Figure C200480009860D00375
CH C-F CH CH
Figure C200480009860D00376
CH CF CH CH
Figure C200480009860D00377
CH CF CH CH
Figure C200480009860D00378
CH C-F CH CH
Figure C200480009860D00379
CH C-F CH CH
Figure C200480009860D003710
CH C-F CH CH
Figure C200480009860D003711
CH C-F CH CH
Figure C200480009860D003712
CH C-F CH CH
CH C-F CH CH
Figure C200480009860D00381
CH C-F CH CH
CH C-F CH CH
CH C-F CH CH
Figure C200480009860D00384
CH C-F CH CH
At one more in the particularly preferred embodiment, radicals R 11, K, X and E among the formula I are defined as follows described:
R11 is preferably selected from following groups:
N-propyl group, n-butyl, different-butyl, different-amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexamethylene-(1)-thiazolinyl, phenyl, p-fluoro phenyl, p-chlorophenyl, p-bromophenyl, p-tolyl, p-p-methoxy-phenyl, p-three fluoro aminomethyl phenyls, p-methylthio group phenyl, o-fluoro phenyl, o-chlorophenyl, o-cyano-phenyl, m-fluoro phenyl, 2,4-phenyl-difluoride base, 3-fluoro-4-aminomethyl phenyl, 2-nitro-4-methyl phenyl, 2-amino-4-aminomethyl phenyl,
Figure C200480009860D00385
Figure C200480009860D00386
And
Figure C200480009860D00387
K is preferably selected from following groups:
-O-, key, C ≡ C, CH 2, CH 2O, CONH, OCH 2, CO, SCH 2And (CH 2) 2O.
X is preferably selected from following groups: key, NH and CH 2
E is preferably selected from following groups:
Figure C200480009860D00388
Figure C200480009860D00391
And
Figure C200480009860D00393
The combination of preferred R11, K, X and E is as follows:
If K and X are key, then particularly preferred E and R11 are defined as follows:
If ■ E is 1, the 4-phenylene, then R11 is selected from following groups:
Cyclohexyl, p-tolyl, p-fluoro phenyl, o-fluoro phenyl, p-p-methoxy-phenyl, p-chlorophenyl, o-chlorophenyl, 2,4-phenyl-difluoride base, 3-fluoro-4-aminomethyl phenyl, o-cyano-phenyl,
Figure C200480009860D00394
With
Figure C200480009860D00395
If ■ E is
Figure C200480009860D00396
Then R11 is selected from following groups:
P-chlorophenyl, p-tolyl, p-fluoro phenyl, p-p-methoxy-phenyl, p-three fluoro aminomethyl phenyls, o-fluoro phenyl, phenyl reach
Figure C200480009860D00397
When K and X are key, the other combination of E and R11 as shown in Table V:
Table V:
R11 E
P-chlorophenyl 1, the 4-cyclohexylidene
2-nitro-4-methyl phenyl
Figure C200480009860D00398
The p-chlorophenyl
P-bromo phenyl
P-fluoro phenyl
Figure C200480009860D00401
The p-chlorophenyl
Figure C200480009860D00402
Figure C200480009860D00404
The p-tolyl
Figure C200480009860D00405
The n-butyl
Figure C200480009860D00406
The p-chlorophenyl
Figure C200480009860D00408
Figure C200480009860D00409
Figure C200480009860D004010
Figure C200480009860D004011
P-methylthio group phenyl
Figure C200480009860D004012
2-amino-4-aminomethyl phenyl
If K is key, NH or CH for-O-and X 2, then preferred especially E and R11 are defined as follows:
If ■ E is 1, the 4-phenylene, then R11 is selected from following groups:
Phenyl, cyclopentyl, n-butyl, different-butyl, different-amyl group, 2,4-phenyl-difluoride base and p-fluoro phenyl.
Is key, NH or CH at K for-O-and X 2The time, the other combination of E and R11 as shown in Table VI:
Table VI:
R11 E
Phenyl
Figure C200480009860D004014
Cyclopentyl
Figure C200480009860D004015
Phenyl
Figure C200480009860D00411
The n-butyl
Figure C200480009860D00412
The n-butyl
Figure C200480009860D00413
If K is C ≡ C and X is a key, then particularly preferred E and R11 are defined as follows:
If E is Then R11 is selected from following groups:
Phenyl, p-fluoro phenyl and p-chlorophenyl.
If K is CH 2And X is a key, and then particularly preferred E and R11 are defined as follows shown in the Table VII:
Table VII:
R11 E
Phenyl 1, the 4-phenylene
Figure C200480009860D00415
1, the 4-phenylene
The p-chlorophenyl
Figure C200480009860D00416
If K is CH 2O and X are a key, and then the particularly preferred of E and R11 is defined as follows:
If ■ E is 1, the 4-phenylene, then R11 is selected from following groups:
Phenyl, cyclopropyl and cyclohexyl.
If K is CONH and X is a key, then the particularly preferred of E and R11 is defined as follows shown in the Table VIII:
Table VIII:
R11 E
Cyclopentyl 1, the 4-phenylene
Hexamethylene-(1)-thiazolinyl 1, the 4-phenylene
Cyclopentyl
If K is OCH 2And X is a key, and then the particularly preferred of E and R11 is defined as follows shown in the Table I X:
Table I X:
R11 E
The o-chlorophenyl
P-tolyl 1, the 4-phenylene
N-propyl group 1, the 4-phenylene
Cyclobutyl 1, the 4-phenylene
Cited R11, K and the combination of E are further particularly preferred combinations except combination mentioned above in the following Table X, and X is more special simultaneously is preferably a key:
Table X:
R11 K E
O-fluoro phenyl CO
Figure C200480009860D00423
Phenyl SCH 21, the 4-phenylene
Cyclopropyl (CH 2) 2O
Figure C200480009860D00424
The more particularly preferred embodiment of formula I compound is the salt that can tolerate on formula Ia compound or its N-oxide compound and their physiology.
Wherein radicals R 1, R2, R10, R11, R42, and radicals X, E, K have the described definition of preamble, and R42 ' defines as R42, and R42 and R42 ' in its Chinese style Ia compound can be identical or different.
In embodiment preferred of the present invention, radicals R 1, R2, R10, R11, R42, R42 ' and radicals X, E, K are as hereinafter defining:
R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl; Perhaps R1 forms 4-10 unit monocycle, dicyclo or a volution with the nitrogen-atoms that R2 is connected with them, described ring also can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur in addition except nitrogen-atoms, described heterocycle ring system can further be replaced by following groups: F, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, N (R31) (R32) or SO 2CH 3R wherein 1And R 2Be not CO (R26), preferred H, (C 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, or R1 forms 4-10 unit's monocycle or dicyclo with nitrogen-atoms that R2 is connected with them, described ring also can comprise 0-2 heteroatoms that is selected from oxygen and nitrogen in addition except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, oxo, CO (R26), hydroxyl, N (R31) are (R32);
O is 0,1,2,3,4, preferred 0,1,2,3;
Q is 1,2,3, preferred 1 or 2;
S is 0,1,2;
R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
Perhaps
R17 and R18, R27 and R28, R31 and R32 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, preferred ring is tetramethyleneimine, piperidines, N methyl piperazine, morpholine ring;
R12 is OH, O-(C 1-C 6)-alkyl, O-(C 0-C 2)-alkylidene group-aryl, CN, S-(C 1-C 6)-alkyl, 3-12 unit monocycle, dicyclo or volution, this ring can comprise 1-3 heteroatoms that is selected from N, O and S, and above-mentioned 3-12 unit ring can comprise other substituting group for example F, OH, CF 3, CN, oxo, (C 1-C 6)-alkyl, (C 0-C 2)-alkylidene group-aryl, N (R34) (R35), COO (R40), CO (C 1-C 6)-alkyl, preferred OH, O-(C 1-C 6)-alkyl, comprise heteroatomic 3-10 unit's monocycle or dicyclo that 1-2 is selected from N, O and S, and this 3-10 unit ring can comprise other substituting group for example F, OH, oxo, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl;
R34, R35 are H, (C independently of one another 1-C 4)-alkyl;
R40 is H, (C 1-C 6)-alkyl, (C 0-C 2)-alkylidene group-aryl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl;
R42, R42 ' are H, F, Cl, Br, CF independently of one another 3, CN, (C 1-C 6)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
X be N (R52), key, C=C, C (R53) (R54), CH 2CH 2
R52, R53, R54 are H, (C independently of one another 1-C 8)-alkyl;
E has 0-3 heteroatomic 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure that is selected from N, O and S, and above-mentioned ring can be chosen wantonly to have and be selected from following substituting group: H, F, Cl, Br, CF 3, OH, CN, OCF 3, NO 2, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, SO 2-CH 3, CO (R65); Preferably have 0-2 heteroatomic 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure that is selected from N, O and S, above-mentioned ring can be chosen wantonly to have and be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65).
For example E is selected from following groups:
Figure C200480009860D00451
Figure C200480009860D00452
With
Above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
Preferably
Figure C200480009860D00454
With
Figure C200480009860D00456
Above-mentioned group can be chosen wantonly has substituting group mentioned above;
R65 is H, (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C ≡ C, SCH 2, SO 2CH 2Preferred key, O, OCH 2, CH 2O, CON (R68), (C (R69) (R70)) v, more preferred CH 2, CO, C ≡ C;
V is 1,2,3, preferred 1,2;
R66, R67, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
R11 is (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, comprise heteroatomic 3-10 unit monocycle, dicyclo, three ring or volutions that 0-4 is selected from oxygen, nitrogen and sulphur, described ring system can further be replaced by following groups: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, oxo, CO (R71), hydroxyl, N (R75) CO (C 1-C 6)-alkyl, or SO 2CH 3Preferred (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, comprise heteroatomic 3-10 unit's monocycle or dicyclo that 0-2 is selected from oxygen, nitrogen and sulphur,, described ring system can further be replaced by following groups: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, oxo, CO (R71), CON (R72) (R73), N (R75) CO (C 1-C 6)-alkyl, or SO 2CH 3
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur.
In a preferred embodiment, the present invention relates to formula Ia compound,
Wherein
X is CH 2CH 2, N (R52), CH 2, OCH 2, SCH 2, CH=CH, preferred CH 2CH 2, CH=CH;
E is
Figure C200480009860D00461
Preferably
K be key, O or C (R69) (R70);
Other symbol R1, R2, R10, R11, R42, R42 ', R52, R69 and R70 have the definition in the formula Ia compound above.
In an other embodiment preferred, the present invention relates to formula Ia compound,
Wherein
X is N (R52), and preferred NH or C (R53) are (R54);
E is
Figure C200480009860D00471
Figure C200480009860D00472
Preferably
Figure C200480009860D00473
Or
Figure C200480009860D00474
K be key, O or C (R69) (R70), preferred 0; Preferred O
Other symbol R1, R2, R10, R11, R42, R42 ', R52, R53, R54, R69 and R70 have the definition in the formula Ia compound above.
In a further particularly preferred embodiment, formula I compound is the salt that can tolerate on formula Ib compound or its N-oxide compound and their physiology
Figure C200480009860D00475
Wherein radicals R 1, R2, R10 and R11 and group E and D have definition mentioned above.
In a preferred embodiment, radicals R 1, R2, R10 and R11 and group E and D are as hereinafter defining:
R1, R2 are H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO-aryloxy-(C 1-C 4)-alkyl, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R19) (R20)) rCON (R21) (R22), CO (C (R23) (R24)) sO (R25); Perhaps R1 forms 4-10 unit monocycle, dicyclo or a volution with the nitrogen-atoms that R2 is connected with them, this ring also can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur in addition except nitrogen-atoms, described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R26), CON (R27) (R28), hydroxyl, COO (R29), N (R30) CO (C 1-C 6)-alkyl, N (R31) are (R32) or SO 2CH 3, wherein R1 and R2 are not CO (R26); Preferred is H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) sO (R25); Perhaps R1 forms 4-10 unit's monocycle or dicyclo with the nitrogen-atoms that R2 is connected with them, and this ring also can comprise 0-2 heteroatoms that is selected from oxygen, nitrogen and sulphur in addition except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, hydroxyl, N (R31) are (R32) or SO 2CH 3, wherein R1 and R2 are not CO-(C 1-C 8)-alkyl;
More preferred is H, (C independently of one another 1-C 8)-alkyl ,-(CR78R79) o-R12, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl ,-CO-(CH 2) o-R12, CO (C (R15) (R16)) qN (R17) (R18); Perhaps R1 forms 4-10 unit's monocycle or dicyclo with the nitrogen-atoms that R2 is connected with them, and this ring also can comprise 0-2 heteroatoms that is selected from oxygen and nitrogen in addition except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, oxo, CO (C 1-C 8)-alkyl, hydroxyl, N (R31) (R32), described R1 and R2 are not CO (C 1-C 8)-alkyl;
O is 0,1,2,3,4,5,6; Preferred 0,1,2,3,4; Preferred more especially 0,1,2,3;
Q, r are 1,2,3 independently of one another; Preferred q is 1 or 2;
S is 0,1,2,3,4; Preferred 0,1,2,3; Preferred more especially 0,1,2;
R13, R14 are independently of one another for comprising the phenyl ring of 0-1 nitrogen-atoms;
R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is H, (C 1-CX)-alkyl, CO (C 1-C 6)-alkyl, CO (R33); Preferred H, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl; More preferred H, (C 1-C 6)-alkyl;
Perhaps
R17 and R18, R21 and R22, R27 and R28, R31 and R32 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur; Preferred ring is tetramethyleneimine, piperidines, N methyl piperazine, morpholine;
R33 is a 5-10 unit aromatics ring system, can comprise one and be selected from the heteroatoms of nitrogen, oxygen and sulphur in addition and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R12 is OH, O-(C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, CN, S-(C 1-C 6)-alkyl, COO (R80), CON (R81) (R82), 3-12 unit monocycle, dicyclo or volution, this ring can comprise one or more heteroatoms that is selected from N, O and S, and above-mentioned 3-12 unit ring can comprise other substituting group for example F, Cl, Br, OH, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, (C 0-C 8)-alkylidene group-aryl, N (R34) (R35), COCH=CH (R36), (C (R37) (R38)) t(R39), CO (C (R37) (R38)) t(R39), CO (C1-C6)-alkyl, COCOO (C1-C6)-alkyl, COO (R40), S (O) u(R41);
Preferred OH, O-(C 1-C 6)-alkyl, O-(C 0-C 8)-alkylidene group-aryl, CN, 3-10 unit's monocycle or dicyclo, this ring can comprise 1-3 heteroatoms that is selected from N, O and S, and this 3-10 unit ring can comprise other substituting group for example F, Cl, Br, OH, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 1-C 6)-alkyl, (C 0-C 2)-alkylidene group-aryl, N (R34) (R35), CO (C 1-C 6)-alkyl;
More preferred OH, O-(C 1-C 6)-alkyl, 3-10 unit's monocycle or dicyclo, this ring can comprise 1-2 heteroatoms that is selected from N, O and S, and this 3-10 unit ring can comprise other substituting group for example F, OH, oxo, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl;
T is 0,1,2,3,4,5,6;
U is 0,1,2; Preferred 0 or 2; Preferred more especially 2;
R34, R35, R37, R38 are H, (C independently of one another 1-C 8)-alkyl;
Perhaps
R34 forms a 5-6 unit ring with the optional nitrogen-atoms that is connected with them of R35, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur, and can choose wantonly by 1-2 oxo group replacement;
R36, R39 are (C independently of one another 3-C 8)-cycloalkyl, 5-10 unit aromatics ring system, above-mentioned aromatics ring system can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur in addition, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 8)-alkylidene group-aryl;
R41 is (C1-C6)-alkyl, 5-10 unit aromatics ring system, and this ring system can comprise 0-2 heteroatoms that is selected from nitrogen, oxygen and sulphur in addition, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl;
R80, R81 are H, (C independently of one another 1-C 8)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
E is 3-8 unit divalence carbocyclic ring or heterocyclic ring structure, and this ring system has 0-4 heteroatoms that is selected from N, O and S, and can choose wantonly to have and be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, O-(C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, O-(C 3-C 8)-cycloalkyl, (C 3-C 8)-cycloalkenyl group, (C 2-C 6)-alkynyl, (C 0-C 8)-alkylidene group-aryl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R57) (R58), SO 2-CH 3, N (R61) CO (R62), N (R63) SO 2(R64), CO (R65), and can be monocycle or dicyclo; Preferred 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure, this ring has 0-3 heteroatoms that is selected from N, O and S, can choose wantonly to have to be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O-(C 1-C 6)-alkyl, S-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, O-(C 0-C 8)-alkylidene group-aryl, S-aryl, N (R57) (R58), SO 2-CH 3, N (R61) CO (R62), CO (R65), and can be monocycle or dicyclo; More preferred 5-7 unit's divalence carbocyclic ring or heterocyclic ring structure, this ring has 0-2 heteroatoms that is selected from N, O and S, can choose wantonly to have to be selected from following substituting group: H, F, Cl, Br, OH, CF 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65).
For example E is selected from following groups:
Figure C200480009860D00511
Figure C200480009860D00512
With
Figure C200480009860D00513
Above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
Preferably
Figure C200480009860D00514
Figure C200480009860D00515
With
Figure C200480009860D00516
Above-mentioned group can be chosen wantonly has foregoing substituting group;
R57, R58, R61, R63 are H, (C independently of one another 1-C 8)-alkyl;
R62, R64, R65 are H, (C independently of one another 1-C 8)-alkyl, aryl; Preferred is H, (C independently of one another 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C=C, C ≡ C, SCH 2, SO 2CH 2Preferred key, O, OCH 2, CH 2O, N (R66), CON (R68), (C (R69) (R70)) v, CO, C ≡ C, SCH 2More preferred key, O, oCH 2, CH 2O, CON (R68), (C (R69) (R70)) v, CO, C ≡ C;
V is 1,2,3,4; Preferred 1,2,3; Preferred more especially 1,2;
R66, R67, R68, R69, R70 are H, (C independently of one another 1-C 8)-alkyl;
R11 is H, (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, (C 3-C 8)-alkynyl comprises 0-4 the first monocycle of heteroatomic 3-10, dicyclo, three ring or the volutions that are selected from oxygen, nitrogen and sulphur, and described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, (C 0-C 8)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3SCF 3
Preferred (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, comprise heteroatomic 3-10 unit monocycle, dicyclo, three ring or volutions that 0-3 is selected from oxygen, nitrogen and sulphur, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, (C 0-C 2)-alkylidene group-aryl, oxo, CO (R71), CON (R72) (R73), hydroxyl, N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3
More preferred (C 1-C 8)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, comprise heteroatomic 3-10 unit's monocycle or dicyclo that 0-2 is selected from oxygen, nitrogen and sulphur, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, oxo, CO (R71), CON (R72) (R73), N (R75) CO (C 1-C 6)-alkyl or SO 2CH 3
R71, R72, R73, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl; Perhaps
R72 and R73, R76 and R77 are independently of one another, and the optional nitrogen-atoms that connects with them forms a 5-6 unit ring, and described ring is selected from N-(C in addition except nitrogen-atoms also can comprise 0-1 1-C 6The heteroatoms of)-alkyl, oxygen and sulphur.
In a preferred embodiment, the present invention relates to formula Ib compound
Wherein
X is a key
E is
Figure C200480009860D00531
Figure C200480009860D00532
Or
Figure C200480009860D00533
Wherein above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
Preferred E is
Figure C200480009860D00534
Or
Figure C200480009860D00535
Wherein said group can have substituting group mentioned above;
K is a key; And
Other radicals R 1, R2, R10 and R11 and group D have the above definition of the group of formula Ib compound.
R11 in the formula Ib compound mentioned above is preferably monocycle or the dicyclo ring system that 5-10 unit replaces especially, this ring can have 0-3 heteroatoms, particularly N, O and/or S, the phenyl, the cyclohexyl that more especially preferably have 0-1 N atom, or the 8-10 unit second cycle line with 1-2 heteroatoms, particularly N, O and/or S is united.
In the another one embodiment preferred, the present invention relates to formula Ib compound
Wherein
X is a key;
E is
Figure C200480009860D00541
Figure C200480009860D00542
Or
Above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2CH 3And CO (R65);
Preferably
Figure C200480009860D00544
Or
Figure C200480009860D00545
Wherein above-mentioned group can have substituting group mentioned above;
K is CH 2, CH 2CH 2, O, CH 2O, OCH 2, CON (R68), N (R67) CO, S, SO 2, SCH 2, SO 2, SO 2CH 2, CO or triple bond;
Preferred CH 2, O, CH 2O, OCH 2, CON (R68), SCH 2, CO or triple bond; And
Other radicals R 1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 and R68 and group D have the above definition of the group of formula Ib compound.
The amount that can reach formula (I) compound of required biology effect depends on many factors, purposes, administering mode and the patient's of for example selected specific compound, expectation clinical setting.Per daily dose is generally per kg body weight per day 0.3mg-100mg (being generally 3mg-50mg), for example 3-10mg/kg/day.The dosage of intravenously administrable can be for example 0.3mg-1.0mg/kg, and can be suitably with the form of infusion with the every kg p m administration of 10ng-100ng.The suitable infusion solution that is used for above-mentioned purpose can comprise, and for example every milliliter of 0.1ng-10mg is generally every milliliter of 1ng-10mg.Single dose can comprise for example 1mg-10g activeconstituents.Therefore, the injection ampoule can comprise, and 1mg-100mg for example is used for the single-dose preparations of oral administration, and for example tablet or capsule can comprise for example 1.0-1000mg, are generally 10-600mg.When being pharmacy acceptable salt, weight data mentioned above is based on the weight of the free cpds of salt derivative.For preventing and treat symptom mentioned above, formula (I) compound can use with compound itself, but preferably it uses with the medicinal compositions form that comprises acceptable carrier.Certainly, this carrier must be compatible with other composition of composition and healthy harmless to the patient.Carrier can for solid or liquid or the two all can, but preferred and compound is made single-dose preparations, tablet for example, said preparation can comprise the activeconstituents of 0.05%-95% weight.Also can comprise other active medicinal matter, comprise other formula (I) compound.Medicinal compositions of the present invention can mainly comprise acceptable carrier and/or mixed with excipients on mentioned component and the pharmacology according to known pharmaceutical methods production.
That pharmaceutical composition of the present invention is suitable for is oral, rectum, part, per os (for example hypogloeeis) and parenteral (for example subcutaneous, muscle, intracutaneous or intravenously) administration, although optimal form of medication depends on the characteristic of employed formula (I) compound under the character of the following disease for the treatment of of each particular case and seriousness and each situation.Coated preparation and coated slow release preparation also are within the scope of the invention.Preferred acidproof and resistant to gastric juice preparation.The dressing of suitable resistant to gastric juice comprises the anionic polymer of cellulose acetate-phthalate, phthalic acid acetate polyvinyl ester, Hydroxypropyl Methylcellulose Phathalate and methacrylic acid and methyl methacrylate.
The suitable medicinal compound that is used for oral administration can exist with its form of divided dose, for example capsule, cachet, can suck tablet or tablet, above-mentioned each divided dose comprises a certain amount of formula (I) compound; As powder or granule; As solution in the aqueous solution or non-aqueous solution or suspension; Or as oil-in-water-type or water-in-oil emulsion.As mentioned before, these compositions can comprise making activeconstituents and carrier (can comprise one or more other compositions) blended step by arbitrary suitable pharmaceutical methods preparation.Composition if desired can be with the product plastotype generally by the solid carrier uniform mixing of activeconstituents and a kind of liquid and/or uniform subdivision is produced.Therefore, for example tablet can be by preparing the powder of compound or particle compacting or plastotype, and can suitably add one or more supplementary components.Compressed tablets can compressing tablet prepares in suitable machine by the compound (for example powder or particle) with free-flowing, perhaps can be suitably with compressing tablet after described compound and tackiness agent, glidant, inert diluent and/or the one or more surfactivity/dispersant.The pressing mold tablet can pass through compound plastotype production in suitable machine, and compound can exist with powder type maybe can be moistening with a kind of inert liquid diluent.
The pharmaceutical composition that is suitable for per os (hypogloeeis) administration comprises can inhale tablet and lozenge, can suck tablet and comprise formula (I) compound and seasonings, is generally sucrose and gum arabic or tragacanth; Lozenge is in the inert media formulation of inclusion compound in gelatin and glycerine or sucrose and the gum arabic for example.
The pharmaceutical composition that is suitable for administered parenterally preferably comprises the aseptic aqueous solution preparation of formula (I) compound, preferably oozes with blood of treatment acceptor etc.Although that administration also can be adopted is subcutaneous, muscle or intradermal injection, the preferred intravenous administration of these preparations.These preparations are preferably by mixing compound with water, and make the solution that obtains aseptic and itself and blood etc. are oozed produce.Injectable of the present invention comprises the active compound of 0.1-5% weight usually with composition.
The pharmaceutical composition that is suitable for rectal administration preferably exists with the suppository form of single dose.Described suppository can by with formula (I) compound and one or more conventional solid carriers for example theobroma oil mix, and prepare the mixture that obtains is moulding.
The pharmaceutical composition that is suitable for the local skin administration preferably exists with the form of paste, creme, lotion, ointment, sprays, aerosol or oil.Spendable carrier is the combination of paraffin, lanolin, polyoxyethylene glycol, alcohol and two or more mentioned components.The concentration of activeconstituents is generally the 0.1-15% of composition weight, for example 0.5-2%.
Also can pass through transdermal administration.The pharmaceutical composition that is suitable for the transdermal use can exist with the form of single card plaster, and this form is suitable for closely contacting for a long time with patient's epidermis.This class plaster is adapted at containing in the aqueous solution activeconstituents, and above-mentioned solution is buffered, and perhaps activeconstituents dissolves in and/or is scattered in tackiness agent or is scattered in the polymkeric substance.Suitable activity component concentration is about 1%-35%, preferably about 3%-15%.Special as at Pharmaceutical Research, 2 (6): described in 318 (1986) can be by electromigration or iontophoresis release of active ingredients.
The feature of formula I compound is useful to lipid metabolism, thus they more be specially adapted in Mammals, to be used to lose weight and keep alleviating after body weight and as the appetite stimulator medicine.And this compound has hypotoxicity and side effect seldom.Compound can use separately or make with other and lose weight or the activeconstituents of appetite stimulator is united use.Other appetite stimulator activeconstituents of this class has for example Rote Liste, the 01st chapter, body weight-alleviate is mentioned in medicine/appetite-inhibiting agent, they also comprise the activeconstituents that increases organic Conversion of energy and therefore reach the purpose that loses weight, perhaps those influence organic total metabolism level, thereby make the calorie absorption that increases can not cause fat stores to increase, a normal simultaneously calorie absorption causes the organism fat stores to reduce.These compounds are suitable for prevention and particularly treat overweight or obesity.These compounds are particularly suitable for prevention, especially treat type ii diabetes, arteriosclerosis and make lipid metabolism normal and treat hypertension.These compounds can be used as the MCH antagonist and are suitable for the healthy unbalance and mental disorder of treatment for example depression, anxiety state, anxiety neurosis, schizophrenia, also can treat disorder relevant with physiological period and medicine habituation.
In others of the present invention, formula I compound can with the active compound combined administration of one or more other medicines, these materials for example are selected from, antidiabetic medicine, anti-obesity medicine, the activeconstituents that can bring high blood pressure down, fat-reducing medicament and treat and/or prevent diabetes or the activeconstituents of the complication relevant with diabetes.
Other suitable pharmaceutically active substance is particularly:
All antidiabetic medicines of being mentioned in Rote Liste 2001, the 12 chapters.They can unite use with formula I compound of the present invention, thereby can be used for the collaborative curative effect that increases medicine.The administration that activeconstituents is used in combination can give patient's activeconstituents respectively or give with the form of combined prod, promptly can have the various active composition in a kind of pharmaceutical preparation.Hereinafter cited most activeconstituentss are at USP Dictionary of USAN and International Drug Names, USPharmacopeia, and Rockville 2001 is open.
Suitable antidiabetic medicine for example comprises Regular Insulin and insulin derivates
Figure C200480009860D0057170910QIETU
Or HMR1964, Semilente Insulin are (referring to US 6,221,633), islet amyloid polypeptide, GLP-1 and GLP-2 derivative as, for example those disclosed derivative and orally active blood-sugar decreasing active among the WO 98/08871 of NoVo Nordisk A/S.
Orally active blood-sugar decreasing active comprises, preferred sulfourea, biguanides, meglitinides (meglitinides); oxadiazole alkane two ketones (oxadiazolidinediones), thiazolidinedione, alpha-glucosidase inhibitors, glucagon receptor antagonist, the GLP-1 agonist, potassium channel openers as, for example be disclosed in the WO 97/26265 of Novo Nordisk A/S and those openers among the WO 99/03861, insulin sensitizer, the insulin receptor kinase activator, the liver enzyme inhibitor that participation stimulation gluconeogenesis and/or glycogen decompose is glycogen phosphorylase inhibitors for example, glucose absorption and glucose are drained conditioning agent, change for example hyperlipidemia disease activeconstituents and lipopenicillinase activeconstituents HMGCoA reductase inhibitor for example of lipometabolic compound, cholesterol transfer/cholesterol absorption inhibitor, bile acide reuptake inhibithors or microsome tri-glyceride transferring protein (MTP) inhibitor, reduce the compound of food absorption, PPAR and rxr agonist and the activeconstituents that acts on β cell ATP-dependence potassium channel.
In one embodiment of the invention, compound can with the insulin combination administration.
In one embodiment of the invention, formula I compound can for example his spit of fland, rosuvastatin Combined Preparation be cut down in Simvastatin, fluvastatin, Pravastatin, lovastatin, Zarator, happiness with the HMGCoA reductase inhibitor.
In one embodiment of the invention, formula I compound can with cholesterol absorption inhibitor for example ezetimibe, tiqueside, Pamaqueside Combined Preparation.
In one embodiment of the invention, formula I compound can with PPAR gamma agonist for example rosiglitazone, pioglitazone, JTT-501, GI 262570 Combined Preparation.
In one embodiment of the invention, formula I compound can with PPAR alfa agonists for example GW 9578, GW 7647 Combined Preparation..
In one embodiment of the invention, formula I compound can with blended PPAR α/gamma agonist, for example GW 1536, AVE 8042, AVE 8134, AVE 0847, or as at compound Combined Preparation described in PCT/US11833, PCT/US 11490, the DE10142734.4.
In one embodiment of the invention, formula I compound can with the special class of shellfish for example fenofibrate, chlorine Bei Te, bezafibrate Combined Preparation.
In one embodiment of the invention, formula I compound can with MTP inhibitor for example implitapide, BMS-201038, R-103757 Combined Preparation.
In one embodiment of the invention, formula I compound can with the bile acide absorption inhibitor (referring to, for example US 6,245,744 or US 6,221,897) HMR 1741 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with CETP inhibitor JTT-705 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with poly-bile acid adsorbent for example QUESTRAN, colesevelam Combined Preparation.
In one embodiment of the invention, formula I compound can with ldl receptor inductor (referring to US 6,342,512) for example HMR1171, HMR1586 Combined Preparation.
In one embodiment of the invention, formula I compound can with ACAT inhibitor avasimibe Combined Preparation for example.
In one embodiment of the invention, formula I compound can with antioxidant OPC-14117 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with lipoprotein lipid enzyme inhibitors NO-1886 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with ATP-citrate lyase inhibitors SB-204990 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with inhibitor for squalene synthetic enzyme BMS-188494 Combined Preparation for example.
In one embodiment of the invention, formula I compound can with lipoprotein (a) antagonist for example CI-1027 or nicotinic acid Combined Preparation.
In one embodiment of the invention, formula I compound can with lipase inhibitor orlistat Combined Preparation for example.
In one embodiment of the invention, formula I compound can with the insulin combination administration.
In one embodiment, formula I compound can with sulfourea for example tolbutamide, Glyburide, Glipizide or glimepiride Combined Preparation.
In one embodiment, formula I compound can with biguanides N1,N1-Dimethylbiguanide Combined Preparation for example.
In other embodiments, formula I compound can with meglitinides repaglinide Combined Preparation for example.
In one embodiment, formula I compound can with thiazolidinedione disclosed compound among the WO97/41097 of troglitazone, thiophene lattice row ketone, pioglitazone, rosiglitazone or Dr.Reddy ' s Research Foundation for example, 5-[[4-[(3 particularly, 4-dihydro-3-methyl-4-oxo-2-quinazolyl methoxyl group) phenyl] methyl]-2,4-thiazolidinedione Combined Preparation.
In one embodiment, formula I compound can with alpha-glucosidase inhibitor for example miglitol or acarbose Combined Preparation.
In one embodiment, for example tolbutamide, Glyburide, Glipizide, glimepiride or repaglinide Combined Preparation of the activeconstituents of the formula I compound potassium channel that can rely on the ATP-that acts on the β cell.
In one embodiment, formula I compound can with not only a kind of compound Combined Preparation mentioned above, for example with sulfourea and N1,N1-Dimethylbiguanide, with sulfourea and acarbose, repaglinide and N1,N1-Dimethylbiguanide, Regular Insulin and sulfourea, Regular Insulin and N1,N1-Dimethylbiguanide, Regular Insulin and troglitazone, Regular Insulin and lovastatin etc.The compounds of this invention also can with one or more anti-obesity medicines or control appetite the activeconstituents Combined Preparation.
In other embodiments, formula I compound can with the following ingredients Combined Preparation: the CART conditioning agent is (referring to ＂ Cocaine-amphetamine-regulated transcript influencesenergy metabolism, anxiety and gastric emptying in mice ＂ Asakawa, A, Deng, M.:Hormone and Metabolic Research (2001), 33 (9), 554-558), NPY antagonist, for example naphthalene-1-sulfonic acid { 4-[(4-amido quinazoline-2-base is amino) methyl] cyclohexyl-methyl } amide hydrochloride (CGP71683A)), MC4 agonist (1-amino-1,2 for example, 3,4-naphthane-2-formic acid [2-(3a-phenmethyl-2-methyl-3-oxo-2,3,3a, 4,6, the 7-hexahydropyrrolo is [4,3-c] pyridine-5-yl also)-1-(4-chlorophenyl)-2-oxoethyl]-acid amides; (WO 01/91752)), increase food factor antagonist (1-(2-Jia base benzoxazole-6-yl)-3-[1 for example, 5] naphthyridines-4-base urea hydrochloride (SB-334867-A)), H3 agonist (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-imidazolidine also [4,5-c] pyridine-5-yl) third-1-ketone oxalate (WO00/63208)), the TNF agonist, CRF antagonist ([2-methyl-9-(2 for example, 4, the 6-trimethylphenyl)-9H-1,3,9-three azepines fluorenes-4-yl] dipropyl amine (WO 00/66585)), CRF BP antagonist (for example excellent Luo Keding), agonist can be decided in excellent Lip river, β 3 agonists (1-(4-chloro-3-methane sulfonyl aminomethyl phenyl)-2-[2-(2 for example, 3-dimethyl-1H-indoles-6-base oxygen base) ethylamino]-ethylate hydrochlorate (WO01/83451)), MSH (melanocyte-stimulation hormone) agonist, CCK-A agonist ({ 2-[4-(4-chloro-2 for example, the 5-Dimethoxyphenyl)-and 5-(2-cyclohexyl ethyl) thiazol-2-yl carbamyl]-5,7-dimethyl indole-1-yl } acetate trifluoroacetate (WO 99/15525)), serotonin reuptake inhibithors (for example dexfenfluramine), blended serotonin energy and norepinephrine energy activated compounds (for example WO 00/71549), the 5HT agonist is 1-(3-ethyl benzofuran-7-yl) piperazine oxalate (WO01/09111) for example, the bombesin agonist, the galanin antagonist, tethelin (for example human growth hormone), tethelin-release compound (6-phenmethyl Oxy-1-(2-diisopropylaminoethyl ethyl carbamyl)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid tert-butyl ester (WO 01/85695)), the TRH agonist (referring to, for example EP 0 462 884), Uncoupling Proteins 2 or 3 conditioning agents, the leptin agonist (referring to, Lee for example, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia.Leptin agonists as a potential approach to the treatmentof obesity.Drugs of Future (2001), 26 (9), 873-881), the DA agonist (bromocriptine, Doprexin), lipase/amylase inhibitor (for example WO 00/40569), PPAR conditioning agent (for example WO 00/78312), RXR conditioning agent or TR-beta-agonists.
In one embodiment of the invention, other activeconstituents is a leptin; Referring to, for example prediction of ＂ leptin therepic use (Perspectives in therapeutic use of leptinn) ＂, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion onPharmacotherapy (2001), 2 (10), 1615-1622.
In one embodiment, other activeconstituents is right Amphetamine or Amphetamine.
In one embodiment, other activeconstituents is Phenfluoramine or dexfenfluramine.
In another embodiment, other activeconstituents is list-and the dinor-active metabolite of sibutramine or sibutramine.
In one embodiment, other activeconstituents is an orlistat.
In one embodiment, other activeconstituents is Mazindol or phentermine hydrochloride.
In one embodiment, formula I compound can with weighting agent, preferred soluble weighting agent is (referring to, carob/ for example
Figure C200480009860D0061171103QIETU
(Zunft H J; Deng, Carob pulp preparation fortreatment of hypercholesterolemia, ADVANCES IN THERAPY (September calendar year 2001-October), 18 (5), 230-6.) Combined Preparation, Caromax is one and contains the carob product, derives from Nutrinova, Nutrition Specialties ﹠amp; Food Ingredients GmbH, Industriepark 65926Frankfurt/Main)).With
Figure C200480009860D00612
The associating use can with combined preparation or respectively giving construction I compound and
Figure C200480009860D00613
Form carry out. Also can be with the food form administration of assorted of baked goods or milk for example.
Figure C200480009860D00621
The compounds of this invention also can with one or more antihypertensive active composition Combined Preparation.The example of antihypertensive active composition is beta-blocker (for example alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol), ACE (Zinc metallopeptidase Zace1) inhibitor (for example, Zinadril Briem, captopril, enalapril, fosinopril, lisinopril, quinapril and Ramipril), blockers of calcium channels (for example NIFEDIPINE, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem leather and verapamil) and alpha blocker (for example Doxazosin, urapidil, Prazosin and terazosin).Other can be with reference to Remington:Science and Practice ofPharmacy, the 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995.
Each compound of the present invention and the described compound of one or more preambles and choose any one kind of them or the suitable combination of multiple other medicines active substance all is regarded as being included in the scope of the present invention.
Embodiment
The effect of The compounds of this invention can be measured by following method:
The biological assay model:
The appetite stimulator effect can be with female NMRI mouse assay.After the fasting 17 hours, gavage was subjected to trial product.Animal is raised separately, can freely be intake, and give enriching milk after 30 minutes giving product.Measure the consumption of enriching milk per half an hour and continue 7 hours, observe the state of animal.The milk consumption of the control animals that the milk consumption measured and solvent are raised contrasts.
Table 1: the minimizing of comparing the cumulative milk consumption of mensuration with control animals shows the effect of appetite stimulator
Embodiment Oral dosage [mg/kg] Size of animal/treatment treated animal accumulation milk consumption N/[ml] The consumption N/[ml of size of animal/control animals accumulation milk] The minimizing % of the consumption of the accumulation milk of comparing with control group
Embodiment 4 30 5/3.55 5/1.76 50
Embodiment 13 30 5/3.70 5/1.34 64
The test explanation
Determine the functional examination of IC50 value
The preparation of the cDNA clone of human MCH acceptor, the reorganization HEK293 clone of the human MCH acceptor of expression and the functional assays of recombinant cell lines all can adopt (J.Biol.Chem.276 such as being similar to Audinot, 13554-13562,2001) described method is carried out.Different is to adopt the pEAK8 plasmid that derives from EDGE Biosystems (USA) to come construction of expression vector with the method for the document.The host who is used for transfection is the conversion HEK clone that is known as " PEAK stabilized cell " (deriving from EDGEBiosystems equally).After adding agonist (MCH) in the presence of the part of the present invention, the functional examination of cell calcium flux adopts the method for equipment manufacturers to carry out under can helping at the FLIPR equipment of Molecular Devices (USA).
The embodiment of detailed description hereinafter and preparation method are used to illustrate the present invention, but are not used in restriction the present invention.
Say that in principle formula I compound of the present invention can be by known prepared in reaction.For example, above-claimed cpd can obtain according to following general reaction process.
Figure C200480009860D00641
Other The compounds of this invention can obtain by other approach of example in the following flow process.
Figure C200480009860D00651
Other example can obtain by following flow process.
Figure C200480009860D00661
The explanation of the universal method that is adopted can be found following position in an embodiment:
Method A among the embodiment 1, B and C;
Method D among the embodiment 2;
Method E among the embodiment 3;
Method E-a among the embodiment 275;
Method E-b among the embodiment 286;
Method F among the embodiment 4;
Method F-a among the embodiment 264;
Method G among the embodiment 15;
Method H among the embodiment 237;
Method H-a among the embodiment 298;
Method I among the embodiment 238;
Method J among the embodiment 245;
Method J-a among the embodiment 297;
Method K among the embodiment 250;
Method L among the embodiment 254;
Method M among the embodiment 274;
Method N among the embodiment 277;
Method O among the embodiment 279;
Method O-a among the embodiment 292;
Method O-b among the embodiment 280;
The method P of embodiment 285;
Method Q among the embodiment 290;
Method R among the embodiment 309.
Universal description
A) method of rendering architecture formula
At the structural formula of described embodiment for clarity sake, only mark non-hydrogen atom.
In table 6-13, the compound of enantiomer enrichment indicates by three-dimensional supercentral mark hydrogen atom.The example of the enantiomer enrichment that illustrates unless otherwise indicated, has (R) configuration in the heart in 3-amino-pyrrolidine solid.
B) salt form
Many The compounds of this invention are alkali, and can form salt with suitable strong acid.Particularly, the moving phase that contains trifluoroacetic acid by employing is carried out high-efficient liquid phase chromatogram purification, and above-claimed cpd can form trifluoroacetate.These salt can for example be handled with sodium carbonate solution by the salts solution simple process is converted into free alkali.
C) unit of characterization data
Described molecular weight unit is " g/mol ".Observed peak value is with merchant (m/z) expression of mole molion amount and molion electric charge in mass spectrum.
Embodiment 1
N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide
Method A
DMF (10 milliliters) drips of solution of 4-phenoxybenzamine (3.33g) is added in DMF (12 milliliters) solution of the carbonyl dimidazoles (2.92g) that is cooled to 0 ℃ ℃.After 30 minutes, be added dropwise to N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-DMF (10 milliliters) of N-methylacetamide (3.80g).Reaction soln was placed 2 hours prior to room temperature, placed 30 minutes in 80 ℃ then.Mixture is dropped in the water (600 milliliters) and the throw out suction that obtains is leached and washes with water.Also can be with product with ethyl acetate extraction and in concentrating after chromatogram purification.The molecular weight of product that obtains is 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).
N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-the N-methylacetamide
Method B
In hydrogen environment (normal atmosphere), with N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] and ethanamide (3.5g) and palladium hydroxide (II) (20%, the charcoal load; 0.9g) ethanol (150 milliliters) and ethyl acetate (300 milliliters) suspension vigorous stirring 3 hours.Remove by filter catalyzer, and filtrate is concentrated.The molecular weight of product that obtains is 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).
N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
Method C
4-fluoro oil of mirbane (25.0g) is slowly added in the suspension of DMF (300 milliliters) of N-methyl-N-tetramethyleneimine-3-yl acetamide (25.2g) and cesium carbonate (57.6g).After 2 hours, reaction mixture is inclined to water, and suction leaches precipitation.Also the product ethyl acetate extraction can be concentrated the back chromatogram purification.The molecular weight of the product that obtains is 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).
Embodiment 2
1-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl]-3-(4-Phenoxyphenyl) urea
Figure C200480009860D00691
Method D
With N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide (6.0g), ethanol (250 milliliters), water (60 milliliters) and sodium hydroxide solution (10M; 80 milliliters) mixture in the heating down 12 hours that refluxes.Alcohol is distillated and the throw out that obtains is aspirated filtering and uses washed with dichloromethane.Concentrate organic phase and chromatogram (silica gel, methylene chloride 9:1 contain 1% triethylamine), obtain compound.The molecular weight of product that obtains is 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).
Embodiment 3
N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-the 2-phenyl-acetamides
Figure C200480009860D00692
Method E
In 0 ℃, TOTU (327 milligrams) is added to 1-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl]-DMF (3 milliliters) solution of 3-(4-Phenoxyphenyl) urea (402 milligrams) in.After 10 minutes, add H ü nig ' s alkali (130 milligrams), add DMF (1 milliliter) solution of phenylacetic acid (136 milligrams) then.After 12 hours, in mixture, add entry in room temperature reaction, and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.Through preparation property high-efficient liquid phase chromatogram purification residue.The molecular weight of product that obtains is 520.64 (C32H32N4O3); MS (ESI): 521 (M+H+) are trifluoroacetate.
Embodiment 4
(R)-and N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide
Figure C200480009860D00701
According to method A, with (R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 4-phenoxybenzamine.The molecular weight of product that obtains is 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).
(R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-the N-methylacetamide
Hydrogenation obtains (R)-N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl according to method B] ethanamide.The molecular weight of product that obtains is 233.32 (C13H19N3O); MS (ESI): 234 (M+H+).
(R)-and N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
Method F
With (R)-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide (1.3g) portioning adds to sodium hydride (50% oil solution; 0.25g) DMF (50 milliliters) suspension in.After no longer including the gas generation, add methyl iodide (0.82g).After one hour, with the hydrolysis and use ethyl acetate extraction carefully of reaction mixture water.Organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).
(R)-and N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
According to method C, make the reaction of (R)-N-tetramethyleneimine-3-yl acetamide and 4-fluoro oil of mirbane.The molecular weight of product that obtains is 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
Embodiment 5
(S)-and N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide
Figure C200480009860D00702
The flow process that to describe in embodiment 4 is applied to (S)-N-tetramethyleneimine-3-yl acetamide.The molecular weight of product that obtains is 444.54 (C26H28N4O3); MS (ESI): 445 (M+H+).
Embodiment 6
(R)-1-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl]-3-(4-Phenoxyphenyl) urea
Figure C200480009860D00711
According to method D, make the reaction of (R)-N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide.The molecular weight of product that obtains is 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).
Embodiment 7
(S)-1-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl]-3-(4-Phenoxyphenyl) urea
Figure C200480009860D00712
According to method D, make the reaction of (S)-N-methyl-N-(1-{4-[3-(4-Phenoxyphenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide.The molecular weight of product that obtains is 402.50 (C24H26N4O2); MS (ESI): 403 (M+H+).
Embodiment 8
(R)-N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-the N-methylacetamide
Figure C200480009860D00713
According to method A, make (R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 4-cyclopentyloxy aniline reaction.The molecular weight of product that obtains is 436.56 (C25H32N4O3); MS (ESI): 437 (M+H+).
Similarly from (S)-N-[1-(4-amino-phenyl)-tetramethyleneimine-3-yl]-N-methyl-ethanamide acquisition (S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-urea groups]-phenyl }-tetramethyleneimine-3-yl)-N-methyl-ethanamide.
4-cyclopentyloxy aniline
In 80 ℃, with the mixture heating up of 4-nitrophenols (63.7g), bromocyclopentane (68.2g), salt of wormwood (63.3g) and DMF (300 milliliters) 24 hours.After the cooling, dilute with water is also used ethyl acetate extraction.Wash organic phase with water, through dried over mgso and concentrated.Residue is through method B hydrogenation.The molecular weight of product that obtains is 177.25 (C11H15NO); MS (ESI): 178 (M+H+).
Embodiment 9
1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea
Figure C200480009860D00721
According to method D, make N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-N-methylacetamide reaction.The molecular weight of product that obtains is 394.52 (C23H30N4O2); MS (ESI): 395 (M+H+).
Similarly from (R)-and (S)-N-(1-{4-[3-(4-cyclopentyloxy-phenyl)-urea groups]-phenyl-tetramethyleneimine-3-yl)-N-methyl-ethanamide obtains (R)-and (S)-1-(4-cyclopentyloxy-phenyl)-3-[4-(3-methylamino-tetramethyleneimine-1-yl)-phenyl]-urea.
Embodiment 10
(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) the methyl carbamic acid ethyl ester
Chloro ethyl formate (8 μ l) is dropped to 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] in methylene dichloride (3 milliliters) solution of urea (20 milligrams) and H ü nig ' s alkali (10 milligrams).After 12 hours, concentrated reaction mixture, and through preparative high-performance liquid chromatographic purifying residue.The molecular weight of product that obtains is 466.59 (C26H34N4O4); MS (ESI): 467 (M+H+) are trifluoroacetate.
Embodiment 11
1-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-3-ethyl-1-methyl urea
Figure C200480009860D00732
Ethyl isocyanate (7 μ l) is dropped to 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] in methylene dichloride (3 milliliters) solution of urea (20 milligrams) and H ü nig ' s alkali (10 milligrams).After 12 hours, concentrated reaction mixture and through the high-efficient liquid phase chromatogram purification residue.The molecular weight of product that obtains is 465.60 (C26H35N5O3); MS (ESI): 466 (M+H+) are trifluoroacetate.
Embodiment 12
1-(4-cyclopentyloxy phenyl)-3-(4-{3-[methyl-((R)-5-oxo-tetramethyleneimine-2-ylmethyl) amino] tetramethyleneimine-1-yl } phenyl) urea
Figure C200480009860D00733
(R)-5-bromomethyl pyrrolidin-2-one (15 milligrams) is added to 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] in the suspension of the DMF (3 milliliters) of urea (30 milligrams) and salt of wormwood (20 milligrams).After 2 hours, reaction mixture is filtered and concentrates, through preparation property high-efficient liquid phase chromatogram purification residue.The molecular weight of product that obtains is 491.64 (C28H37N5O3); MS (ESI): 492 (M+H+) are trifluoroacetate.
Embodiment 13
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D00741
According to method A, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and carbonyl dimidazoles reaction, react with 4-(4-chlorophenyl) piperidines then.The molecular weight of product that obtains is 455.00 (C25H31ClN4O2); MS (ESI): 455 (M+H+).
Similarly from (R)-and (S)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-the N-methylacetamide obtains (R)-and (S)-4-(4-chlorophenyl) piperidines-1-formic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides.
Embodiment 14
(R)-[1-(4-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Figure C200480009860D00742
According to method A, make (R)-reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester and carbonyl dimidazoles reacts with 4-(4-chlorophenyl) piperidines then.The molecular weight of product that obtains is 513.09 (C28H37ClN4O3); MS (ESI): 513 (M+H+).
(R)-[1-(4-aminophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
According to method B, with (R)-methyl-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate hydrogenation.The molecular weight of product that obtains is 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
(R)-methyl-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
According to method F, with (R)-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate methyl iodide alkanisation.The molecular weight of product that obtains is 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+).
(R)-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
According to method C, make (R)-tetramethyleneimine-the 3-aminocarbamic acid tert-butyl ester and the reaction of 4-fluoro oil of mirbane.The molecular weight of product that obtains is 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Embodiment 15
(R)-4-(4-chlorophenyl) piperidines-1-formic acid [4-(3-methylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D00751
Method G
Trifluoroacetic acid (6.67g) is added to (R)-[1-(4-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } phenyl) tetramethyleneimine-3-yl] in methylene dichloride (50 milliliters) solution of the methyl carbamic acid tert-butyl ester (1.5g).After 3 hours, remove the volatility part and residue is dissolved in methylene dichloride.After the sodium carbonate solution washing, organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 412.97 (C23H29ClN4O); MS (ESI): 413 (M+H+).
Embodiment 16
4-(4-chlorophenyl) piperidines-1-formic acid (4-{ (R)-3-[methyl-(1-methyl piperidine-3-base carbonyl) amino] tetramethyleneimine-1-yl } phenyl) acid amides
Figure C200480009860D00752
According to method E, make (R)-4-(4-chlorophenyl) piperidines-1-formic acid [4-(3-methylamino tetramethyleneimine-1-yl) phenyl] acid amides and 1-methyl piperidine-3-formic acid reaction.The molecular weight of product that obtains is 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).
Embodiment 17
4-(4-chlorophenyl) piperidines-1-formic acid (4-(R)-and 3-[methyl-(2-piperidines-1-base ethanoyl) amino] tetramethyleneimine-1-yl } phenyl) acid amides
Figure C200480009860D00761
According to method E, make (R)-4-(4-chlorophenyl) piperidines-1-formic acid [4-(3-methylamino tetramethyleneimine-1-yl) phenyl] acid amides and piperidines-1-guanidine-acetic acid reaction.The molecular weight of product that obtains is 538.14 (C30H40ClN5O2); MS (ESI): 538 (M+H+).
Embodiment 18
4-(4-chlorophenyl) piperidines-1-formic acid (4-(R)-and 3-[methyl-(2-oxo-thiazolidine-4-carbonyl) amino] tetramethyleneimine-1-yl } phenyl) acid amides
Figure C200480009860D00762
According to method E, make (R)-4-(4-chlorophenyl) piperidines-1-formic acid [4-(3-methylamino tetramethyleneimine-1-yl) phenyl] acid amides and 2-oxo thiazolidine-4-formic acid reaction.The molecular weight of product that obtains is 542.10 (C27H32ClN5O3S); MS (ESI): 542 (M+H+).
Embodiment 19
(R)-and 4-(4-chlorophenyl) piperidines-1-formic acid (4-{3-[methyl-(2,2,2-three fluoro ethanoyl) amino] tetramethyleneimine-1-yl } phenyl) acid amides
Figure C200480009860D00763
According to method A, make (R)-[N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-2,2,2-three fluoro-N-methylacetamide and carbonyl dimidazoles reaction are reacted with 4-(4-chlorophenyl) piperidines then.The molecular weight of product that obtains is 508.98 (C25H28ClF3N4O2); MS (ESI): 509 (M+H+).
(R)-and [N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-2,2,2-three fluoro-N-methylacetamide
According to method B, with (R)-2,2,2-three fluoro-N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide hydrogenation.The molecular weight of product that obtains is 287.29 (C13H16F3N3O); MS (ESI): 288 (M+H+).
(R)-2,2,2-three fluoro-N-methyl-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
Trifluoroacetic anhydride (0.5 milliliter) is dropped in pyridine (2 milliliters) solution of (R)-methyl-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] amine (0.48g).After 3 hours, with the reaction mixture dilute with water and use ethyl acetate extraction.Organic phase is washed with citric acid solution, through dried over mgso and concentrated.The molecular weight of product that obtains is 317.27 (C13H14F3N3O3); MS (ESI): 318 (M+H+).
(R)-methyl-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] amine
Methylene dichloride (5 milliliters) solution of (R)-methyl-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (0.7g) was handled 1 hour with trifluoroacetic acid (3 milliliters).Concentrated reaction solution also is dissolved in methylene dichloride with residue.After the sodium carbonate solution washing, organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 221.26 (C11H15N3O2); MS (ESI): 222 (M+H+).
Embodiment 20
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } methyl nitrosourea
Figure C200480009860D00771
According to method F, make 4-(4-chlorophenyl) piperidines-1-formic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides and iodomethane reaction.The molecular weight of product that obtains is 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).
Embodiment 21
(R)-and 4-(4-chlorophenyl) piperidines-1-formic acid (4-{3-[ethanoyl-(2-diethylamino ethyl) amino] tetramethyleneimine-1-yl } phenyl) acid amides
Figure C200480009860D00781
According to method A, make (R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-(2-diethylamino ethyl) ethanamide and the reaction of 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 540.15 (C30H42ClN5O2); MS (ESI): 540 (M+H+).
(R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-(2-diethylamino ethyl) ethanamide
According to method B, with (R)-N-(2-diethylamino ethyl)-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide hydrogenation.The molecular weight of product that obtains is 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).
(R)-and N-(2-diethylamino ethyl)-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
According to method F, make (R)-N-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide and the reaction of 2-chloro ethyl diethylamide.The molecular weight of product that obtains is 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
Embodiment 22
1-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-3-(4-Phenoxyphenyl) urea
Figure C200480009860D00782
According to method A, B and C, make dimethyl pyrrolidine-3-base amine and the reaction of 4-fluoro oil of mirbane, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-phenoxybenzamine.The molecular weight of product that obtains is 416.53 (C25H28N4O2); MS (ESI): 417 (M+H+).
Embodiment 23
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-isobutoxy-phenyl) propionic acid amide
Figure C200480009860D00791
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 2-(4-isobutoxy phenyl) propionic acid.The molecular weight of product that obtains is 437.59 (C26H35N3O3); MS (ESI): 438 (M+H+).
Embodiment 24
N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide
Figure C200480009860D00792
According to method A, B and C, make the reaction of N-tetramethyleneimine-3-yl acetamide and 4-fluoro oil of mirbane, last with the nitro-compound that hydrogen reduction obtains, make aniline and CDI and 4-cyclopentyloxy aniline reaction.The molecular weight of product that obtains is 422.53 (C24H30N4O3); MS (ESI): 423 (M+H+).
With similar approach, adopt (R)-and (S)-N-tetramethyleneimine-3-yl acetamide is as raw material, obtain (R)-and (S)-N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide.
Embodiment 25
N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-the N-ethyl acetamide
Figure C200480009860D00801
According to method A, B and C, N-ethyl-N-tetramethyleneimine-3-yl acetamide and the reaction of 4-fluoro oil of mirbane, last with the nitro-compound that hydrogen reduction obtains, make aniline and CDI and 4-cyclopentyloxy aniline reaction.The molecular weight of product that obtains is 450.59 (C26H34N4O3); MS (ESI): 451 (M+H+).
Embodiment 26
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl]-the 3-aminomethyl phenyl } acid amides
Figure C200480009860D00802
According to method A, B and C, make N-methyl-N-tetramethyleneimine-3-yl acetamide and 1-fluoro-2-methyl-4-oil of mirbane reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).
Embodiment 27
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl]-3-fluoro phenyl } acid amides
Figure C200480009860D00803
According to method A, B and C, N-methyl-N-tetramethyleneimine-3-yl acetamide and 1,2-two fluoro-4-oil of mirbane reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).
Embodiment 28
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and-2,6-phenyl-difluoride base } acid amides
Figure C200480009860D00811
According to method A, B and C, make N-methyl-N-tetramethyleneimine-3-yl acetamide and 1,3,5-three fluoro-2-oil of mirbane reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).
Embodiment 29
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino)-tetramethyleneimine-1-yl]-the 2-aminomethyl phenyl } acid amides
Figure C200480009860D00812
According to method A, B and C, make N-methyl-N-tetramethyleneimine-3-yl acetamide and 4-fluoro-2-methyl isophthalic acid-oil of mirbane reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 469.03 (C26H33ClN4O2); MS (ESI): 469 (M+H+).
Embodiment 30
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino)-tetramethyleneimine-1-yl]-2-fluoro phenyl } acid amides
According to method A, B and C, make N-methyl-N-tetramethyleneimine-3-yl acetamide and 2,4-two fluoro-1-oil of mirbane reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 472.99 (C25H30ClFN4O2); MS (ESI): 473 (M+H+).
Embodiment 31
(R)-[1-(5-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } pyridine-2-yl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Figure C200480009860D00822
With preparation (R)-[1-(4-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } phenyl) tetramethyleneimine-3-yl] the synthetic order of the methyl carbamic acid tert-butyl ester, adopt 2-chloro-5-nitropyridine to substitute 4-fluoro oil of mirbane as raw material.The molecular weight of product that obtains is 514.07 (C27H36ClN5O3); MS (ESI): 514 (M+H+).
Embodiment 32
(R)-[4-(4-chlorophenyl) piperidines-1-formic acid [6-(3-methylamino tetramethyleneimine-1-yl) pyridin-3-yl] acid amides
Figure C200480009860D00823
According to method G, with (R)-[1-(5-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } pyridine-2-yl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester handles with trifluoroacetic acid.The molecular weight of product that obtains is 413.95 (C22H28ClN5O); MS (ESI): 414 (M+H+).
By similar approach, also can obtain racemize [4-(4-chlorophenyl) piperidines-1-formic acid [6-(pyridin-3-yl of 3-methylamino tetramethyleneimine-yl)] acid amides.
Embodiment 33
4-(4-chlorophenyl) piperidines-1-formic acid 6-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and pyridin-3-yl } acid amides
Figure C200480009860D00831
According to method A, B and C, make N-methyl-N-tetramethyleneimine-3-yl acetamide and 2-chloro-5-nitropyridine reaction, last with the nitro-compound that hydrogen reduction obtains, make the reaction of aniline and CDI and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 490.99 (C25H29ClF2N4O2); MS (ESI): 491 (M+H+).
Embodiment 34
1-[4-(4-dimethylamino phenylpiperidines-1-yl) phenyl]-3-(4-Phenoxyphenyl) urea
Figure C200480009860D00832
According to method A, B and C, make lupetidine-4-base amine and the reaction of 4-fluoro oil of mirbane, last with the nitro-compound that hydrogen reduction obtains, make aniline ([1-(4-aminophenyl) piperidin-4-yl] dimethyl amine) and CDI and the reaction of 4-phenoxybenzamine.The molecular weight of product that obtains is 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+).
Embodiment 35
1-(4-cyclopentyloxy phenyl)-3-[4-(4-morpholine-4-phenylpiperidines-1-yl) phenyl] urea
Figure C200480009860D00841
According to method A, B and C, make the reaction of 4-piperidin-4-yl morpholine and 4-fluoro oil of mirbane, last with the nitro-compound that hydrogen reduction obtains, make aniline and CDI and 4-cyclopentyloxy aniline reaction.The molecular weight of product that obtains is 464.61 (C27H36N4O3); MS (ESI): 465 (M+H+).
Embodiment 36
4-butoxy-N-[4-(4-dimethylamino phenylpiperidines-1-yl) phenyl] benzamide
Figure C200480009860D00842
According to method E, make ([1-(4-aminophenyl) piperidin-4-yl] dimethyl amine) and 4-butoxy benzoic acid.The molecular weight of product that obtains is 395.55 (C24H33N3O2); MS (ESI): 396 (M+H+).
Embodiment 37
4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(ethanoyl methylamino) azetidine-1-yl] and phenyl } acid amides
According to method A, make N-[1-(4-aminophenyl) azetidine-3-yl]-N-methylacetamide and carbonyl dimidazoles and the reaction of 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 440.98 (C24H29ClN4O2); MS (ESI): 441 (M+H+).
N-[1-(4-aminophenyl) azetidine-3-yl]-the N-methylacetamide
According to method B, hydrogenation N-methyl-N-[1-(4-nitrophenyl) azetidine-3-yl] ethanamide.The molecular weight of product that obtains is 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).
N-methyl-N-[1-(4-nitrophenyl) azetidine-3-yl] ethanamide
According to method F, with methyl iodide alkanisation N-[1-(4-nitrophenyl) azetidine-3-yl] ethanamide.The molecular weight of product that obtains is 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
N-[1-(4-nitrophenyl) azetidine-3-yl] ethanamide
Diacetyl oxide (0.6 milliliter) is added in pyridine (1.2 milliliters) solution of 1-(4-nitrophenyl) azetidine-3-base amine (0.5g).After one hour, remove volatile fraction.The molecular weight of product that obtains is 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).
1-(4-nitrophenyl) azetidine-3-base amine
According to method G, [1-(4-nitrophenyl) azetidine-3-yl] t-butyl carbamate is handled with trifluoroacetic acid.The molecular weight of product that obtains is 193.21 (C9H11N3O2); MS (ESI): 194 (M+H+).
[1-(4-nitrophenyl) azetidine-3-yl] t-butyl carbamate
According to method C, make the reaction of azetidine-3-aminocarbamic acid tert-butyl ester and 4-fluoro oil of mirbane.The molecular weight of product that obtains is 293.33 (C14H19N3O4); MS (ESI): 294 (M+H+).
Embodiment 38
[1-(4-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } phenyl) azetidine-3-yl] the methyl carbamic acid tert-butyl ester
Figure C200480009860D00851
According to method A, make the reaction of [1-(4-aminophenyl) azetidine-3-yl] the methyl carbamic acid tert-butyl ester and carbonyl dimidazoles and 4-(4-chlorophenyl) piperidines.The molecular weight of product that obtains is 499.06 (C27H35ClN4O3; MS (ESI): 499 (M+H+).
[1-(4-aminophenyl) azetidine-3-yl] methyl carbamic acid tert-butyl ester
According to method B, with methyl-[1-(4-nitrophenyl) azetidine-3-yl] t-butyl carbamate hydrogenation.The molecular weight of product that obtains is 277.37 (C15H23N3O2); MS (ESI): 278 (M+H+).Methyl-[1-(4-nitrophenyl) azetidine-3-yl] t-butyl carbamate
According to method F, with [1-(4-nitrophenyl) azetidine-3-yl] t-butyl carbamate methyl iodide alkanisation.The molecular weight of product that obtains is 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Embodiment 39
4-(4-chlorophenyl) piperidines-1-formic acid [4-(3-methylamino azetidine-1-yl) phenyl] acid amides
Figure C200480009860D00861
According to method G, make [1-(4-{[4-(4-chlorophenyl) piperidines-1-carbonyl] amino } phenyl) azetidine-3-yl] the methyl carbamic acid tert-butyl ester and trifluoroacetic acid reaction.The molecular weight of product that obtains is 398.94 (C22H27ClN4O); MS (ESI): 399 (M+H+).
Embodiment 40
N-methyl-N-[1-(4-{3-[4-(pyridin-3-yl oxygen base) phenyl] urea groups } phenyl) tetramethyleneimine-3-yl] ethanamide
Figure C200480009860D00862
According to method A, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and carbonyl dimidazoles reaction, then with 4-(pyridin-3-yl oxygen base) aniline reaction.The molecular weight of product that obtains is 445.53 (C25H27N5O3); MS (ESI): 446 (M+H+).
Embodiment 41
N-methyl-N-(1-{4-[3-(4-piperidines-1-base phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) ethanamide
Figure C200480009860D00871
According to method A, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and carbonyl dimidazoles reaction, then with 4-piperidines-1-base aniline reaction.The molecular weight of product that obtains is 435.57 (C25H33N5O2); MS (ESI): 436 (M+H+).
Embodiment 42
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-the 4-phenoxy benzamide
Figure C200480009860D00872
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 4-phenoxy benzoic acid.The molecular weight of product that obtains is 429.52 (C26H27N3O3); MS (ESI): 430 (M+H+).
Embodiment 43
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-4-butyl phenyl ether methane amide
Figure C200480009860D00873
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 4-butoxy benzoic acid.The molecular weight of product that obtains is 409.53 (C24H31N3O3); MS (ESI): 410 (M+H+).
Embodiment 44
4-(4-chlorophenyl) naphthenic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D00881
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 4-(4-chlorophenyl) naphthenic acid.The molecular weight of product that obtains is 454.02 (C26H32ClN3O2); MS (ESI): 454 (M+H+).
Embodiment 45
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-3-(4-isopropyl phenyl) acrylamide
Figure C200480009860D00882
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 3-(4-isopropyl phenyl) vinylformic acid.The molecular weight of product that obtains is 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).
Embodiment 46
Tetrahydrofuran (THF)-2-formic acid (1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) methyl nitrosourea
Figure C200480009860D00883
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and tetrahydrofuran (THF)-2-formic acid reaction.The molecular weight of product that obtains is 492.62 (C28H36N4O4); MS (ESI): 493 (M+H+).
Embodiment 47
1-acetyl-pyrrolidine-2-formic acid (1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) methyl nitrosourea
Figure C200480009860D00891
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and 1-acetyl-pyrrolidine-2-formic acid reaction.The molecular weight of product that obtains is 533.68 (C30H39N5O4); MS (ESI): 534 (M+H+).
Embodiment 48
5-oxo-pyrrolidine-2-formic acid (1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) methyl nitrosourea
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and 5-oxo-pyrrolidine-2-formic acid reaction.The molecular weight of product that obtains is 505.62 (C28H35N5O4); MS (ESI): 506 (M+H+).
Embodiment 49
2-oxo thiazolidine-4-formic acid (1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl) methyl nitrosourea
Figure C200480009860D00893
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and 2-oxo thiazolidine-4-formic acid reaction.The molecular weight of product that obtains is 523.66 (C27H33N5O4S); MS (ESI): 524 (M+H+).
Embodiment 50
(R)-1-methyl piperidine-3-formic acid 1-[4-(4-phenylcyclohexane formyl radical-amino) phenyl] and tetramethyleneimine-3-yl } methyl nitrosourea
Figure C200480009860D00901
According to method E, make (R)-4-cyclohexyl-N-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] benzamide and 1-methyl piperidine-3-formic acid reaction.The molecular weight of product that obtains is 502.71 (C31H42N4O2); MS (ESI): 503 (M+H+).
Embodiment 51
N-(1-{4-[3-(6-cyclopentyloxy pyridin-3-yl) urea groups] phenyl } tetramethyleneimine-3-yl)-the N-methylacetamide
Figure C200480009860D00902
According to method A, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and carbonyl dimidazoles reaction, react with 6-cyclopentyloxy pyridin-3-yl amine then.The molecular weight of product that obtains is 437.55 (C24H31N5O3); MS (ESI): 438 (M+H+).
6-cyclopentyloxy pyridin-3-yl amine
The mixture of 5-nitropyridine-2-alcohol (14.0g), bromocyclopentane (8.0g), salt of wormwood (14g) and DMF (200 milliliters) was heated 6 hours in 80 ℃.After the cooling, the dilute with water reaction mixture is used ethyl acetate extraction.Wash organic phase with water, through dried over mgso and concentrated.Residue is through the silica gel chromatography purifying.According to method B, the product that hydrogenation obtains (2-cyclopentyloxy-5-nitropyridine).The molecular weight of product that obtains is 178.24 (C10H14N2O); MS (ESI): 179 (M+H+).
Embodiment 52
1-(6-cyclopentyloxy pyridin-3-yl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea
Figure C200480009860D00911
According to method D, handle N-(1-{4-[3-(6-cyclopentyloxy pyridin-3-yl) urea groups] phenyl } tetramethyleneimine-3-yl)-N-methylacetamide with sodium hydroxide solution.The molecular weight of product that obtains is 395.51 (C22H29N5O2); MS (ESI): 395 (M+H+).
Embodiment 53
4 '-fluorodiphenyl base-4-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 4 '-fluorodiphenyl base-4-formic acid reaction.The molecular weight of product that obtains is 431.51 (C26H26FN3O2); MS (ESI): 432 (M+H+).
Embodiment 54
4 '-three fluoro methyl biphenyl-4-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D00921
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 4 '-three fluoro methyl biphenyl-4-formic acid reaction.The molecular weight of product that obtains is 481.52 (C27H26F3N3O2); MS (ESI): 482 (M+H+).
Embodiment 55-103
According to method E, make 1-(4-Phenoxyphenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and the reaction of various formic acid.Product is as shown in table 2.
Embodiment 104-144
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and the reaction of various formic acid.Product is as shown in table 3.
Embodiment 145-185
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of various formic acid.Product is as shown in table 4.
Embodiment 186-234
According to method A, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and carbonyl dimidazoles reaction, then with various amine reactions.Product is as shown in table 5.
Figure C200480009860D00941
Figure C200480009860D00951
Figure C200480009860D00961
Figure C200480009860D00971
Figure C200480009860D00981
Figure C200480009860D00991
Figure C200480009860D01001
Figure C200480009860D01011
Figure C200480009860D01021
Figure C200480009860D01031
Figure C200480009860D01041
Figure C200480009860D01051
Figure C200480009860D01071
Figure C200480009860D01081
Figure C200480009860D01091
Figure C200480009860D01121
Figure C200480009860D01131
Figure C200480009860D01151
Figure C200480009860D01181
Figure C200480009860D01191
Figure C200480009860D01201
Figure C200480009860D01211
Figure C200480009860D01221
Figure C200480009860D01231
Figure C200480009860D01241
Figure C200480009860D01251
Figure C200480009860D01261
Figure C200480009860D01271
Figure C200480009860D01281
Figure C200480009860D01291
Figure C200480009860D01311
Figure C200480009860D01321
Figure C200480009860D01331
Figure C200480009860D01341
Figure C200480009860D01351
Figure C200480009860D01361
Figure C200480009860D01371
Figure C200480009860D01381
Figure C200480009860D01391
Figure C200480009860D01401
Figure C200480009860D01411
Figure C200480009860D01421
Figure C200480009860D01441
Figure C200480009860D01451
Embodiment 235
N-(1-{4-[3-(4-cyclopentyloxy phenyl) urea groups] phenyl } tetramethyleneimine-3-yl)-N-methyl-2-piperidines-1-base-ethanamide
Figure C200480009860D01461
According to method E, make 1-(4-cyclopentyloxy phenyl)-3-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] urea and piperidines-1-guanidine-acetic acid reaction.The molecular weight of product that obtains is 519.69 (C30H41N5O3); MS (ESI): 520 (M+H+).
Embodiment 236
1-methyl piperidine-3-formic acid (R)-and 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl } methyl nitrosourea
According to method E, make (R)-4-cyclohexyl-N-[6-(3-methylamino tetramethyleneimine-1-yl) pyridin-3-yl] benzamide and 1-methyl piperidine-3-formic acid reaction.The molecular weight of product that obtains is 503.69 (C30H41N5O2); MS (ESI): 504 (M+H+).
Embodiment 237
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-butoxy phenyl) propionic acid amide
Figure C200480009860D01463
Method H
Cesium carbonate (36 milligrams) and n-butyl bromide (15 milligrams) are added N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl-DMF (1 milligram) solution of 2-(4-hydroxy phenyl) propionic acid amide (27 milligrams) in.After 2 hours, in mixture, add entry in room temperature reaction, use ethyl acetate extraction then.Through dried over sodium sulfate organic phase and concentrated, residue is from diethyl ether/methanol crystallization.The molecular weight of product that obtains is 437.59 (C26H35N3O3); MS (ESI): 438 (M+H+).
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-hydroxy phenyl) propionic acid amide
According to method I, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and the reaction of 2-(4-hydroxy phenyl) propionic acid.The molecular weight of product that obtains is 381.48 (C22H27N3O3); MS (ESI): 382 (M+H+).
Embodiment 238
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-isobutoxy phenyl) ethanamide
According to method H, make N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-hydroxy phenyl) ethanamide and the reaction of isobutyl-bromination thing.The molecular weight of product that obtains is 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-hydroxy phenyl) ethanamide
Method I
Under room temperature, with the DMF (5 milliliters) of 4-hydroxyphenyl acetic acid (305 milligrams), I-hydroxybenzotriazole (300 milligrams) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (480 milligrams) and N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide (470 milligrams) stirred 3 hours.In mixture, add entry, use ethyl acetate extraction.Organic phase, concentrates and crystallization in diethyl ether through dried over sodium sulfate with saturated sodium chloride solution washing.The molecular weight of product that obtains is 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).
Embodiment 239
(R)-and N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-butoxy phenyl) ethanamide
Figure C200480009860D01481
According to method E, make (R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 4-butoxy phenyl acetic acidreaction.The molecular weight of product that obtains is 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Embodiment 240
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-cyclo propyl methoxy phenyl) propionic acid amide
Figure C200480009860D01482
According to method H, make N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-hydroxy phenyl) propionic acid amide and the reaction of bromomethyl cyclopropane.The molecular weight of product that obtains is 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).
Embodiment 241
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-cyclobutyl methoxy base phenyl) propionic acid amide
Figure C200480009860D01483
According to method H, make N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-2-(4-hydroxy phenyl) propionic acid amide and the reaction of bromomethyl tetramethylene.The molecular weight of the product that obtains is 449.60 (C27H35N3O3); MS (ESI): 450 (M+H+).
Embodiment 242
1-(4-p-methoxy-phenyl) cyclopropane-carboxylic acid 4-[3-(ethanoyl methyl-amino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D01491
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 1-(4-p-methoxy-phenyl)-1-cyclopropane-carboxylic acid reaction.The molecular weight of product that obtains is 407.52 (C24H29N3O3); MS (ESI): 408 (M+H+).
Embodiment 243
1-(4-butoxy phenyl) cyclopropane-carboxylic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
According to method H, make the reaction of 1-(4-hydroxy phenyl) cyclopropane-carboxylic acid { 4-[3-(ethanoyl methyl-amino) tetramethyleneimine-1 base] phenyl } acid amides and n-butyl bromide.The molecular weight of product that obtains is 449.60 (C27H35N3O3); MS (ESI): 450 (M+H+).
1-(4-hydroxy phenyl) cyclopropane-carboxylic acid 4-[3-(ethanoyl methyl-amino) tetramethyleneimine-1-yl] and phenyl } acid amides
In 0 ℃; boron tribromide-dimethylsulphide (460 milligrams) is added in methylene dichloride (5.5 milliliters) solution of 1-(4-p-methoxy-phenyl) cyclopropane-carboxylic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides (540 milligrams); under room temperature; react after 12 hours; in mixture, add entry; separate each layer, the water dichloromethane extraction.The organic phase that merges is through dried over sodium sulfate, concentrates and through chromatography purification (silica gel, toluene/ethanol/ethyl acetate 8:1:1 also adds 0.1% triethylamine).The molecular weight of product that obtains is 393.49 (C23H27N3O3); MS (ESI): 394 (M+H+).
Embodiment 244
(R)-4-(4-fluoro phenyl) piperidines-1-formic acid 4-[3-(ethanoyl methyl-amino) tetramethyleneimine-1-yl] phenyl }-the N-methane amide
Figure C200480009860D01501
(R)-4-(4-fluoro phenyl) piperidines-1-formic acid { 4-[3-(ethanoyl methyl-amino) tetramethyleneimine-1-yl] phenyl } acid amides (22 milligrams) is added to sodium hydride (95% oil solution; 0.005g) DMF (1 milliliter) suspension in.After no longer including the gas generation, add methyl iodide (0.02 milliliter).After 2 hours,, and use dichloromethane extraction with the hydrolysis carefully of reaction mixture water.Organic phase is through dried over mgso and concentrated, and residue is crystallization in pentane.The molecular weight of product that obtains is 452.58 (C26H33FN4O2); MS (ESI): 453 (M+H+).
Embodiment 245
5-2-[(2-fluoro phenyl) ethynyl] furans-2-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D01502
Method J
Under inert conditions; at first; Diisopropylamine (14.9 milligrams) is added in the suspension of DMF (0.5 milliliter) of two (three-tert-butyl phosphine) palladium chloride (3.8 milligrams) and cupric iodide (I) (0.9 milligram), and then add 5-bromo furan-2-formic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides (50.0 milligrams) and 1-ethynyl-2-fluorobenzene (solution of 17.7 milligrams of) De dioxs (0.5 milliliter) and DMF (0.2 milliliter).Under room temperature, react after 12 hours, with ethyl acetate diluted mixture thing, use filtered through silica gel then, filtrate is concentrated and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 445.18 (C26H24FN3O3); MS (ESI): 446 (M+H+) are the trifluoroacetic acid hydrogen salt.
5-bromo furan-2-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
According to method E, make N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-methylacetamide and 5-bromo-2-furancarboxylic acid reaction.The molecular weight of product that obtains is 406.28 (C18H20BrN3O3); MS (ESI): 407 (M+H+).
Embodiment 246
5-2-[(4-fluoro phenyl) ethynyl] furans-2-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
According to method J, make 5-bromo furan-2-formic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides and 1-ethynyl-4-fluorobenzene reaction.The molecular weight of product that obtains is 445.18 (C26H24FN3O3); MS (ESI): 446 (M+H+) are trifluoroacetate.
Embodiment 247
The 5-2-[(2-chlorophenyl) ethynyl] furans-2-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D01521
According to method J, make 5-bromo furan-2-formic acid { 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl } acid amides and 1-ethynyl-2-chlorinated benzene reaction.The molecular weight of product that obtains is 461.15 (C26H24ClN3O3); MS (ESI): 462 (M+H+) are trifluoroacetate.
Embodiment 248
R-4-butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methyl propyl group) methylamino]-tetramethyleneimine-1-yl }-phenyl) benzamide
Figure C200480009860D01522
In refluxing down, with (R)-4-butoxy N-[3-fluoro-4-(3-methylamino tetramethyleneimine-1-yl) phenyl] ethanol (5 milliliters) solution of benzamide (0.03g) and oxidation iso-butylene heated 3 hours.Vacuum concentration then.The molecular weight of product that obtains is 457.59 (C26H36FN3O3); MS (ESI): 458 (M+H+).
Embodiment 249
R-4-butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3-methyl butyl) methylamino] tetramethyleneimine-1-yl }-phenyl)-N-methyl-benzamide
Figure C200480009860D01531
With (R)-4-butoxy-N-[3-fluoro-4-(3-methylamino tetramethyleneimine-1-yl) phenyl] DMF (2 milliliters) solution of benzamide (0.03g), triethylamine (0.02g) and 4-bromo-2-methyl fourth-2-alcohol (0.03g) is in 80 ℃ of heating 16 hours.After the cooling, add ethyl acetate (100 milliliters).Water (2x50 milliliter) purging compound, organic phase dried over sodium sulfate, filtration also concentrate.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 471.62 (C27H38FN3O3); MS (ESI): 472 (M+H+).
4-bromo-2-methyl fourth-2-alcohol
Under room temperature, in the argon environment, methyl-magnesium-bromide (in the diethyl ether, 3M, 46 milliliters) is added in diethyl ether (100 milliliters) solution of 3-ethyl bromide (10g).In this process, remain in mixture more than 20 ℃ and below 35 ℃.After 2 hours, mixture is inclined to saturated ammonium chloride solution.With the diethyl ether extraction, dried over sodium sulfate, filtration also concentrate then.Obtain required product.
Embodiment 250
R-4-butoxy-N-[6-(3-two cyclopropyl amino-pyrrolidine-1-yl)-pyridin-3-yl] benzamide
Figure C200480009860D01532
Method K
With (R)-N-[6-(3-amino-pyrrolidine-1-yl) pyridin-3-yl]-methyl alcohol (2 milliliters) solution and the glacial acetic acid (0.11 milliliter) of 4-butyl phenyl ether methane amide (0.065g) reach [(1-oxyethyl group cyclopropyl) oxygen base] trimethyl silane (0.19g) to be mixed.Add sodium cyanoborohydride (0.051g) then, in refluxing down, with said mixture heating 16 hours.Then mixture is filtered, concentrates, be dissolved in methylene dichloride, with sodium hydroxide (2N; 20 milliliters) and sodium chloride solution (20 milliliters) washing, through dried over mgso and concentrated.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 434.59 (C26H34N4O2);
MS(ESI)：435(M+H+)。
Embodiment 251
R-4-butoxy-N-[6-(3-two cyclopropyl amino-pyrrolidine-1-yl) pyridin-3-yl]-N-methyl-benzamide
Figure C200480009860D01541
According to method F, with (R)-4-butoxy-N-[6-(3-two cyclopropyl amino-pyrrolidine-1-yl) pyridin-3-yl] benzamide methylates.The molecular weight of product that obtains is 448.61 (C27H36N4O2); MS (ESI): 449 (M+H+).
Embodiment 252
R-4-butoxy-N-{6-[3-(cyclopropyl methylamino) tetramethyleneimine-1-yl] pyridin-3-yl } benzamide
Figure C200480009860D01542
According to method K, with (R)-4-butoxy-N-[6-(3-methylamino tetramethyleneimine-1-yl) pyridin-3-yl] the benzamide cyclopropylization.The molecular weight of product that obtains is 408.551 (C24H32N4O2); MS (ESI): 409 (M+H+).
Embodiment 253
1-[4-(2-amino-4-butoxy benzoyl-amido)-3-fluoro phenyl] and tetramethyleneimine-3-yl } the methyl carbamic acid tert-butyl ester
According to method E, make [1-(4-amino-3-fluoro phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester and 4-butoxy-2-nitrobenzoyl acid-respons, hydrogenation subsequently.The molecular weight of product that obtains is 500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+).
4-butoxy-2-nitrobenzoic acid
Butanols (20 milliliters) solution and mixed 110 ℃ of stirrings 4 hours that are incorporated in of sulfuric acid (3 milliliters) with 4-fluoro-2-nitrobenzoic acid (1.81g).Add ethyl acetate (100 milliliters).Mixture is with saturated sodium bicarbonate solution (3 * 50 milliliters) washing, with dried over sodium sulfate, filtration and vacuum concentration.Under-10 ℃, residue (2.2g) is added dropwise to preparation in the fourth sodium hydroxide solution (10 ℃, under the argon environment) of butanols (20 milliliters) and sodium hydride (2.18g), stirred then 20 hours.Add ethyl acetate (100 milliliters), mixture is washed with water (2 * 50 milliliters), through dried over sodium sulfate, filtration and vacuum concentration.Residue is through preparation property high-efficient liquid phase chromatogram purification.Under room temperature, with 4-butoxy-2-nitrobenzoyl acid butyl ester sodium hydroxide (5N; 100 milliliters) ethanolic soln hydrolysis 3 hours.Mixture hcl acidifying (10N; 100 milliliters) and use dichloromethane extraction.Organic phase is through dried over sodium sulfate, filtration and concentrated.The molecular weight of product that obtains is 239.23 (C11H13NO5); MS (ESI): 240 (M+H+).
Embodiment 254
N-{4-[3-(7-azabicyclo [2.2.1] heptan-7-yl)-2-oxo-pyrrolidine-1-yl] phenyl }-4-cyclohexyl-N-methyl-benzamide
Method L
In 50 ℃ with N-[4-(3-bromo-2-oxo-pyrrolidine-1-yl) phenyl]-mixture of 4-cyclohexyl-N-methyl-benzamide (100 milligrams), salt of wormwood (60 milligrams), 7-azabicyclo [2.2.1] heptane (44 milligrams) and DMF (2 milliliters) placed 6 hours.With the mixture dilute with water and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 471.65 (C30H37N3O2); MS (ESI): 472 (M+H+).
N-[4-(3-bromo-2-oxo-tetramethyleneimine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide
Acetonitrile (30 milliliters) solution of N-(4-aminophenyl)-4-cyclohexyl-N-methyl-benzamide (3.0g) is mixed with tertiary sodium phosphate (0.95g),, add 2-bromo-4-chloro butyryl bromide (2.9g) in 0 ℃.After one hour, add water (10 milliliters) solution of sodium hydroxide (0.85g).Under room temperature, with mixture vigorous stirring 6 hours.Add the sodium hydroxide solution of same amount then, and continue to stir 48 hours.The reaction soln dilute with water is also used ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.Residue is through silica gel chromatography purifying (moving phase ethyl acetate/heptane 1:2).The molecular weight of product that obtains is 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+).
N-(4-aminophenyl)-4-cyclohexyl-N-methyl-benzamide
4-hexahydrobenzoic acid (5.0g) and 4-nitrophenyl isocyanic ester (4.0g) were stirred 3 hours in toluene (150 milliliters), place then and spend the night.Suction leaches throw out and washs with diethyl ether.The acid amides that obtains ethylizes according to method F, according to method B hydrogenation.The molecular weight of product that obtains is 308.43 (C20H24N2O); MS (ESI): 309 (M+H+).
Embodiment 255
4-cyclohexyl-N-methyl-N-[4-(3-morpholine-4-base-2-oxo-pyrrolidine-1-yl) phenyl] benzamide
According to method L, make N-[4-(3-bromo-2-oxo-tetramethyleneimine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and morpholine reaction.The molecular weight of product that obtains is 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).
Embodiment 256
4-cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidines-1-base tetramethyleneimine-1-yl) phenyl] benzamide
Figure C200480009860D01572
According to method L, make N-[4-(3-bromo-2-oxo-pyrrolidine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and piperidines reaction.The molecular weight of product that obtains is 459.64 (C29H37N3O2); MS (ESI): 460 (M+H+).
Embodiment 257
4-cyclohexyl-N-methyl-N-[4-(2 '-oxo [1,3 '] bipyrrolidine base-1 '-yl) phenyl] benzamide
Figure C200480009860D01573
According to method L, make N-[4-(3-bromo-2-oxo-pyrrolidine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and tetramethyleneimine reaction.The molecular weight of product that obtains is 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Embodiment 258
4-cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxo-pyrrolidine-1-yl) phenyl] benzamide
Figure C200480009860D01581
According to method L, make N-[4-(3-bromo-2-oxo-pyrrolidine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and methylamine reaction.The molecular weight of product that obtains is 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).
Embodiment 259
4-cyclohexyl-N-[4-(3-cyclohexyl amino-2-oxo-pyrrolidine-1-yl) phenyl]-N-methyl-benzamide
Figure C200480009860D01582
According to method L, make N-[4-(3-bromo-2-oxo-tetramethyleneimine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and cyclo-hexylamine reaction.The molecular weight of product that obtains is 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).
Embodiment 260
4-cyclohexyl-N-{4-[3-(cyclopropyl methylamino)-2-oxo-pyrrolidine-1-yl] phenyl }-N-methyl-benzamide
Figure C200480009860D01591
According to method L, make N-[4-(3-bromo-2-oxo-pyrrolidine-1-yl) phenyl]-4-cyclohexyl-N-methyl-benzamide and the reaction of cyclopropyl methylamine.The molecular weight of product that obtains is 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Embodiment 261
N-{4-[3-(ethanoyl methylamino)-2-oxo-pyrrolidine-1-yl] phenyl }-4-cyclohexyl-N-methyl-benzamide
Figure C200480009860D01592
With 4-cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxo-pyrrolidine-1-yl) phenyl] benzamide (52 milligrams) mixes with pyridine (0.5 milliliter) and diacetyl oxide (130 milligrams), after 3 hours, removes volatile fraction in a vacuum.The molecular weight of product that obtains is 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).
Embodiment 262
4-cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidine-1-yl) phenyl] benzamide
Figure C200480009860D01601
Earlier with uncle-butanols (8 milliliters), triethylamine (350 milligrams) then; at last diphenyl phosphoryl azide (1.18g) is added to 1-{4-[(4-phenylcyclohexane formyl radical) methylamino] phenyl-5-oxo-tetramethyleneimine-3-formic acid (1.5g) in, with mixture in 95 ℃ the heating 48 hours.With reaction soln with ethyl acetate dilution and wash with water twice.Organic phase is through dried over mgso and concentrated.According to method G, the crude product product is further reacted.The molecular weight of product that obtains is 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).
1-{4-[(4-phenylcyclohexane formyl radical) methylamino] phenyl }-5-oxo-tetramethyleneimine-3-formic acid
In 100 ℃, with N-(4-aminophenyl)-4-cyclohexyl-N-methyl-benzamide (3.0g) and methylene-succinic acid (1.27g) heating 3 hours.Filter purifying through silica gel (moving phase ethyl acetate/methanol 5: 1).The molecular weight of product that obtains is 420.51 (C25H28N2O4); MS (ESI): 421 (M+H+).
Embodiment 263
N-{4-[4-(ethanoyl methylamino)-2-oxo-pyrrolidine-1-yl] phenyl }-4-cyclohexyl-N-methyl-benzamide
Figure C200480009860D01602
With 4-cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-tetramethyleneimine-1-yl) phenyl] benzamide (101 milligrams) mixes with pyridine (20 milligrams) and diacetyl oxide (25 milligrams), after 3 hours, remove volatile fraction in a vacuum, the molecular weight of product that obtains is 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).
Embodiment 264
(1-{5-[(4-phenylcyclohexane formyl radical) propyl group amino] pyridine-2-yl } tetramethyleneimine-3-yl) methyl-t-butyl carbamate
Figure C200480009860D01611
Method F-a
Will { 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl } methyl carbamic acid tert-butyl ester (50 milligrams), cesium carbonate (249 milligrams), potassiumiodide (17 milligrams), N-Methyl pyrrolidone (1.5 milliliters) and propyl group iodide (40 milligrams) stirred 5 hours in 60 ℃.If transform and not finish, with mixture heating up to 100 ℃, add propyl group iodide (40 milligrams) again after, in 140 ℃ of heating 12 hours.Reaction mixture dilutes with ethyl acetate, and water and sodium hydrogen carbonate solution washing are dry and concentrated through Chromabond XTR.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 520.72 (C31H44N4O3); MS (ESI): 521 (M+H+).
Embodiment 265
(1-{5-[(4-phenylcyclohexane formyl radical)-(1-ethyl propyl) amino] pyridine-2-yl } tetramethyleneimine-3-yl)-the methyl carbamic acid tert-butyl ester
Figure C200480009860D01612
According to method F-a, make 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl the methyl carbamic acid tert-butyl ester and the reaction of 2-ethyl-butyl bromide.The molecular weight of product that obtains is 548.78 (C33H48N4O3); MS (ESI): 549 (M+H+).
Embodiment 266
(1-{5-[(4-phenylcyclohexane formyl radical)-(3-methyl but-2-ene base) amino] pyridine-2-yl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester
Figure C200480009860D01621
According to method F-a, make 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl the methyl carbamic acid tert-butyl ester and the reaction of 3-methyl-2-butene base bromide.The molecular weight of product that obtains is 546.76 (C33H46N4O3); MS (ESI): 547 (M+H+).
Embodiment 267
(1-{5-[(4-phenylcyclohexane formyl radical) methylamino] pyridine-2-yl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester
Figure C200480009860D01622
According to method F-a, make 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl methyl carbamic acid tert-butyl ester and the reaction of methyl iodide.The molecular weight of product that obtains is 492.67 (C29H40N4O3); MS (ESI): 493 (M+H+).
According to method F-a, can obtain following compounds in addition from { 1-[5-(4-cyclohexyl benzoyl-amido) pyridine-2-yl] tetramethyleneimine-3-yl } methyl carbamic acid tert-butyl ester and suitable alkylating agent:
(the 1-{5-[second month in a season-butyl-(4-phenylcyclohexane formyl radical) amino] pyridine-2-yl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester,
(1-{5-[(4-phenylcyclohexane formyl radical) sec.-propyl amino] pyridine-2-yl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester,
(1-{5-[(4-phenylcyclohexane formyl radical) Propargyl amino] pyridine-2-yl } tetramethyleneimine-3-yl)-the methyl carbamic acid tert-butyl ester.
Embodiment 268
5-is right-tolyl ethynyl furans-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01631
Under ar gas environment, 0.042 milliliter of Diisopropylamine is added to 3.8 milligrams of Pd (tBu) 2Cl 2In 0.2 milliliter of DMF of 0.95 milligram of CuI.Be added dropwise to 0.3 milliliter of DMF solution of 94.6 milligrams of 5-bromo furan-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and 0.3 milliliter of DMF solution of 4-ethynyl toluene then.Spend the night in stirring at room solution.The suction isolated throw out of filtering and with filtrate through preparation property high-efficient liquid phase chromatogram purification.Obtaining molecular weight is 413.52; MS (ESI): 414 required product is trifluoroacetate.
5-bromo furan-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method E, make [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine and 5-bromo-2-furancarboxylic acid reaction.Obtain molecular weight 378.27 (C17H20BrN3O2); MS (ESI): the product of 379 (M+H+) is trifluoroacetate.
Can prepare embodiment 269-273 similarly:
Figure C200480009860D01632
Figure C200480009860D01641
Embodiment 274
(R)-4 '-fluorodiphenyl base-4-formic acid [6-(3-dimethylamino tetramethyleneimine-1-yl) pyridin-3-yl]-acid amides
Method M
To be dissolved in (R)-4 of formic acid (230 milligrams) '-fluorodiphenyl base-4-formic acid [6-(3-methylamino tetramethyleneimine-1-yl) the pyridin-3-yl]-acid amides (390 milligrams) and formaldehyde solution (37% aqueous solution; 0.4 milliliter) mix, and in 80 ℃ with mixture heating up 3 hours.The refrigerative reaction soln is concentrated and is allocated between ethyl acetate and the saturated sodium carbonate solution.Organic phase is through dried over mgso and concentrated.The crude product product is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+).
Embodiment 275
1-(4-fluoro phenyl) piperidines-4-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D01651
Method E-a
The mixture of 0.048g1-(4-fluoro phenyl) piperidines-4-formic acid and 0.5 a milliliter of SOCl2 and a DMF was stirred under room temperature 2 hours.Vacuum is removed excessive SOCl2.Residue is dissolved in 0.4 milliliter of DMF, adds 0.033 milligram of triethylamine and 0.048g N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-the N-methylacetamide.Spend the night in stirring at room solution.Filtering solution and through preparation property high-efficient liquid phase chromatogram purification then.The molecular weight of product that obtains is 438.20 (C25H31FN4O2); MS (ESI): 439 (M+H+) are trifluoroacetate.
1-(4-fluoro phenyl) piperidines-4-formic acid
0.875g4-bromo fluorobenzene, 0.016g Pd (dba) 3*CHCl3,0.022g2-(dicyclohexyl phosphino-) biphenyl and 2.28g cesium carbonate are placed flask heated drying and that be full of argon gas, add the 0.943g4-piperidine ethyl formate in 5 milliliters of degassed toluenes.In 100 ℃ with the solution heated overnight.Cooling mixture, vacuum concentration then.Residue is dissolved in ethyl acetate/water.Organic phase 10%NaHCO3 solution washing is through dried over sodium sulfate and vacuum concentration.Residue is through preparation property high-efficient liquid phase chromatogram purification.
4.4 milliliters of 2N potassium hydroxide solutions are added in the 100 ml methanol solution of 1.1g1-(4-fluoro phenyl) piperidine-4-ethyl formate.In the stirring at room mixture overnight.Use 5% hydrochloric acid with pH regulator to 6, with solution for vacuum concentration then.Residue is through preparation property high-efficient liquid phase chromatogram purification.
Embodiment 276
4-phenoxy group naphthenic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] and phenyl } acid amides
Figure C200480009860D01661
In 0 ℃, 0.251g PyBOP and 0.135 milliliter of triethylamine are added to 0.106g4-phenoxy group naphthenic acid and 0.113g N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-9 milliliters of DMF solution of N-methylacetamide in.After 10 minutes, make solution rise to room temperature and stir and spend the night in this temperature.Solvent removed in vacuo, residue is water-soluble/ethyl acetate.Ethyl acetate used 10% citric acid and 10%NaHCO3 solution washing mutually and through dried over sodium sulfate, solvent removed in vacuo.Residue is through preparation property high-efficient liquid phase chromatogram purification.Obtain molecular weight and be 435.25 required product (C26H33N3O3), MS:436 (M+H+).
4-phenoxy group naphthenic acid
The 0.63g p-toluenesulfonyl chloride is added in 5.0 milliliters of pyridine solutions of 0.522g4-hydroxyl naphthenic acid ethyl ester.In stirring at room reactant 3 hours.The vacuum concentration reaction mixture.Water-soluble and the ethyl acetate of the solid that obtains, organic phase be with 2N salt acid elution 3 times, with saturated NaCl solution washing 1 time.Organic phase is through dried over sodium sulfate and vacuum concentration.The product that obtains can be used for next step without being further purified.
The product (0.55g) that obtains is dissolved in 11.2 milliliters of DMF, and adds 0.159g phenol and 0.549g cesium carbonate.Then in 80 ℃ of heated solutions 6 hours.After the cooling, mixture vacuum concentration and through purification by silica gel column chromatography (elutriant: ethyl acetate/n-heptane 1:1).Obtain required product, molecular weight is 248.32 (C15H20O3), MS:249 (M+H+).
0.06 milliliter of 2N potassium hydroxide solution is added in 8 ml waters/THF (1:1) solution of 0.12g4-phenoxy group naphthenic acid ethyl ester.In 60 ℃ of heated solutions 3 hours.Ethyl acetate and 10% citric acid are added mixture.With ethyl acetate extraction water 3 times, through dried over sodium sulfate and vacuum concentration.The compound that obtains can be used for next step without being further purified.
Embodiment 277
N-[4-(3-cyclohexyl amino-pyrrolidine-1-yl) phenyl]-4-isobutoxy benzamide
Figure C200480009860D01671
Method N
Will (4-isobutoxy-N-[4-(3-oxo-pyrrolidine-1-yl) phenyl] methyl alcohol (2 milliliters) liquid of benzamide (50 milligrams) mixes adding sodium cyanoborohydride (the toluene liquid of 1M with aminocyclohexane (28 milligrams) and glacial acetic acid (10 milligrams); 0.17 solution milliliter).After 8 hours, concentrated reaction solution also is allocated in ethyl acetate and water.Organic phase is through dried over mgso and concentrated.The crude product product is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 435.61 (C27H37N3O2); MS (ESI): 436 (M+H+).
4-isobutoxy-N-[4-(3-oxo-pyrrolidine-1-yl) phenyl] benzamide
According to method E-a, make 4-isobutoxy phenylformic acid and 4-(1,4-two oxa-s-7-azaspiro [4.4] ninth of the ten Heavenly Stems-7-yl) phenyl amine reaction, acetone (10 milliliters) liquid and right-toluenesulphonic acids (monohydrate with the acid amides (0.25g) that obtains, 109 milligrams) mix, in refluxing down, make mixture boiling 8 hours.After adding triethylamine (0.5 milliliter), with the mixture dilute with water and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+).
With similar approach, adopt 4-butyl phenyl ether formic acid to obtain 4-butoxy-N-[4-(3-oxo-pyrrolidine-1-yl)-phenyl] benzamide.Similarly, earlier with 4-butyl phenyl ether formic acid and 4-(1,4-two oxa-s-7-azaspiro [4.4] ninth of the ten Heavenly Stems-7-yl)-3-fluoro phenyl amine obtains 4-butoxy-N-[4-(1,4-two oxa-s-7-azaspiro [4.4] ninth of the ten Heavenly Stems-7-yl)-and 3-fluoro phenyl] benzamide, after methylating according to method F, and usefulness as indicated above right-after toluenesulphonic acids is handled, obtain 4-butoxy-N-[3-fluoro-4-(3-oxo-pyrrolidine-1-yl) phenyl] benzamide.
4-(1,4-two oxa-s-7-azaspiro [4.4] ninth of the ten Heavenly Stems-7-yl) phenyl amine
Trimethylammonium chlorosilane (9.3g) is slowly added in the solution of the methylene dichloride (30 milliliters) of 1-phenmethyl-3-pyrrolidone (5.0g) and ethylene glycol (2.67g).After 18 hours, mixture is inclined to sodium hydroxide solution (1N).Isolate organic phase, through dried over mgso and concentrated.Residue is dissolved in methyl alcohol (30 milliliters), adds ammonium formiate (5.2g) and palladium hydroxide (10% carbon load, 300 milligrams).Boiling mixture is 8 hours under refluxing, and filters also to concentrate.According to method C, make the reaction of residue and 4-fluoro oil of mirbane.According to method B, carry out hydrogenation at last.The molecular weight of product that obtains is 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).
Can be with similar approach, adopt 3,4-two fluoro oil of mirbane obtain 4-(1,4-two oxa-s-7-azaspiro [4.4] ninth of the ten Heavenly Stems-7-yl)-3-fluoro phenyl amine.
Embodiment 278
(R)-4-(4-chlorophenyl) piperidines-1-formic acid 4-[3-(methylpyrimidine-2-base-amino) tetramethyleneimine-1-yl]-phenyl } acid amides
Figure C200480009860D01681
In 100 ℃, (R)-4-(4-chlorophenyl) piperidines-1-formic acid [4-(the 3-methylamino tetramethyleneimine-1-yl) phenyl] acid amides (100 milligrams) and N-Methyl pyrrolidone (3 milliliters) liquid of salt of wormwood (100 milligrams) and 2-brominated pyrimidine (50 milligrams) were reacted 4 hours.Then reaction soln is allocated in ethyl acetate and water.Organic phase is through dried over mgso and concentrated.The crude product product is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 491.04 (C27H31ClN6O); MS (ESI): 491 (M+H+).
Embodiment 279
[1-(4-{[5-(2-fluoro phenyl) furans-2-carbonyl] amino } phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Figure C200480009860D01682
Method O
Under ar gas environment, four (triphenyl phosphine) palladium (0) (20 milligrams) is added to (1-{4-[(5-bromo furan-2-carbonyl) amino in 10 milliliters of double-neck flasks] phenyl } tetramethyleneimine-3-yl) in degassed toluene (4 milliliters) solution of the methyl carbamic acid tert-butyl ester (252 milligrams), in stirring at room 10 minutes.Add 2-fluorobenzene boric acid (73 milligrams, 1 milliliter of ethanolic soln) solution and 0.35 milliliter of 2M sodium carbonate solution then,, stirred the mixture 24 hours in 100 ℃.
Add entry (5 milliliters) and ethyl acetate (5 milliliters) then in reaction mixture, separate organic phase, water extracts 2 times with ethyl acetate (10 milliliters).Concentrate the organic phase that merges, residue is through preparation property high-efficient liquid phase chromatogram purification.Obtain required product, molecular weight is 479.56 (C27H30FN3O4); MS (ESI): 480 (M+H+) are trifluoroacetate.Also can adopt cesium carbonate as alkali, in 150 ℃, the reacting by heating thing is 3 minutes in microwave equipment.
(1-{4-[(5-bromo furan-2-carbonyl) amino] phenyl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester
According to method E, make 5-bromo furan-2-formic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester.The molecular weight of product that obtains is 464.36 (C21H26BrN3O4); MS (ESI): 464 (M+H+).
Following compounds also can adopt the similar approach preparation:
5-bromo furan-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides,
(1-{4-[(5-bromo thiophene-2-carbonyl) amino] phenyl } tetramethyleneimine-3-yl) the methyl carbamic acid tert-butyl ester,
2-bromethiazole-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides,
4-iodo-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] benzamide,
(R)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl]-4-phenyl-iodide methane amide,
4-bromo-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-the 3-fluoro benzamide.
Embodiment 280
(3R)-3 '-cyanobiphenyl base-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl] acid amides
Figure C200480009860D01691
Method O-b
0.002 milligram of Pd (PPh3) 4 is added 0.022g (R)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl]-0.45 milliliter of degassing DMF solution of 4-phenyl-iodide methane amide and in stirring at room 10 minutes.Then 0.035 ml water, 0.021g K3PO4 and 0.008g3-cyano-phenyl boric acid are added above-mentioned solution.Spend the night in 80 ℃ of reacting by heating solution.Filtering solution and through preparation property high-efficient liquid phase chromatogram purification then.The molecular weight of product that obtains is 428.20 (C26H25FIN4O); MS (ESI): 429 (M+H+) are trifluoroacetate.
Embodiment 281
3,2 ', 4 '-three fluoro xenyl-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-acid amides
Figure C200480009860D01701
According to method O-b, make 1-bromo-2,4-phenyl-difluoride and N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-fluoro-4-boric acid benzamide reaction.The molecular weight of product that obtains is 439.19 (C25H24F3N3O); MS (ESI): 440 (M+H+) are trifluoroacetate.N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-fluoro-4-boric acid benzamide
According to method E-b, make 4-carboxyl-3-fluorobenzene ylboronic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 371.18 (C19H23BFN3O3); MS (ESI): 372 (M+H+) are trifluoroacetate.
Embodiment 282
5-(2,4-phenyl-difluoride base) thiophene-2-carboxylic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] acid amides
Figure C200480009860D01702
According to method O-b, make 1-bromo-2, the reaction of 4-phenyl-difluoride and 2-boric acid thiophene-5-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides.The molecular weight of product that obtains is 427.52 (C23H23F2N3OS); MS (ESI): 428 (M+H+) are trifluoroacetate.
2-boric acid thiophene-5-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method E-b, make 5-carboxyl-2-thienyl boric acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl]-dimethyl amine.The molecular weight of product that obtains is 359.15 (C17H22BN3O3S); MS (ESI): 360 (M+H+) are trifluoroacetate.
Embodiment 283
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-6-(4-fluoro phenyl) niacinamide
Figure C200480009860D01711
(140 ℃ were heated 15 minutes in microwave equipment) makes 5-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenylamino formyl radical under the condition of method O-b] pyridine-2-base three fluoro-mesylate and 4-fluorobenzene acid reaction.The molecular weight of product that obtains is 404.20 (C24H25FN4O); MS (ESI): 405 (M+H+) are trifluoroacetate.
5-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenylamino formyl radical] pyridine-2-base three fluoro mesylates
In 0 ℃, with 0.05g N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-0.4 milliliter of DME suspension of 6-hydroxy nicotinoyl amine adds in 0.4 milliliter of DME solution of 0.084 milliliter of LDA solution (2M).Stirred the mixture 2 hours in 0 ℃.In mixture, add the solution of 0.055gN-phenyl trifluoromethanesulfonate then for 0.2 milliliter of DME of Toluidrin.With reaction soln rise to room temperature and in 80 ℃ the heating 3 hours.After the cooling, vacuum concentrated solution.Residue is dissolved in ethyl acetate/water, water ethyl acetate extraction 3 times.The organic phase that merges is through dried over sodium sulfate, vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.
N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl]-the 6-hydroxy nicotinoyl amine
According to method E-b, make 6-hydroxy niacin and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) are trifluoroacetate.
Embodiment 284
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-6-(2,4-phenyl-difluoride base) niacinamide
Figure C200480009860D01721
According to method O-b, make 2,4-phenyl-difluoride ylboronic acid and 5-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenylamino formyl radical] [the three fluoro mesylates reaction of pyridine-2-base.The molecular weight of product that obtains is 422.00 (C24H24F2N4O); MS (ESI): 423 (M+H+) are trifluoroacetate.
Embodiment 285
2 ', 4 '-two fluoro xenyl-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01722
According to method E-a, make 2 ', the reaction of 4 '-two fluoro xenyl-4-formic acid [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 421.20 (C25H25F2N3O); MS (ESI): 422 (M+H+) are trifluoroacetate.
2 ', 4 '-two fluoro xenyl-4-formic acid
Method P
0.098 milliliter of 1N lithium hydroxide solution is added to 0.051g2 ', in 1 milliliter of THF/ water (1:1) solution of 4 '-two fluoro xenyl-4-ethyl formates, in the stirring at room mixture overnight.Adopt 5% hydrochloric acid neutralization solution, vacuum concentration, residue is through preparation property high-efficient liquid phase chromatogram purification.
2 ', 4 '-two fluoro xenyl-4-ethyl formates
0.009g Pd (PPh3) 4 is added in 0.96 milliliter of degassed toluene solution of 0.091g4-iodobenzoic acid ethyl ester, in stirring at room 10 minutes.In reaction soln, add 0.047g2 then, 0.114 milliliter of ethanolic soln and 0.201 milliliter of 2N Na2CO3 solution of 4-phenyl-difluoride ylboronic acid.Spend the night in 100 ℃ of heated solutions.The vacuum concentration reaction mixture adds entry/ethyl acetate in residue then.Water is with ethyl acetate extraction 3 times, through dried over sodium sulfate, and solvent removed in vacuo and through preparation property high-efficient liquid phase chromatogram purification.
Embodiment 286
2 ', 4 '-two fluoro xenyl-4-formic acid 4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-acid amides
Figure C200480009860D01731
Method E-b
In 0 ℃, 0.095g HATU, 0.068g HOBT and 0.035 milliliter of triethylamine are added to 0.047g 2 ', 4 '-two fluoro xenyl-4-formic acid and 0.058g N-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-2 milliliters of DMF solution of N-methylacetamide in.After 10 minutes, make solution rise to room temperature and stir and spend the night in this temperature.Solvent removed in vacuo, residue is water-soluble/ethyl acetate.Ethyl acetate is used 10%NaHCO3 solution and water washing mutually.Ethyl acetate is through dried over sodium sulfate, solvent removed in vacuo.Residue is through preparation property high-efficient liquid phase chromatogram purification.Obtain required product, molecular weight is 449.19 (C26H25F2N3O2), MS:450 (M+H+).
Embodiment 287
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-3-fluoro-4-(4-methyl piperidine-1-yl)-benzamide
According to method E-a, make 3-fluoro-4-(4-methyl piperidine-1-yl) phenylformic acid and the reaction of [1-(4-aminophenyl)-tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 424.00 (C25H33FN4O); MS (ESI): 425 (M+H+) are trifluoroacetate.
3-fluoro-4-(4-methyl piperidine-1-yl) phenylformic acid
According to method P, 3-fluoro-4-(4-methyl piperidine-1-yl) methyl benzoate is handled with lithium hydroxide.The molecular weight of product that obtains is 237.28 (C13H16FNO2); MS (ESI): 238 (M+H+).
3-fluoro-4-(4-methyl piperidine-1-yl) methyl benzoate
0.076g salt of wormwood is added to 0.086g3, in 0.5 milliliter of DMF solution of 4-phenyl-difluoride methyl-formiate and 0.050g4-methyl piperidine.In 60 ℃, reacting by heating 2 days.Filter and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) are trifluoroacetate.
Embodiment 288
4-butoxy-N-(4-{3-[(2-dimethylamino ethanoyl) methylamino] tetramethyleneimine-1-yl } phenyl)-N-methyl-benzamide
Figure C200480009860D01742
According to method E, make 4-butoxy-N-methyl-N-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] benzamide and N, the reaction of N-N-methylsarcosine.The molecular weight of product that obtains is 466.63 (C27H38N4O3); MS (ESI): 467 (M+H+).
Can obtain (R)-4-butoxy-N-(4-{3-[(2-dimethylamino ethanoyl) methylamino similarly] tetramethyleneimine-1-yl } phenyl)-N-methyl-benzamide.
Embodiment 289
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-4-butoxy-N-methyl-benzamide
Figure C200480009860D01751
With 4-butoxy-N-methyl-N-[4-(3-methylamino tetramethyleneimine-1-yl) phenyl] benzamide mixes with pyridine and diacetyl oxide.Remove volatile fraction after 2 hours.The molecular weight of product that obtains is 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Embodiment 290
4-butyryl radicals amino-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] benzamide
Figure C200480009860D01752
Method Q
With 4-amino-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] methylene dichloride (2 milliliters) of benzamide (32 milligrams) mixes with salt of wormwood (50 milligrams) and butyryl chloride (11 milligrams).12 hours after-filtration mixtures also concentrate.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 394.52 (C23H30N4O3); MS (ESI): 395 (M+H+).
According to method E, also can make 4-amino-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] benzamide and butyric acid reaction.
4-amino-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] benzamide
According to method E, make uncle 4--butoxy carbonyl benzaminic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine, handle product according to method G.The molecular weight of product that obtains is 324.43 (C19H24N4O); MS (ESI): 325 (M+H+).
Embodiment 291
2-phenylacetylene base thiazole-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-acid amides
2-bromethiazole-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (100 milligrams) is dissolved in tetrahydrofuran (THF) (2 milliliters), adds phenylacetylene (52 milligrams), triethylamine (52 milligrams), triphenylphosphine (17 milligrams), two (triphenyl phosphine) palladium dichloride (89 milligrams) and cupric iodide (I) (9.6 milligrams).In 150 ℃, the reacting by heating mixture is 3 minutes in microwave equipment, concentrates then.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).
Embodiment 292
5-(4-fluoro phenyl) pyridine-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-acid amides
Figure C200480009860D01762
Method O-a
To be dissolved in 5-chloro-pyridine-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (100 milligrams) and 4-fluorobenzene ylboronic acid (81 milligrams), POPD (15 milligrams) and cesium carbonate (the 2M aqueous solution of toluene; 0.5 milliliter) mix.In 150 ℃ of reacting by heating things 10 minutes in microwave equipment, concentrate then.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 404.49 (C24H25FN4O); MS (ESI): 405 (M+H+).
5-chloro-pyridine-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method E, make [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine and 5-chloro-pyridine-2-formic acid reaction.The molecular weight of product that obtains is 344.85 (C18H21ClN4O); MS (ESI): 345 (M+H+).
Embodiment 293
5-(4-fluoro phenyl) pyridine-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-acid amides
Figure C200480009860D01771
According to method O-a, make 5-chloro-pyridine-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and 4-aminomethyl phenyl acid reaction.The molecular weight of product that obtains is 400.53 (C25H28N4O); MS (ESI): 401 (M+H+).
Embodiment 294
1-benzenesulfonyl piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] acid amides
Figure C200480009860D01772
Piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (70 milligrams) that will be dissolved in N-Methyl pyrrolidone (2 milliliters) mixes with salt of wormwood (45 milligrams) and benzene sulfonyl chloride (35 milligrams).After 12 hours, filtering mixt, filtrate is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+).
Embodiment 295
1-(4-fluorobenzene alkylsulfonyl) piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01781
Piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (70 milligrams) that will be dissolved in N-Methyl pyrrolidone (2 milliliters) mixes with salt of wormwood (45 milligrams) and 4-fluorobenzene SULPHURYL CHLORIDE (40 milligrams).After 12 hours, filtering mixt, filtrate is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 474.60 (C24H31FN4O3S); MS (ESI): 475 (M+H+).
Embodiment 296
1-(butane-1-alkylsulfonyl) piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] acid amides
Figure C200480009860D01782
Piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (70 milligrams) that will be dissolved in N-Methyl pyrrolidone (2 milliliters) mixes with salt of wormwood (45 milligrams) and butyl sulfochlorides (30 milligrams).After 12 hours, filtering mixt, filtrate is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).
Embodiment 297
5-(4-butoxy phenyl ethynyl) furans-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] acid amides
Method J-a
5-bromo furan-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (75 milligrams) is dissolved in N with 1-butoxy-4-acetylenylbenzene (35 milligrams), dinethylformamide (1 milliliter), under ar gas environment, drop to Pd (tBu3P) 2Cl2 (4 milligrams), cupric iodide (I) (75 milligrams) and N, in the suspension of the anhydrous tetrahydro furan (3 milliliters) of N-Diisopropylamine (20 milligrams).Under room temperature, stirred the mixture 8 hours.Reaction filtrate is handled and is concentrated through washing filter, and the crude product product is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 471.6 (C29H33N3O3); MS (ESI): 472 (M+H+) are the trifluoroacetic acid hydrogen salt.
Embodiment 298
6-butoxy-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] niacinamide
Method H-a
Under room temperature,, add 0.1g N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl then with 1 milliliter of DMSO solution stirring of 0.1g potassium hydroxide 10 minutes]-the 6-hydroxy nicotinoyl amine.Stirring reaction solution 10 minutes adds the 0.084g1-butyl bromide then, in the stirring at room mixture overnight.After adding entry and ethyl acetate, use ethyl acetate extraction water 3 times.The organic phase that merges is through dried over sodium sulfate, vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) are trifluoroacetate.
Embodiment 299
6-cyclo propyl methoxy-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] niacinamide
Figure C200480009860D01792
According to method H-a, make (bromomethyl) cyclopropane and N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl]-reaction of 6-hydroxy nicotinoyl amine.The molecular weight of product that obtains is 380.22 (C22H28N4O2); MS (ESI): 381 (M+H+) are trifluoroacetate.
Embodiment 300
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-6-isobutoxy niacinamide
Figure C200480009860D01801
According to method H-a, make 1-bromo-2-methylpropane and N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl]-reaction of 6-hydroxy nicotinoyl amine.The molecular weight of product that obtains is 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) are trifluoroacetate.
Embodiment 301
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-6-(4-fluorinated phenoxy) niacinamide
Figure C200480009860D01802
49 milligrams of salt of wormwood are added to 0.041g6-chloro-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] in 0.8 milliliter of DMF solution of niacinamide and 4-fluorophenol (30 milligrams), in 140 ℃ of reacting by heating 90 minutes in microwave equipment.After adding entry and ethyl acetate, use ethyl acetate extraction water 3 times.The organic phase that merges is through dried over sodium sulfate, vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) are trifluoroacetate.
6-chloro-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] niacinamide
According to method E-b, make 6-chloro-nicotinic acid and the reaction of [1-(4-amino-phenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 344.14 (C18H21ClN4O); MS (ESI): 345 (M+H+) are trifluoroacetate.
The following example also can adopt the similar approach preparation:
Figure C200480009860D01811
Embodiment 305
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-fluoro-4-phenoxy benzamide
With powder molecular sieve (4A), 0.01g venus crystals and 0.02g N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-fluoro-4-boric acid benzamide adds in 0.5 milliliter of dichloromethane solution of 0.008g phenol, and stirred 24 hours in 40 ℃.Solvent removed in vacuo then, residue is water-soluble/ethyl acetate, with ethyl acetate extraction water 3 times.The organic phase that merges is through dried over sodium sulfate, vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 419.2 (C25H26FN3O2); MS (ESI): 420 (M+H+) are trifluoroacetate.
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-fluoro-4-boric acid benzamide
According to method E-b, make 4-carboxyl-3-fluorobenzene ylboronic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 371.18 (C19H23BFN3O3); MS (ESI): 372 (M+H+) are trifluoroacetate.
Embodiment 306
4-(3-cyano-phenyl)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method O-a, make 4-(4,4,5, the 5-tetramethyl--[1,3,2l two oxa-boron heterocycle pentane-2-yls)-3, the reaction of 6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and 3-bromo benzonitrile.The molecular weight of product that obtains is 415.54 (C25H29N5O); MS (ESI): 416 (M+H+) 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method A, make 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1,2,3,6-tetrahydropyridine and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 440.40 (C24H37BN4O3); MS (ESI): 441 (M+H+)
Embodiment 307
4-(2-cyano-phenyl)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01822
According to method O-a, make 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and the reaction of 2-bromo benzonitrile.The molecular weight of product that obtains is 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)
Embodiment 308
4-(3-methylthio group phenyl)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method O-a, make 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-3,6-dihydro-2H-pyridine-1-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and the reaction of 3-bromo thioanisole.The molecular weight of product that obtains is 436.62 (C25H32N4OS); MS (ESI): 437 (M+H+)
Embodiment 309
4-(5-chloro-pyridine-2-base oxygen base)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] benzamide
Figure C200480009860D01832
0.143g salt of wormwood is added to 0.19g4-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenylamino formyl radical] in 2 milliliters of DMF solution of phenylacetic acid salt, with solution in microwave equipment in 130 ℃ of heating 15 minutes.Then solution is mixed with water and ethyl acetate, the freeze-drying water, residue can be used for next step without being further purified.
Method R
In 230 ℃, with 0.05g N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-4-hydroxybenzamide, 0.017g 2,0.8 milliliter of DMF solution of 5-dichloropyridin and 0.064g salt of wormwood heated in microwave equipment 30 minutes.Filtering solution and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 436.17 (C24H25ClN4O2); MS (ESI): 437 (M+H+) are trifluoroacetate.
4-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenylamino formyl radical] phenylacetic acid salt
According to method E-b, make 4-acetoxy-benzoic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine.The molecular weight of product that obtains is 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) are trifluoroacetate.
Embodiment 310
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-4-(5-fluorinated pyridine-2-base oxygen base) benzamide
Figure C200480009860D01841
According to method R, make 2-chloro-5-fluorinated pyridine and N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-reaction of 4-hydroxybenzamide.The molecular weight of product that obtains is 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) are the trifluoroacetic acid hydrogen salt.
Embodiment 311
4-(6-chloro-pyridine-3-base oxygen base)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] benzamide
Figure C200480009860D01842
Can obtain by the by product of reaction among the embodiment 310.The molecular weight of product that obtains is 436.95 (C24H25ClN4O2); MS (ESI): 437 (M+H+) are trifluoroacetate.
Embodiment 312
5-chloro-3 ', 6 '-dihydro-2 ' H-[2,4 '] bipyridyl-1 '-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01843
[1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine (32 milligrams) and carbonyl dimidazoles (27.1 milligrams) are dissolved in acetonitrile (1.5 milliliters), stirred the mixture 3 hours.With triethylamine (63.4 μ l) add 5-chloro-1 ', 2 ', 3 ', 6 '-THF (1 milliliter) and chloroform (0.5 milliliter) solution of tetrahydrochysene-[2,4 '] dipyridyl (40.7 milligrams) in.After 15 minutes, mixture dropped to first solution and stir spend the night.Enriched mixture, residue are allocated in methylene dichloride and water.Organic phase is through dried over sodium sulfate, filtration and concentrated.By residue being dissolved in methylene dichloride (1.5 milliliters), and solution is added in the methylene dichloride (6 milliliters) and triethylamine (128 μ l) suspension of p-toluenesulfonyl chloride (0.5g) of polymkeric substance combination of stirring, remove primary amine and/or secondary amine.After 3 hours, filtering resin and for several times with washed with dichloromethane.Concentrate the organic phase that merges.Residue is through chromatogram (silica gel, moving phase: ethyl acetate/dichloromethane (5%), ammonia (methanol solution of 7N, 2%), ethyl acetate/dichloromethane (5%), ammonia (methanol solution of 7N, 3%) subsequently) purifying.The molecular weight of product that obtains is 425.97 (C23H28ClN5O); MS (ESI): 426 (M+H+).
5-chloro-1 ', 2 ', 3 ', 6 '-tetrahydrochysene-[2,4 '] dipyridyl
With 5-chloro-3 ', 6 '-dihydro-2 ' H-[2,4 '] dipyridyl-1 '-chloroform (2.4 milliliters) solution and hydrogenchloride (the 4N De dioxane solution of t-butyl formate (50 milligrams); 0.8 milliliter) mix enriched mixture after 13 hours.The molecular weight of product that obtains is 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+).
5-chloro-3 ', 6 '-dihydro-2 ' H-[2,4 '] dipyridyl-1 '-t-butyl carbamate
The DMF of 2-bromo-5-chloro-pyridine (131 milligrams) (is outgased with nitrogen; 4.5 milliliter) solution adds to 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-3,6-dihydro-2H-pyridine-1-t-butyl carbamate (Eastwood, Paul R., Tetrahedron Lett, 41,19,2000,3705-3708; 200 milligrams), salt of wormwood (0.265g) and Pd (dppf) Cl 2In the mixture of (50 milligrams).In 80 ℃ of heated mixt 8 hours.After the cooling, with methylene dichloride diluted mixture thing, with sodium carbonate solution and water washing.Organic phase is through dried over sodium sulfate, filtration and concentrated.The residue purifying is through chromatography (silica gel, moving phase: heptane/ethyl acetate (2%)/methylene dichloride (5%), heptane/ethyl acetate (5%)/methylene dichloride (5%) subsequently.
Embodiment 313
5-(2-amino-4-aminomethyl phenyl) furans-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] acid amides
Figure C200480009860D01861
According to method B, with 5-(2-nitro-4-methyl phenyl) furans-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl)-phenyl] amide hydrogenation.The molecular weight of product that obtains is 404.22 (C24H28N4O2); MS (ESI): 405 (M+H+).
Embodiment 314
5-(2-acetylamino-4-aminomethyl phenyl) furans-2-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01862
By method Q, make 5-(2-amino-4-aminomethyl phenyl) furans-2-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl)-phenyl] acid amides and excess acetyl chloride.The molecular weight of product that obtains is 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+).
Embodiment 315
5-(2-isobutyryl amino-4-aminomethyl phenyl) furans-2-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01863
By method Q, make the reaction of 5-(2-amino-4-aminomethyl phenyl) furans-2-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl)-phenyl] acid amides and isobutyryl chloride.The molecular weight of product that obtains is 474.26 (C28H34N4O3); MS (ESI): 475 (M+H+).
Embodiment 316
5 '-chloro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] methane amide
Figure C200480009860D01871
In 160 ℃, with piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] methane amide (44.4 milligrams) and 2,5-dichloropyridin (60 milligrams) heating 15 minutes.Add ortho-xylene (0.5 milliliter), continue heating 2 hours in 160 ℃.The refrigerative crude mixture is through chromatogram (silica gel, elutriant: purifying ethyl acetate/ammonia (methanol solution of 7N)).The molecular weight of product that obtains is 442.01 (C24H32ClN5O); MS (ESI): 442 (M+H+).
Piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] methane amide
According to method G, with 4-{[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] the methyl carbamyl } piperidines-1-t-butyl formate handles with trifluoroacetic acid.The molecular weight of product that obtains is 330.48 (C19H30N4O); MS (ESI): 331 (M+H+).
Can prepare piperidines-4-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] acid amides similarly.
4-{[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] the methyl carbamyl } piperidines-1-t-butyl formate
Methylene dichloride (15 milliliters) solution of N-Boc-piperidines-4-formic acid (550 milligrams) and pyridine (0.47 milliliter) is mixed with thionyl chloride (thinoyl chloride) (0.21 milliliter), after 30 minutes, drip dimethyl [1-(4-methylamino phenyl) tetramethyleneimine-3-yl] amine (0.5g), triethylamine (1.17 milliliters), DMAP (0.44g) and methylene dichloride (10 milliliters) solution.After 16 hours, with methylene dichloride diluted mixture thing, water and saturated brine washing are through dried over sodium sulfate and concentrated.Residue is through chromatography (silica gel, elutriant: purifying ethyl acetate/ammonia (methanol solution of 7N)).The molecular weight of product that obtains is 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+).
Can prepare 4-{[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl similarly] carbamyl } piperidines-1-t-butyl formate.
Can adopt similar approach to prepare the compound of the following example:
Figure C200480009860D01881
Embodiment 320
3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
Figure C200480009860D01882
In 160 ℃, piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (30 milligrams) and 2-chloro-pyridine (90 milligrams) were heated 2 hours.Add 2-chloro-pyridine (0.2 milligram), in 160 ℃, reheat mixture 4 hours.The refrigerative crude mixture is through chromatogram (silica gel, elutriant: purifying ethyl acetate/ammonia (methanol solution of 3N)).The molecular weight of product that obtains is 393.54 (C23H31N5O); MS (ESI): 394 (M+H+).
The compound that can prepare the following example similarly:
Figure C200480009860D01891
Embodiment 323
5 '-chloro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] acid amides
In 160 ℃, with piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides (30 milligrams), 2,5-dichloropyridin (30 milligrams) and tributylamine (0.2 milliliter) heating 2 hours.Refrigerative crude mixture heptane wash is through chromatogram (silica gel, elutriant: purifying ethyl acetate/ammonia (methanol solution of 3N)).The molecular weight of product that obtains is 427.98 (C23H30ClN5O); MS (ESI): 428 (M+H+).
Embodiment 324
1-(4-chloro-2-cyano-phenyl) piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
As described in the embodiment 323, make piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides and 2, the reaction of 5-dichloro-benzonitrile.The molecular weight of product that obtains is 452.00 (C25H30ClN5O); MS (ESI): 452 (M+H+).
Embodiment 325
1-(2-acetylamino-4-chlorophenyl) piperidines-4-formic acid [4-(3-dimethylamino-tetramethyleneimine-1-yl) phenyl] methane amide
Figure C200480009860D01901
With palladium carbon (10%; 10 milligrams) add to glacial acetic acid (5 milliliters) solution of 1-(4-chloro-2-nitro-phenyl) piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] methane amide (50 milligrams).(1bar) stirred solution under hydrogen environment, and add diacetyl oxide (14 μ l).After one hour, add diacetyl oxide (6 μ l) again, stirred the mixture 15 minutes.Concentrate with suspension filtered and with filtrate.Residue is through chromatogram (silica gel, elutriant: purifying ethyl acetate/ammonia (methanol solution of 7N)).The molecular weight of product that obtains is 498.07 (C27H36ClN5O2); MS (ESI): 498 (M+H+).
The compound for preparing the following example similarly:
Figure C200480009860D01902
Embodiment 329
(R)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl]-2-(4-Phenylpiperidine-1-yl) ethanamide
Cesium carbonate (100 milligrams) and 4-Phenylpiperidine (48 milligrams) are added to (R)-2-chloro-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] in the acetonitrile (5 milliliters) and DMF (1 milliliter) solution of ethanamide (80 milligrams), in 65 ℃, mixture was placed 12 hours.Mixture is removed volatile fraction, and residue is allocated in water and methylene dichloride.Organic phase is through dried over sodium sulfate, filtration and concentrated.Residue is through chromatogram (silica gel, elutriant: ethanol/methylene) purifying.The molecular weight of product that obtains is 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).
Also can adopt salt of wormwood or pyridine as auxiliary alkali, add potassiumiodide as catalyzer, or, in microwave equipment, react in 150 ℃.
(R)-and 2-chloro-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] ethanamide
Triethylamine (2.03g) is added in methylene dichloride (120 milliliters) solution of (R)-[1-(4-aminophenyl) tetramethyleneimine-3-yl]-dimethyl amine (3.15g), be added dropwise to chloro-acetyl chloride (2.26g) then.After 3 hours, with methylene dichloride diluted mixture thing and water and salt water washing.Organic phase is through dried over sodium sulfate, filtration and concentrated.Residue is through chromatography (silica gel, elutriant: ethanol/methylene) purifying.The molecular weight of product that obtains is 281.79 (C14H20ClN3O); MS (ESI): 282 (M+H+).
Obtain following compounds similarly:
N-{4-[3-(ethanoyl methylamino) tetramethyleneimine-1-yl] phenyl }-the 2-chloro-acetamide,
2-chloro-N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] ethanamide,
(R)-and 2-chloro-N-[6-(3-dimethylamino tetramethyleneimine-1-yl) pyridin-3-yl] ethanamide.
Employing is similar to the compound that embodiment 329 described methods prepare the following example:
Figure C200480009860D01921
Embodiment 340
(R)-4-phenmethyl piperidines-1-formic acid [6-(3-dimethylamino tetramethyleneimine-1-yl) pyridin-3-yl]-acid amides
In 0 ℃, (R)-6-(3-dimethylamino tetramethyleneimine-1-yl) pyridin-3-yl amine is added in DMF (0.5 milliliter) solution of carbonyl dimidazoles (53 milligrams).After 15 minutes, add 4-phenmethyl piperidines (57 milligrams).In 90 ℃, heated mixt one hour.Cooling mixture is removed volatile fraction.Residue is through chromatogram (silica gel, elutriant: ethanol/methylene) purifying.The molecular weight of product that obtains is 407.56 (C24H33N5O); MS (ESI): 408 (M+H+).
The compound for preparing the following example similarly:
Figure C200480009860D01931
Embodiment 348
(R)-4-cyclo propyl methoxy-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl]-benzamide
Figure C200480009860D01932
According to method B, making (R)-4-phenmethyl oxygen base-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl] benzamide takes off phenmethyl hydrogenation.According to method H, (R)-N-[4-(3-dimethylamino tetramethyleneimine-1-the yl)-3-fluoro phenyl that will obtain with the cyclopropyl MB]-4-(2-hydroxybenzoyl) amino-alkylation.The molecular weight of product that obtains is 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).
Can obtain the compound of the following example equally according to method H:
Figure C200480009860D01941
Embodiment 352
(R)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl]-4-(pyridine-2-base oxygen base) benzamide
According to method R, make (R)-N-[4-(3-dimethylamino tetramethyleneimine-1-yl)-3-fluoro phenyl]-4-hydroxybenzamide and the reaction of 2-chloro-pyridine.The molecular weight of product that obtains is 434.52 (C25H27N4O2); MS (ESI): 435 (M+H+).
Embodiment 353-embodiment 507
According to method A, make various pyrrolidyl aniline and different amine reactions.The product that obtains is as shown in table 6.
Embodiment 508-embodiment 1130
According to method E, make various pyrrolidyl aniline and different acid-responss.The product that obtains is as shown in table 7.
Embodiment 1131-embodiment 1232
According to method O, make various (mixing) aryl halide and different acid reactions.The product that obtains is as shown in table 8.
Embodiment 1233-embodiment 1237
According to method J, make various aryl halides and different acetylene reactions.The product that obtains is as shown in table 9.
Embodiment 1238-embodiment 1403
According to method N, make various amino-pyrrolidines and N-aryl pyrrolidones and different aldehyde, ketone and amine reactions.The product that obtains such as institute's table 10 show.
Embodiment 1404-embodiment 1423
According to method E, various amino-pyrrolidine reduction are methylated with formaldehyde.The product that obtains is as shown in table 11.
Embodiment 1424-embodiment 1443
According to method F, with various alkylation of amide.The product that obtains is as shown in table 12.
Embodiment 1444-embodiment 1618
According to method G, make various t-butyl carbamate cracking.The product that obtains is as shown in table 13.
Table 6
Figure C200480009860D01961
Figure C200480009860D01971
Figure C200480009860D01981
Figure C200480009860D01991
Figure C200480009860D02001
Figure C200480009860D02011
Figure C200480009860D02021
Figure C200480009860D02031
Figure C200480009860D02041
Figure C200480009860D02061
Figure C200480009860D02071
Figure C200480009860D02081
Figure C200480009860D02091
Figure C200480009860D02101
Table 7
Figure C200480009860D02102
Figure C200480009860D02111
Figure C200480009860D02121
Figure C200480009860D02131
Figure C200480009860D02141
Figure C200480009860D02151
Figure C200480009860D02161
Figure C200480009860D02171
Figure C200480009860D02181
Figure C200480009860D02191
Figure C200480009860D02201
Figure C200480009860D02221
Figure C200480009860D02231
Figure C200480009860D02241
Figure C200480009860D02251
Figure C200480009860D02261
Figure C200480009860D02271
Figure C200480009860D02281
Figure C200480009860D02291
Figure C200480009860D02301
Figure C200480009860D02321
Figure C200480009860D02331
Figure C200480009860D02351
Figure C200480009860D02361
Figure C200480009860D02371
Figure C200480009860D02391
Figure C200480009860D02401
Figure C200480009860D02421
Figure C200480009860D02431
Figure C200480009860D02441
Figure C200480009860D02451
Figure C200480009860D02461
Figure C200480009860D02471
Figure C200480009860D02481
Figure C200480009860D02491
Figure C200480009860D02501
Figure C200480009860D02511
Figure C200480009860D02521
Figure C200480009860D02531
Figure C200480009860D02541
Figure C200480009860D02551
Figure C200480009860D02561
Figure C200480009860D02571
Figure C200480009860D02581
Figure C200480009860D02591
Figure C200480009860D02601
Figure C200480009860D02621
Figure C200480009860D02631
Figure C200480009860D02641
Figure C200480009860D02651
Figure C200480009860D02661
Figure C200480009860D02671
Figure C200480009860D02681
Figure C200480009860D02691
Figure C200480009860D02701
Figure C200480009860D02711
Table 8
Figure C200480009860D02712
Figure C200480009860D02721
Figure C200480009860D02741
Figure C200480009860D02751
Figure C200480009860D02761
Figure C200480009860D02781
Figure C200480009860D02791
Figure C200480009860D02801
Figure C200480009860D02811
Figure C200480009860D02821
Table 9
Figure C200480009860D02822
Table 10
Figure C200480009860D02831
Figure C200480009860D02841
Figure C200480009860D02851
Figure C200480009860D02861
Figure C200480009860D02871
Figure C200480009860D02881
Figure C200480009860D02891
Figure C200480009860D02901
Figure C200480009860D02911
Figure C200480009860D02921
Figure C200480009860D02931
Figure C200480009860D02941
Figure C200480009860D02951
Figure C200480009860D02971
Figure C200480009860D02981
Table 11
Figure C200480009860D02982
Figure C200480009860D02991
Figure C200480009860D03001
Table 12
Figure C200480009860D03002
Figure C200480009860D03011
Figure C200480009860D03021
Table 13
Figure C200480009860D03022
Figure C200480009860D03031
Figure C200480009860D03041
Figure C200480009860D03061
Figure C200480009860D03071
Figure C200480009860D03081
Figure C200480009860D03091
Figure C200480009860D03101
Figure C200480009860D03111
Figure C200480009860D03121
Figure C200480009860D03131
Figure C200480009860D03151
Figure C200480009860D03171
Figure C200480009860D03181
Figure C200480009860D03191
Figure C200480009860D03201
Synthetic as the pyrrolidyl aniline of intermediate
[1-(4-amino-2-chlorophenyl) tetramethyleneimine-3-yl] dimethyl amine
Method C-a
3-dimethylamino tetramethyleneimine (0.34g) is slowly added in DMF (5 milliliters) solution of 2-chloro-1-fluoro-4-oil of mirbane (0.52g).After 1 hour, ethyl acetate (30 milliliters) is added in the reaction mixture, and extract with 10% hydrochloric acid (2 * 20 milliliters).Water is adjusted to pH with ethyl acetate (2 * 20 milliliters) washing with 10% ammonia〉10 and use ethyl acetate extraction.With yellow solution dried over sodium sulfate, filtration and concentrated in rotatory evaporator.Then residue is dissolved in methylene dichloride (50 milliliters), adds zinc (10g), and slowly drip glacial acetic acid (5 milliliters) during the Yu Bingzhong cooling.Suspension was stirred 15 minutes, filter, with 10% ammonia (2 * 20 milliliters) washing and concentrated.The molecular weight of product that obtains is 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),
5-amino-2-(3-dimethylamino tetramethyleneimine-1-yl) benzonitrile
The dimethylamino tetramethyleneimine is handled with 2-fluoro-5-nitrobenzonitrile, reduced according to method C-a then.The molecular weight of product that obtains is 230.32 (C13H18N4); MS (ESI): 231 (M+H+),
[1-(4-amino-3-chlorophenyl) tetramethyleneimine-3-yl] dimethyl amine
The dimethylamino tetramethyleneimine is handled with 3-chloro-1-fluoro-4-oil of mirbane, reduced according to method C-a then.The molecular weight of product that obtains is 239.75 (C12H18ClN3); MS (ESI): 239 (M+H+), 240 (M+H+),
[1-(4-amino-3-aminomethyl phenyl) tetramethyleneimine-3-yl] dimethyl amine
The dimethylamino tetramethyleneimine is handled with 4-fluoro-2-methyl isophthalic acid-oil of mirbane, reduced according to method C-a then.The molecular weight of product that obtains is 219.33 (C13H21N3); MS (ESI): 220 (M+H+).
(R)-[1-(4-amino-2-fluoro phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Method C-b
(R)-(+)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester (1.86g) is slowly added 3, in DMF (10 milliliters) suspension of 4-two fluoro oil of mirbane (1.59g) and salt of wormwood (2.8g).After 10 minutes, add ethyl acetate (50 milliliters), the mixture water washs (3 * 50 milliliters) in separating funnel, use dried over sodium sulfate, filters and concentrates.Residue is dissolved in DMF (10 milliliters), and adds sodium hydride (0.48g).After 15 minutes, add methyl iodide (1.41g) during the Yu Bingzhong cooling.After 30 minutes, add ethyl acetate (50 milliliters), and the mixture water is washed (3 * 50 milliliters) in separating funnel, use dried over sodium sulfate, filter and concentrate.Then as this material of processing as described in the method B.The molecular weight of product that obtains is 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).
Obtain (S)-[1-(4-amino-2-fluoro phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester with similar method.
(R)-[1-(2-fluoro-4-sec.-propyl aminophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Adopt nitrilotriacetic base hydroborate as reductive agent, according to method N with (R)-[1-(4-amino-2-fluoro phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester acetone alkylation.The molecular weight of product that obtains is 351.47 (C19H30FN3O2); MS (ESI): 352 (M+H+).
(R)-[1-(2-fluoro-4-cyclobutyl aminophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
Adopt nitrilotriacetic base hydroborate as reductive agent, according to method N with (R)-[1-(4-amino-2-fluoro phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester cyclobutanone alkylation.The molecular weight of product that obtains is 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+).
(R)-[1-(2-fluoro-4-methylamino phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
As processing (R) as described in the method B-{ 1-[4-(phenmethyl oxygen base carbonyl methylamino)-2-fluoro phenyl] tetramethyleneimine-3-yl }-methyl carbamic acid tert-butyl ester.The molecular weight of product that obtains is 323.41 (C17H26FN3O2); MS (ESI): 324 (M+H+).
(R)-1-[4-(phenmethyl oxygen base carbonyl methylamino)-2-fluoro phenyl] tetramethyleneimine-3-yl }-the methyl carbamic acid tert-butyl ester
(R)-(+)-[1-(4-amino-2-fluoro phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester (0.93g) is added in methylene dichloride (30 milliliters) solution of N-(phenmethyl oxygen base ketonic oxygen base) succinimide (2.49g).After 12 hours, mixture washes (2 * 30 milliliters) with water, and dried over sodium sulfate is filtered and concentrated.Residue is from the acetonitrile recrystallization.The product that obtains like this is dissolved among the DMF (10 milliliters), and adds sodium hydride (0.24g).After 15 minutes, add methyl iodide (0.71g) during the Yu Bingzhong cooling.After 15 minutes, add ethyl acetate (50 milliliters), and wash mixture with water (3 * 30 milliliters), dried over sodium sulfate is filtered and is concentrated.The molecular weight of product that obtains is 457.55 (C25H32FN3O4); MS (ESI): 458 (M+H+).
(R)-[1-(2-fluoro-4-methylamino phenyl) tetramethyleneimine-3-yl] dimethyl amine
Handle (R)-{ 1-[4-(phenmethyl oxygen base carbonyl methylamino)-2-fluoro phenyl] tetramethyleneimine-3-yl } the methyl carbamic acid tert-butyl ester according to method G, and the amine that methylates and produce according to method M.At last, carry out hydrogenation according to method B.The molecular weight of product that obtains is 237.32 (C13H20FN3); MS (ESI): 238 (M+H+).
Similarly method prepares dimethyl-[1-(4-methylamino phenyl) tetramethyleneimine-3-yl] amine.
2-dimethylamino-N-[1-(2-fluoro-4-methylamino phenyl) tetramethyleneimine-3-yl]-the N-methylacetamide
Handle (R)-{ 1-[4-(phenmethyl oxygen base carbonyl methylamino)-2-fluoro phenyl] tetramethyleneimine-3-yl } the methyl carbamic acid tert-butyl ester according to method G, and according to method E with the amine and the N that produce, the reaction of N-N-methylsarcosine.At last, carry out hydrogenation according to method B.The molecular weight of product that obtains is 308.40 (C16H25FN4O); MS (ESI): 309 (M+H+).
(R)-[1-(4-amino-3-fluoro phenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
With 2,4-two fluoro oil of mirbane are handled with (R)-(+)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester, methylate, then according to method C-b hydrogenation.The molecular weight of product that obtains is 309.39 (C16H24FN3O2); MS (ESI): 310 (M+H+).
[1-(4-amino naphthalenes-1-yl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
Method C-c
The methylpyrrolidin-3-aminocarbamic acid tert-butyl ester (1.86g) is slowly added in DMF (10 milliliters) suspension of 4-fluoro-1-nitro-naphthalene (1.91g) and salt of wormwood (2.8g).After 10 minutes, add ethyl acetate (50 milliliters), and the mixture water is washed (3 * 50 milliliters) in separating funnel, use dried over sodium sulfate, filter and concentrate.Then as this material of processing as described in the method B.The molecular weight of product that obtains is 341.46 (C20H27N3O2); MS (ESI): 342 (M+H+).
[1-(4-amino-3-bromo phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-bromo-4-fluoro-1-oil of mirbane is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, reduced according to method C-a then.The molecular weight of product that obtains is 370.29 (C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+).
[1-(4-amino-3-cyano-phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-cyano group-4-fluoro-1-oil of mirbane is handled, reduced according to method C-a then with methylpyrrolidin-3-base-t-butyl carbamate.The molecular weight of product that obtains is 316.41 (C17H24N4O2); MS (ESI): 317 (M+H+).
[1-(5-amino-6-chloro-pyridine-2-yl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-6-fluoro-3-nitropyridine is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, reduced according to method C-c then.The molecular weight of product that obtains is 326.83 (C15H23ClN4O2); MS (ESI): 326 (M+H+), 327 (M+H+).
[1-(4-amino-2,3-phenyl-difluoride base) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
With 2,3,4-three fluoro oil of mirbane are handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, reduce according to method C-c then.The molecular weight of product that obtains is 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).
[1-(4-amino-2-bromo phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
3-bromo-4-fluoro-1-oil of mirbane is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, reduced according to method C-a then.The molecular weight of product that obtains is 370.29 (C16H24BrN3O2); MS (ESI): 370 (M+H+), 372 (M+H+).
[1-(4-amino-2,6-phenyl-difluoride base) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
With 3,4,5-three fluoro oil of mirbane are handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).
(R)-[1-(4-amino-2-hydroxymethyl phenyl) tetramethyleneimine-3-yl] t-butyl carbamate
(2-fluoro-5-nitrophenyl) methyl alcohol is handled with (R)-(+)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 307.40 (C16H25N3O3); MS (ESI): 308 (M+H+).
[1-(4-amino-2-chlorophenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-1-fluoro-4-oil of mirbane is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 311.81 (C15H22ClN3O2); MS (ESI): 311 (M+H+), 312 (M+H+).
[1-(4-amino-2,5-phenyl-difluoride base) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
With 3,4,6-three fluoro oil of mirbane are handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 327.38 (C16H23F2N3O2); MS (ESI): 328 (M+H+).
[1-(4-amino-2-methyl phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
4-fluoro-3-methyl oil of mirbane is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
[1-(4-amino-3-three fluoro aminomethyl phenyls) tetramethyleneimine-3-ylmethyl t-butyl carbamate
4-fluoro-2-three fluoro methyl oil of mirbane are handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).
[1-(4-amino-2-chloro-3-fluoro phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
With 2,4-two fluoro-3-chloronitrobenzene is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 329.80 (C15H21ClN3O2); MS (ESI): 329 (M+H+), 330 (M+H+).
[1-(4-amino-2-cyano-phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
3-cyano group-4-fluoro oil of mirbane is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 302.38 (C16H22N4O2); MS (ESI): 303 (M+H+).
[1-(4-amino-5-chloro-2-aminomethyl phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
1-chloro-5-fluoro-4-methyl-2-oil of mirbane is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 325.84 (C16H24ClN3O2); MS (ESI): 325 (M+H+), 326 (M+H+).
(R)-[1-(5-aminopyridine-2-yl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
2-chloro-5-nitropyridine is handled with (R)-(+)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester, then according to method C-b hydrogenation.The molecular weight of product that obtains is 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).
[1-(5-aminopyridine-2-yl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-5-nitropyridine is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 322.37 (C16H24FN3O2); MS (ESI): 323 (M+H+).
(R)-[1-(4-aminophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester
4-fluoro oil of mirbane is handled with (R)-(+)-tetramethyleneimine-3-base-t-butyl carbamate, then according to method C-b hydrogenation.The molecular weight of product that obtains is 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
[1-(4-amino-2-three fluoro aminomethyl phenyls) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
4-fluoro-3-three fluoro methyl oil of mirbane are handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 345.37 (C16H22F3N3O2); MS (ESI): 346 (M+H+).
[1-(5-amino-4-picoline-2-yl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-4-methyl-5-nitro pyridine is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).
[1-(5-amino-3-picoline-2-yl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-3-methyl-5-nitro pyridine is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 306.419 (C16H26N4O2); MS (ESI): 306 (M+H+), 307 (M+H+).
[1-(4-amino-2-hydroxymethyl phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
(2-fluoro-5-nitrophenyl) methyl alcohol is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 321.42 (C17H27N3O3); MS (ESI): 322 (M+H+).
[1-(4-amino-3-chloro-2-cyano-phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
2-chloro-6-fluoro-3-nitrobenzonitrile is handled with methylpyrrolidin-3-base-t-butyl carbamate, then according to method C-c hydrogenation.The molecular weight of product that obtains is 350.5 (C17H23ClN4O2); MS (ESI): 350 (M+H+), 351 (M+H+).
[1-(4-amino-3-aminomethyl phenyl) tetramethyleneimine-3-yl] methyl carbamic acid tert-butyl ester
4-fluoro-2-methyl oil of mirbane is handled with the methylpyrrolidin-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 291.40 (C16H25N3O2); MS (ESI): 292 (M+H+).
[1-(5-aminopyridine-2-yl) tetramethyleneimine-3-yl] t-butyl carbamate
2-chloro-5-nitropyridine is handled with (R)-(+)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester, then according to method C-c hydrogenation.The molecular weight of product that obtains is 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).
5-(3-dimethylamino tetramethyleneimine-1-yl) pyridine-2-base amine
In 100 ℃, with 5-bromo-2-nitropyridine (2g), 3-(dimethylamino) tetramethyleneimine (1.14g), (R)-(+) 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene (0.5g), acid chloride (II) (0.09g), toluene (20 milliliters) suspension of cesium carbonate (4.5g) heating 3 hours.Be cooled to room temperature and use 1N hydrochloric acid (2 * 100 milliliters) extraction then.Water is adjusted to pH with ammonia〉10, with ethyl acetate (2 * 100 milliliters) extraction, use dried over sodium sulfate, filter and concentrate.Then as this material of processing as described in the method B.The molecular weight of product that obtains is 206.29 (C11H18FN4); MS (ESI): 207 (M+H+).
N-[1-(4-aminophenyl)-4-hydroxyl pyrrolidine-3-yl]-the N-methylacetamide
According to method C, with the reaction of cis-N-(4-hydroxyl pyrrolidine-3-yl)-N-methylacetamide and 4-fluoro oil of mirbane, then with product according to method B hydrogenation.The molecular weight of product that obtains is 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+).
Trans-N-(4-hydroxyl pyrrolidine-3-yl)-N-methylacetamide
Trans-3-hydroxy-4-methyl amino-pyrrolidine-1-t-butyl formate (1.0g, tetrahedron: Asymmetry2001,12,2989) is mixed with pyridine (1.5g) and diacetyl oxide (0.567g).After 3 hours, under high vacuum, remove volatile fraction.Residue is handled according to method G.The molecular weight of product that obtains is 158.20 (C7H14N2O2); MS (ESI): 159 (M+H+).
Anti-form-1-(4-aminophenyl)-4-dimethylamino tetramethyleneimine-3-alcohol
6-oxa--3-azabicyclo [3.1.0] hexane-3-t-butyl formate (2.0g, tetrahedron: Asymmetry2001,12,2989) and dimethyl amine (40% aqueous solution, 10 milliliters) were stirred 12 hours together.Enriched mixture and be allocated in water and ethyl acetate between.Organic phase is through dried over mgso and concentrated.Handle the crude product product according to method G.According to method C, make the amine and the reaction of 4-fluoro oil of mirbane of generation.The nitro-compound that produces is according to method B hydrogenation.The molecular weight of product that obtains is 221 (C12H19N3O); MS (ESI): 222 (M+H+).
[1-(4-aminophenyl)-4-methoxyl group tetramethyleneimine-3-yl] dimethyl amine
For the nitro-compound of preceding method preparation, also can be according to method F with the alkylation of methyl iodide, then according to method B hydrogenation.The molecular weight of product that obtains is 235 (C13H21N3O); MS (ESI): 236 (M+H+).
[1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine
Dimethyl pyrrolidine-3-base amine is reacted with 4-fluoro oil of mirbane according to method C, then with product according to method B hydrogenation.The molecular weight of product that obtains is 205.31 (C12H19N3); MS (ESI): 206 (M+H+).
1-(4-aminophenyl)-3-dimethylamino pyrrolidin-2-one
Tertiary sodium phosphate (3.56g) is added in acetonitrile (30 milliliters) solution of 4-N-methyl-p-nitroaniline (5.0g), and, add 2-bromo-4-chloro butyryl bromide (11g) in 0 ℃.After one hour, add water (10 milliliters) solution of sodium hydroxide (3.2g), and under room temperature with the mixture vigorous stirring.After 6 hours, add the equivalent sodium hydroxide solution again, and the mixture placement is spent the night.With the reaction soln dilute with water and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.In 80 ℃, toluene (20 milliliter) liquid of crude product product (0.5g) with dimethyl amine (160 milligrams) was heated 3 hours.The reaction soln dilute with water is also used ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.The crude product product is according to method B hydrogenation.The molecular weight of product that obtains is 219.29 (C12H17N3O); MS (ESI): 220 (M+H+).
Similarly method obtains 1-(4-aminophenyl)-3-(7-azabicyclo [2.2.1] heptan-7-yl) pyrrolidin-2-one.
4-[3-(7-azabicyclo [2.2.1] heptan-7-yl) tetramethyleneimine-1-yl] phenyl amine
THF (10 milliliters) solution of 1-(4-nitrophenyl)-3-(7-azabicyclo [2.2.1] heptan-7-yl) pyrrolidin-2-one (0.25g) and borine-THF mixture (the THF solution of 1M, 0.83 milliliter) mixed being incorporated in the boiling down 3 hours that refluxes.After reaction is finished, the mixture dilute with water also is adjusted to pH9-10 with hydrochloric acid (4N).Use ethyl acetate extraction, dry and concentrated organic phase, the crude product product that obtains is according to method B hydrogenation.The molecular weight of product that obtains is 257.38 (C16H23N3); MS (ESI): 258 (M+H+).
(R)-1 '-(4-aminophenyl)-[1,3 '] bipyrrolidine base-2-ketone
Handle [1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate according to method G.Crude product product (1.4g) is dissolved in acetonitrile (20 milliliters), and mixes with tertiary sodium phosphate (0.67g) and 4-chlorobutyroyl chloride (1.1g).After 2 hours, add water (10 milliliters) solution of sodium hydroxide (0.6g), and the vigorous stirring mixture.After 12 hours, add the equivalent sodium hydroxide solution again, and with mixture restir 24 hours.Spissated reaction soln is allocated in water and the ethyl acetate dry and concentrated organic phase.Residue is according to method B hydrogenation.The molecular weight of product that obtains is 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).
1-methyl piperidine-3-formic acid [(R)-and 1-(4-aminophenyl) tetramethyleneimine-3-yl] methyl nitrosourea
(R)-[1-(4-nitrophenyl) tetramethyleneimine-3-yl] the methyl carbamic acid tert-butyl ester is handled according to method G, and according to method E and 1-methyl piperidine-3-formic acid reaction.At last, carry out hydrogenation according to method E again.The molecular weight of product that obtains is 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).
Adopt N, the N-N-methylsarcosine obtains (R)-N-[1-(4-aminophenyl) tetramethyleneimine-3-yl with similar method]-2-dimethylamino-N-methylacetamide.
N-[(R)-1-(4-aminophenyl) tetramethyleneimine-3-yl]-N-(2-diethylamino ethyl) ethanamide
According to method B hydrogenation N-(2-diethylamino ethyl)-N-[(R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide.The molecular weight of product that obtains is 318.47 (C18H30N4O); MS (ESI): 319 (M+H+).
N-(2-diethylamino ethyl)-N-[(R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
Acetyl Chloride 98Min. (2.9g) is dissolved in 50 milliliters of anhydrous methylene chlorides, mixes, add N with 5.3 milliliters of triethylamines, N-diethyl-N '-[(R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl]-ethane-1, behind the 2-diamines (5.8g), under room temperature, stirred 30 minutes.Then, (checking through LCMS) adds water (10 milliliters) in the reactant, and mixture extracts with methylene dichloride (2 * 10 milliliters).The organic phase that merges is removed and is desolvated through dried over mgso, and the crude product product separates through silica gel chromatography (methylene chloride 10:1).The molecular weight of product that obtains is 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
N, N-diethyl-N '-[(R)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethane-1, the 2-diamines
According to method G, with (2-diethylamino ethyl)-[(R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (7.9g) and trifluoroacetic acid reaction.The molecular weight of product that obtains is 306.41 (C16H26N4O2); MS (ESI): 307 (M+H+).
(2-diethylamino ethyl)-[(R)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
[(R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (6.0g) is dissolved in 50 milliliters of N, in the dinethylformamide, after adding sodium hydride (1.1g), under room temperature, stirred 30 minutes, add chloroethyldiethylamine hydrochloride (4.1g) then.Under room temperature, dehumidify then and stirred the mixture 4 hours.Add entry (50 milliliters) stopped reaction, use ethyl acetate (3 * 50 milliliters) extraction then,, remove and desolvate through the organic phase that dried over mgso merges.The molecular weight of product that obtains is 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).
Piperidines-4-formic acid [4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] acid amides
According to method E, make piperidines-1,4-diformate mono-tert-butyl ester and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine are handled product according to method G then.The molecular weight of product that obtains is 316.45 (C18H28N4O); MS (ESI): 317 (M+H+).
As synthesizing of the required amine of intermediate
Spiral shell [1,3-benzo dioxole-2,1 '-pentamethylene]-5-amine
In 6 bar pressures, palladium carbon (10%, 0.1g) under the condition of Cun Zaiing, the hydrogenation spiral shell [5-nitro-1,3-benzo dioxole-2,1 '-pentamethylene] (8.8g) methyl alcohol (90 milliliters) solution.After following 30 minutes, filtering mixt also concentrates in room temperature.The molecular weight of product that obtains is 191.23 (C11H13NO2); MS (ESI): 192 (M+H+).
Spiral shell [5-nitro-1,3-benzo dioxole-2,1 '-pentamethylene]
In 10 ℃, with spiral shell [1,3-benzo dioxole-2,1 '-pentamethylene] (8.5g) 20 milliliters of dichloromethane solutions drop in 65% nitric acid (65 milliliters).In 5-10 ℃ after 2 hours,, separate organic phase, water dichloromethane extraction secondary with the mixture dilute with water.The organic phase that merges is washed with water to neutrality,, concentrates and crystallization in heptane through dried over sodium sulfate.The molecular weight of product that obtains is 221.21 (C11H11NO4); MS (ESI): 222 (M+H+).
Spiral shell [1,3-benzo dioxole-2,1 '-pentamethylene]
In refluxing down, in toluene (150 milliliters), pyrocatechol (11g) and cyclopentanone (9 milliliters) are refluxed in water trap with right-toluenesulphonic acids (0.18g).After 18 hours, enriched mixture and through chromatogram purification (silica gel, heptane/ethyl acetate 4:1).The molecular weight of product that obtains is 176.22 (C11H12O2); MS (ESI): 177 (M+H+).
5-chloro-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,4 '] bipyridyl-4 '-alcohol
In-78 ℃, with butyllithium (15% hexane solution; 7.6 milliliter) drop in diethyl ether (50 milliliters) solution of 2-bromo-5-chloro-pyridine (2.0g), after one hour, drip diethyl ether (10 milliliters) solution of uncle N--butoxy carbonyl-4-piperidone (2.1g).After 30 minutes, add entry carefully, and with the mixture ethyl acetate extraction.Organic phase is filtered and is concentrated through dried over sodium sulfate.Residue is handled according to method G.The molecular weight of product that obtains is 212.68 (C10H13ClN2O); MS (ESI): 213 (M+H+).
Can obtain following compound with similar method:
5-fluoro-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,4 '] bipyridyl-4 '-alcohol
6-chloro-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[3,4 '] bipyridyl-4 '-alcohol.
6-cyclopentyloxy pyridin-3-yl amine
In 80 ℃, the mixture of 2-hydroxyl-5-nitropyridine (1.4g), cyclopentyl bromination thing (1.5g) and salt of wormwood (3g) was heated 6 hours in DMF (20 milliliters).With the mixture dilute with water and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.Residue is through silica gel chromatography purifying (moving phase is ethyl acetate/heptane 1: 2).So the nitro-compound that obtains is according to method B hydrogenation.The molecular weight of product that obtains is 178.24 (C10H14N2O2); MS (ESI): 179 (M+H+).
6-(4-fluoro phenyl)-3-azabicyclo [4.1.0] heptane
In 0 ℃, the methylene dichloride (100 milliliters) of zinc ethyl (hexane solution of 1M, 19 milliliters) is mixed with trifluoroacetic acid (3 milliliters).After 20 minutes, add methylene dichloride (10 milliliters) liquid of methylene iodide (3 milliliters).Add 4-(4-fluoro phenyl)-1,2,3 then, the methylene dichloride of 6-tetrahydropyridine (3.0g) (10 milliliters) liquid, and under room temperature, stir the mixture and spend the night.After adding hydrochloric acid (1N), separate each phase and wash organic phase with water, also concentrate through dried over mgso.The molecular weight of product that obtains is 191.25 (C12H14FN); MS (ESI): 192 (M+H+).
Required carboxylic acid as intermediate synthetic
4-(4-methyl piperidine-1-yl) phenylformic acid
The water (2 milliliters) and ethylene glycol (8 milliliters) solution of 4-(4-methyl piperidine-1-yl) benzonitrile (1.2g) and potassium hydroxide (0.7g) are heated to backflow 3 hours.The dilute with water mixture washs and uses the 2N hcl acidifying with ethyl acetate.Suction filtering sedimentary product is dissolved in methylene dichloride, through dried over sodium sulfate, concentrates and from the diethyl ether crystallization, the molecular weight of product that obtains is 219.29 (C13H17NO2); MS (ESI): 220 (M+H+).
4-(4-methyl piperidine-1-yl) benzonitrile
In 180 ℃, with 4-methyl piperidine (1.00g) and 4-fluoro benzonitrile (1.21g) heating 1 hour.Then mixture is dissolved in ethyl acetate, water, 2N sodium hydroxide solution and saturated sodium bicarbonate solution washing through dried over sodium sulfate, concentrate, and from the crystallization of n-pentane.The molecular weight of product that obtains is 200.29 (C13H16N2); MS (ESI): 201 (M+H+).
4-butoxy naphthenic acid
Under Yu Bingzhong cooling, the ar gas environment, sodium hydride (2.78g) is added in the DMF solution of 4-hydroxyl naphthenic acid ethyl ester (10g) and butyl iodide (10.6g).After 12 hours, mixture is inclined on ice (200g),, wash (3 * 50 milliliters) then with water with ethyl acetate (100 milliliters) extraction.Concentrate organic phase, and mix with ethanol (50 milliliters) and 5N sodium hydroxide (30 milliliters).In 60 ℃ of heated solutions 4 hours.Be cooled to room temperature, regulate pH＜2,,, filter and concentrate through dried over mgso with ethyl acetate (3 * 50 milliliters) extraction with 2N hydrochloric acid.The molecular weight of product that obtains is 200.28 (C11H20O3); MS (ESI): 201 (M+H+).
1-phenmethyl-1H-[1,2,3] triazole-4-formic acid
With 1-phenmethyl-1H-[1,2,3] triazole-4-methyl-formiate (217 milligrams) is dissolved in 4 ml methanol, and with the hydrolysis of 2 milliliters of 2N sodium hydroxide solutions.Behind 4 milliliters of 2N hcl acidifyings, leach the throw out of generation, be dissolved in 5 milliliters of ethyl acetate and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 203.2 (C10H9N3O2); MS (ESI): 204 (M+H+).
1-phenmethyl-1H-[1,2,3] triazole-4-methyl-formiate
Phenmethyl trinitride (266 milligrams) is dissolved in 8 milliliters of solvent mixtures (uncle-butanol/water 3:1) with sodium ascorbate (20 milligrams) and copper sulfate (5 milligrams), adds methyl propionate (336 milligrams).Stirred solution is 2 hours under room temperature.Isolate white depositions, suction leaches through the filter plate, and is dry then.The molecular weight of product that obtains is 217.23 (C11H11N3O2); MS (ESI): 218 (M+H+).
Prepare 1-xenyl-4-base-1H-[1,2,3 from 4-ethynyl biphenyl and nitrine ethyl acetate similarly] triazole-4-formic acid.
1-butyl-1H-indole-5-carboxylic acid
(50% oil solution 1.4g) adds among the DMF (100 milliliters) of 1H-indole-5-carboxylic acid methyl esters (5.0g), after no longer including the gas generation, adds butyl bromide (3.9g) with sodium hydride.After 12 hours, reaction soln dilutes with ethyl acetate and washes with water 3 times.Organic phase is through dried over mgso and concentrated.Residue is through silica gel chromatography purifying (moving phase: ethyl acetate/heptane 1:6).The gained ester is dissolved in methyl alcohol (10 milliliters) and with the boiling 12 hours that refluxes of water (10 milliliters) solution of sodium hydroxide (0.6g).The dilute with water mixture is also used hcl acidifying, uses ethyl acetate extraction subsequently.Organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).
3 '-acetylamino xenyl-4-formic acid
3 '-phenylaniline base-4-formic acid (0.2g) mixes with pyridine (0.7g) and diacetyl oxide (180 milligrams), after 14 hours, removes volatile fraction.Residue is dissolved in sodium hydroxide solution (2N) and washs with diethyl ether.Water is with hcl acidifying and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 255.28 (C15H13NO3); MS (ESI): 256 (M+H+).
3 '-isobutyryl phenylaniline base-4-formic acid
With 3 '-phenylaniline base-4-formic acid (0.2g) mixes with salt of wormwood (121 milligrams) and isobutyryl chloride (94 milligrams) in methylene dichloride.After 12 hours, mixture dilutes with sodium hydroxide solution, washs with diethyl ether.Water is with hcl acidifying and use ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.The molecular weight of product that obtains is 283.33 (C17H17NO3); MS (ESI): 284 (M+H+).
5-butoxy pyridine-2-formic acid
Sodium hydride (50% oil solution, 250 milligrams) adds in the 5-pyridone-2-formic acid benzhydryl ester (2.0g) that is dissolved in DMF (20 milliliters), after no longer including the gas generation, adds 1-butyl bromide (0.72g).In 90 ℃ of heated mixt 6 hours.Dilute with water is also used ethyl acetate extraction.Organic phase is through dried over mgso and concentrated.Be similar to method B with residue hydrogenation.The molecular weight of product that obtains is 195.22 (C10H13NO3); MS (ESI): 196 (M+H+).
4-methyl-3,4,5,6-tetrahydrochysene-2H-[1,3 '] bipyridyl-6 '-formic acid
In 80 ℃, with 5-three fluoro methylsulfonyl oxygen yl pyridines-2-formic acid benzhydryl esters (3.0g) and 4-methyl piperidine (1.4g) heating 1 hour.Reaction mixture is rapidly through preparation property high-efficient liquid phase chromatogram purification, then with similar approach hydrogenation.The molecular weight of product that obtains is 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] to the carbamyl yl benzoic acid
Method P-a
Under room temperature, will be dissolved in N-[4-(the 3-dimethylamino tetramethyleneimine-1-yl) phenyl of methyl alcohol (20 milliliters)] formamyl methyl benzoate (1.7g) and sodium hydroxide solution (2N, 15 milliliters) were stirred 24 hours together.Do not finish if transform, can be heated to backflow yet.Organic solvent is removed in distillation, and with the mixture hcl acidifying.Isolated throw out suction leaches and is dry.The molecular weight of product that obtains is 353.42 (C20H23N3O3); MS (ESI): 354 (M+H+).
N-[4-(3-dimethylamino tetramethyleneimine-1-yl) phenyl] to the formamyl methyl benzoate
According to method E, make the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl] dimethyl amine and terephthalic acid mono-methyl.The molecular weight of product that obtains is 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).
4-(pentamethylene carbonyl methylamino) phenylformic acid
According to method E, make the reaction of 4-methylamino methyl benzoate and cyclopentane-carboxylic acid, then according to method P-a hydrolysis.The molecular weight of product that obtains is 247.30 (C14H17NO3); MS (ESI): 248 (M+H+).
Can obtain following compounds with similar approach:
4-(pentamethylene carbonylamino)-3-methoxybenzoic acid,
2-chloro-4-(pentamethylene carbonylamino) phenylformic acid,
2-fluoro-4-(pentamethylene carbonylamino) phenylformic acid,
4-(pentamethylene carbonylamino)-3-tolyl acid,
4-(pentamethylene carbonylamino) phenylformic acid,
4-(pentamethylene carbonylamino)-3-three fluoro methoxybenzoic acids,
3-chloro-4-(pentamethylene carbonylamino) phenylformic acid,
5-chloro-4-(pentamethylene carbonylamino)-O-Anisic Acid,
4-[(hexamethylene-1-alkene carbonyl) amino] phenylformic acid,
4-[(ring penta-1-alkene carbonyl) amino] phenylformic acid.
3-fluoro-4-(1-methyl butoxy) phenylformic acid
With 0.449g1-[3-fluoro-4-(1-methyl butoxy) phenyl] 6.8 milliliters of dioxane solutions of ethyl ketone drop in 1.36g NaOH, 1.6g bromine and 6.8 ml waters.Under room temperature, stirred the mixture 30 minutes, then in 50 ℃ of heating 1 hour.Add the bromide of sodium sulfite solution decomposing excessive, then solution is inclined to 25% hydrochloric acid soln, stirred 20 minutes.Use ethyl acetate extraction solution.The organic phase that merges is through dried over sodium sulfate, vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 226.1 (C12H15FO3); MS (ESI): 227 (M+H+).
1-[3-fluoro-4-(1-methyl butoxy) phenyl] ethyl ketone
0.058g NaH is added in 2 milliliters of DMF solution of 0.176g2-amylalcohol, stirred solution is 1 hour under room temperature.Add 0.312g3 then, 4-two fluoro phenyl methyl ketones are in the stirring at room mixture overnight.Reaction soln is dissolved in ethyl acetate and washes with water twice.Organic phase is through dried over sodium sulfate and vacuum concentration.The compound that produces can be used for further reaction without being further purified.
Can obtain following compounds with similar approach:
4-cyclobutoxy group-3-fluorinated acid,
3-fluoro-4-(2-methyl cyclo propyl methoxy) phenylformic acid,
4-(2-cyclopropyl oxyethyl group)-3-fluorinated acid,
3-fluoro-4-(1-methyl piperidine-3-base oxygen base) phenylformic acid,
4-(1-ethanoyl piperidines-3-base oxygen base)-3-fluorinated acid,
3-fluoro-4-(1-methylpyrrolidin-3-base oxygen base) phenylformic acid,
4-(1-acetyl-pyrrolidine-3-base oxygen base)-3-fluorinated acid,
3-fluoro-4-(1-methyl piperidine-3-ylmethoxy) phenylformic acid.
4-(2,4-phenyl-difluoride oxygen base) phenylformic acid
0.518g potassium hydroxide is added in 2mlTHF/ water (1:1) solution of 0.428g4-(2,4-phenyl-difluoride oxygen base) ethyl benzoate.In 110 ℃ of heated solutions 6 hours.Vacuum is removed THF, water freeze-drying and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 250.04 (C13H8F2O3); MS (ESI): 251 (M+H+).
4-(2,4-phenyl-difluoride oxygen base) ethyl benzoate
0.018g NaH is added to 0.1g2, in 0.5 milliliter of DMF solution of 4-phenyl-difluoride phenol.In stirring at room reactant 45 minutes.Be added dropwise to 0.5 milliliter of DMF of 0.129g4-fluorinated acid ethyl ester then.Spend the night in 110 ℃ of reacting by heating things.The cooling final vacuum concentrates, and residue is dissolved in ethyl acetate/water.Ethyl acetate washes with water 3 times mutually, through dried over sodium sulfate, and vacuum concentration and through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 278.08 (C15H12F2O3); MS (ESI): 279 (M+H+)
According to method E-b, make 4-(2,4-phenyl-difluoride oxygen base) phenylformic acid and the reaction of [1-(4-aminophenyl) tetramethyleneimine-3-yl]-dimethyl amine.The molecular weight of product that obtains is 437.19 (C25H25F2N3O2); MS (ESI): 438 (M+H+) are the trifluoroacetic acid hydrogen salt.
4-butoxy-3-methoxybenzoic acid
According to method H, make the alkylation of vanillic acid methyl esters with butyl bromide, and according to method P-a hydrolysis.The molecular weight of product that obtains is 224.26 (C12H16O4); MS (ESI): 225 (M+H+).
Following compounds also can adopt the similar approach preparation:
4-butoxy-3,5-dichlorobenzene formic acid,
4-butoxy-3-nitrobenzoic acid,
4-butoxy-3-chlorinated benzene formic acid,
4-butoxy-3, the 5-mesitylenic acid,
4-butoxy-2,3-dichloro--5-methoxybenzoic acid,
4-butoxy-2,3,5,6-tetrafluoro be for phenylformic acid,
4-butoxy-3-fluorinated acid,
3-ethanoyl-4-butyl phenyl ether formic acid,
2,4-dibutoxy phenylformic acid,
4-butoxy-2-chlorinated benzene formic acid.
4-propoxy-tolyl acid
With sodium hydride (50% oil solution; 0.42g) carefully add in DMF (8 milliliters) solution of propyl alcohol (0.6g).After no longer including the gas generation, add 4-bromomethyl methyl benzoate (1.0g).After 4 hours, mixture is allocated between water and the ethyl acetate.Organic phase is through dried over mgso and concentrated.According to method P-a with the residue hydrolysis.The molecular weight of product that obtains is 194.23 (C11H14O3); MS (ESI): 195 (M+H+).
Following compounds also can adopt the similar approach preparation:
4-(ethoxymethyl) yl benzoic acid,
4-butoxymethyl phenylformic acid,
4-isobutoxy tolyl acid,
4-phenoxymethyl phenylformic acid,
4-(pyridin-3-yl oxygen ylmethyl) phenylformic acid,
4-(pyridine-2-base oxygen ylmethyl) phenylformic acid,
4-benzoglyoxaline-1-ylmethyl phenylformic acid,
4-indoles-1-ylmethyl phenylformic acid,
4-thiophenyl tolyl acid,
4-(pyrimidine-2-base sulfane ylmethyl) phenylformic acid,
4-(pyridine-2-base sulfane ylmethyl) phenylformic acid,
4-(2-cyano-benzene oxygen methyl) phenylformic acid,
4-(2-chloro phenoxymethyl) phenylformic acid,
4-cyclobutoxy group tolyl acid,
4-cyclopentyloxy tolyl acid,
4-cyclohexyl oxygen ylmethyl phenylformic acid,
4-second month in a season-butoxymethyl phenylformic acid,
4-pentyloxy tolyl acid.
4-(3-oxo-3a, 4,5,6-tetrahydrochysene-3H-cyclopenta pyrroles-2-yl) phenylformic acid
Ethanol (12 milliliters) solution with 4-hydrazino-benzoic acid (0.3g), 2-oxo-cyclopentane ethyl formate (0.31g) and right-toluenesulphonic acids (340 milligrams) under refluxing seethed with excitement 12 hours.Concentrated reaction solution is through preparation property high-efficient liquid phase chromatogram purification.According to the isolating reaction product of method P-a hydrolysis (as ethyl ester).The molecular weight of product that obtains is 244.25 (C13H12N2O3); MS (ESI): 245 (M+H+).
4-butoxy-O-Anisic Acid
According to method H, use the 1-butyl bromide with 4-hydroxyl-2-methoxybenzaldehyde alkylation.(6.4g) De diox (100 milliliters) solution mixes with SODIUM PHOSPHATE, MONOBASIC (14.4g) and sulfuric acid (2.4 milliliters) gained aldehyde, cooling solution to 10 ℃.Make temperature be no more than 10 ℃ of water (100 milliliters) solution that add Textone (3.61g) down.Add finish after 15 minutes, add S-WAT (4.6g) again.After 15 minutes, with pH regulator to 2, in rotatory evaporator, remove diox with hydrochloric acid.The water ethyl acetate extraction.Organic phase is filtered and is concentrated through dried over mgso.Residue is through preparation property high-efficient liquid phase chromatogram purification.The molecular weight of product that obtains is 224.26 (C12H16O4); MS (ESI): 225 (M+H+).
Obtain 4-butoxy-5-chloro-O-Anisic Acid as by product.
4-(1-propoxy-ethyl) phenylformic acid
4-(1-hydroxyethyl) methyl benzoate (2.0g) that will be dissolved in DMF (30 milliliters) mixes with propyl group iodide (3.8g), add then sodium hydride (50% oil solution, 0.53g).After exothermic reaction is finished, stirred the mixture 1 hour, carefully add entry then.Use ethyl acetate extraction, organic phase is filtered and is concentrated through dried over sodium sulfate.According to method P-a hydrolysis residue.The molecular weight of product that obtains is 208.26 (C12H16O3); MS (ESI): 209 (M+H+).

Claims (12)

1. the salt that can tolerate on formula I compound or its physiology:
Figure C200480009860C00021
Wherein:
R1, R2 are H, (C independently of one another 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) sO (R25); Or R1 and R2 form 4-10 unit's monocycle or volution with the nitrogen-atoms that they were connected, and this ring also can comprise the individual heteroatoms that is selected from oxygen, nitrogen in addition of 0-2 except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, hydroxyl;
Q is 1;
S is 0;
R13, R14 are benzyl ring or pyridyl independently of one another;
R15, R16, R17, R25, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is (C 1-C 6)-alkyl, CO (R33);
Perhaps
R17 forms 5-6 unit ring with R18 with the nitrogen-atoms that they were connected;
R33 is a phenyl, can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl;
R12 is OH, O-(C 1-C 6)-alkyl, CN, S-(C 1-C 6)-alkyl, COO (R80), CON (R81) (R82), saturated C 3-C 7The C of cycloalkyl, saturated or fractional saturation 7-C 10Bicyclic alkyl, phenyl, comprise 1 or 2 heteroatomic 5-10 unit monocycle or bicyclic heterocyclic radical that is selected from N, O and S, comprise 1-3 heteroatomic 5-6 unit heteroaryl that is selected from N, O and S, above-mentioned ring can comprise in addition and is selected from following substituting group: F, Cl, Br, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, N (R34) (R35), COCH=CH (R36), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40), S (O) u(R41); 5 membered nitrogen-containing heteroaryl bases, (C 0-C 8) the alkylidene group phenyl;
U is 2;
R34, R35 and R38 are (C independently of one another 1-C 8)-alkyl;
R36 is 5 yuan and contains the oxa-aryl;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 6)-alkylidene group-phenyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH;
R80, R81 and R82 are (C independently of one another 1-C 8)-alkyl;
R3 is H;
R4, R5 be independently of one another H, OH;
R6, R7, R8, R9 are H;
Perhaps
R6 and R7, R8 and R9 are optional independently of one another to be oxo;
N is 1;
M is 1;
A, B, D, G are N, C (R42) independently of one another;
Group D and G are C (R42), and form a neighbour-phenylene-unit together, obtain one 1, the dibasic naphthalene of 4-system;
R42 is H, F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
X is a key;
R52, R53, R54 are H, (C independently of one another 1-C 8)-alkyl;
E is selected from following groups:
Figure C200480009860C00041
With
Figure C200480009860C00043
Above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
R57, R58 are H independently of one another;
R65 is H or (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C=C, C ≡ C, SCH 2
V is 1;
R66, R67, R68, R69, R70 are H independently of one another;
R11 is H, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, C 3-C 7Cycloalkyl, 7-10 unit's three rings or spiro cycloalkyl group, C 3-C 7Cycloalkenyl group, phenyl, naphthyl, contain heteroatomic 5-6 unit heteroaryl that 1-3 is selected from N, S and O, contain 1 or 2 the heteroatomic 9 yuan of bicyclic heteroaryls that are selected from N, S and O, contain 1 or 2 heteroatomic 5-6 unit saturated heterocyclyl that is selected from N, S and O, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, phenyl, oxo, CO (R71), COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3
R71, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Prerequisite is if K is a key, and R11 is not a hydrogen so.
2. the salt that can tolerate on claim 1 formula I compound required for protection or its physiology: wherein:
R1, R2 are H, (C independently of one another 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18), CO (C (R23) (R24)) sO (R25); Or R1 and R2 form 4-10 unit's monocycle or dicyclo with the nitrogen-atoms that they connected, and this ring also comprises the individual heteroatoms that is selected from oxygen, nitrogen in addition of 0-2 except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl, N (R31) are (R32);
Q is 1;
S is 0;
R13, R14 are benzyl ring or pyridyl independently of one another;
R15, R16, R17, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is (C 1-C 6)-alkyl;
Perhaps
R17 forms a 5-6 unit ring that is selected from following groups with R18 with the nitrogen-atoms that they were connected:
Tetramethyleneimine, piperidines, N methyl piperazine, morpholine;
R12 is OH, O-(C 1-C 6)-alkyl, CN, saturated C 3-C 7The C of cycloalkyl, saturated or fractional saturation 7-C 10Bicyclic alkyl, phenyl, comprise 1 or 2 heteroatomic 5-10 unit monocycle or bicyclic heterocyclic radical that is selected from N, O and S, comprise 1-3 heteroatomic 5-6 unit heteroaryl that is selected from N, O and S, above-mentioned ring can comprise in addition and is selected from following substituting group: F, Cl, Br, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, N (R34) (R35), CO (C 1-C 6)-alkyl; 5 membered nitrogen-containing heteroaryl bases, (C 0-C 8) the alkylidene group phenyl;
U is 2;
R34, R35 are (C independently of one another 1-C 8)-alkyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH;
R3 is H;
R4, R5 are H, OH independently of one another;
R6, R7, R8, R9 are H;
N is 1
M is 1;
B is N, C (R42) among A, B, D, the G; D, G are C (R42);
R42 is H, F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
X is a key;
R52, R53, R54 are H, (C independently of one another 1-C 8)-alkyl;
E is selected from following groups:
Figure C200480009860C00061
Figure C200480009860C00062
With
Figure C200480009860C00063
Above-mentioned group can be chosen the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
R57, R58 are H independently of one another;
R65 is H or (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, N (R66), CON (R68), (C (R69) (R70)) v, CO, C ≡ C, SCH 2
V is 1;
R66, R68, R69, R70 are H independently of one another;
R11 is (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, C 3-C 7Cycloalkyl, 7-10 unit's three rings or spiro cycloalkyl group, C 3-C 7Cycloalkenyl group, phenyl, naphthyl, contain heteroatomic 5-6 unit heteroaryl that 1-3 is selected from N, S and O, contain 1 or 2 the heteroatomic 9 yuan of bicyclic heteroaryls that are selected from N, S and O, contain 1 or 2 heteroatomic 5-6 unit saturated heterocyclyl that is selected from N, S and O, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C1-C8)-alkyl, phenyl, oxo, CO (R71), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3
R71, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Prerequisite is if K is a key, and R11 is not a hydrogen so.
3. the salt that can tolerate on claim 1 formula I compound required for protection or its physiology:
Wherein:
R1, R2 are H, (C independently of one another 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl, CO (C (R15) (R16)) qN (R17) (R18), or R1 forms 4-10 unit's monocycle or dicyclo with R2 with the nitrogen-atoms that they were connected, this ring can comprise 0-2 the heteroatoms that is selected from oxygen and nitrogen in addition except nitrogen-atoms, described heterocycle ring system can further be replaced by following groups: F, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl, N (R31) are (R32);
Q is 1;
R15, R16, R17, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is (C 1-C 6)-alkyl;
Perhaps
R17 forms a 5-6 unit ring that is selected from following groups with R18 with the nitrogen-atoms that they were connected:
Tetramethyleneimine, piperidines, N methyl piperazine, morpholine;
R12 is OH, O-(C 1-C 6)-alkyl, saturated C 3-C 7The C of cycloalkyl, saturated or fractional saturation 7-C 10Bicyclic alkyl, phenyl, comprise 1 or 2 heteroatomic 5-10 unit monocycle or bicyclic heterocyclic radical that is selected from N, O and S, comprise 1-3 heteroatomic 5-6 unit heteroaryl that is selected from N, O and S, above-mentioned ring can comprise in addition and is selected from following substituting group: F, oxo, (C 1-C 6)-alkyl, CO (C 1-C 6)-alkyl; 5 membered nitrogen-containing heteroaryl bases, (C 0-C 8) the alkylidene group phenyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH;
R3 is H;
R4, R5 are H, OH independently of one another;
R6, R7, R8, R9 are H;
N is 1;
M is 1;
A, B, D, G are C (R42);
R42 is H, F, Cl, CF 3, CN, (C 1-C 6)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
X is a key;
R53, R54 are H, (C independently of one another 1-C 8)-alkyl;
E is
Figure C200480009860C00081
Figure C200480009860C00082
With
Figure C200480009860C00083
And can choose the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
R57, R58 are H independently of one another;
R65 is H, (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, CON (R68), (C (R69) (R70)) v, CO, C ≡ C;
V is 1;
R68, R69, R70 are H independently of one another;
R11 is (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, C 3-C 7Cycloalkyl, 7-10 unit's three rings or spiro cycloalkyl group, C 3-C 7Cycloalkenyl group, phenyl, naphthyl, contain heteroatomic 5-6 unit heteroaryl that 1-3 is selected from N, S and O, contain 1 or 2 the heteroatomic 9 yuan of bicyclic heteroaryls that are selected from N, S and O, contain 1 or 2 heteroatomic 5-6 unit saturated heterocyclyl that is selected from N, S and O, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, phenyl, oxo, CO (R71), N (R75) CO (C 1-C 6)-alkyl, or SO 2CH 3
R71, R75 are H, (C independently of one another 1-C 8)-alkyl;
Prerequisite is if K is a key, and R11 is not a hydrogen so.
4. the salt that can tolerate on claim 1 claimed compounds or its physiology is characterized by and has structural formula Ia:
Figure C200480009860C00091
Wherein
R1, R2 are H, (C independently of one another 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, or R1 forms 4-10 unit's monocycle or volution with nitrogen-atoms that R2 is connected with them, this ring also can comprise the individual heteroatoms that is selected from oxygen, nitrogen in addition of 0-2 except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, hydroxyl, N (R31) are (R32);
Q is 1;
S is 0;
R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R12 is OH, O-(C1-C6)-alkyl, CN, S-(C 1-C 6)-alkyl, saturated C 3-C 7The C of cycloalkyl, saturated or fractional saturation 7-C 10Bicyclic alkyl, phenyl, comprise 1 or 2 heteroatomic 5-10 unit monocycle or bicyclic heterocyclic radical that is selected from N, O and S, comprise 1-3 heteroatomic 5-6 unit heteroaryl that is selected from N, O and S, above-mentioned ring can comprise in addition and is selected from following substituting group: F, CF 3, CN, oxo, (C 1-C 6)-alkyl, N (R34) (R35), COO (R40), CO (C 1-C 6)-alkyl; 5 membered nitrogen-containing heteroaryl bases, (C 0-C 8) the alkylidene group phenyl; R34, R35 are (C independently of one another 1-C 4)-alkyl;
R40 is H, (C 1-C 6)-alkyl, (C 0-C 2)-alkylidene group-phenyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH;
R42, R42 ' are H, F, Cl, Br, CF independently of one another 3, CN, (C 1-C 6)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
X is a key;
R52, R53, R54 are H, (C independently of one another 1-C 8)-alkyl;
E is:
Figure C200480009860C00102
With
Figure C200480009860C00103
And can choose the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
R57, R58 are H independently of one another;
R65 is H, (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C ≡ C, SCH 2
V is 1,
R66, R67, R68, R69, R70 are H independently of one another;
R11 is (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, C 3-C 7Cycloalkyl, 7-10 unit's three rings or spiro cycloalkyl group, C 3-C 7Cycloalkenyl group, phenyl, naphthyl, contain heteroatomic 5-6 unit heteroaryl that 1-3 is selected from N, S and O, contain 1 or 2 the heteroatomic 9 yuan of bicyclic heteroaryls that are selected from N, S and O, contain 1 or 2 heteroatomic 5-6 unit saturated heterocyclyl that is selected from N, S and O, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, phenyl, oxo, CO (R71), N (R75) CO (C 1-C 6)-alkyl, or SO 2CH 3
R71, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Prerequisite is if K is a key, and R11 is not a hydrogen so.
5. the salt that can tolerate on the desired compound of claim 1 or its physiology is characterized in that they have formula Ib structure:
Figure C200480009860C00111
Wherein:
R1, R2 are H, (C independently of one another 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, CO-(C 1-C 8)-alkyl, COCH=CH (R13), COCC (R14), CO (C (R15) (R16)) qN (R17) (R18); Or R1 and R2 form 4-10 unit's monocycle or volution with the nitrogen-atoms that they were connected, and this ring can comprise the individual heteroatoms that is selected from oxygen, nitrogen in addition of 0-2 except nitrogen-atoms, and described heterocycle ring system can be replaced by following groups in addition: F, Cl, CF 3, (C 1-C 6)-alkyl, O-(C 1-C 4)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, hydroxyl-(C 1-C 4)-alkyl, hydroxyl;
Q is 1;
S is 0;
R13, R14 are phenyl or pyridyl ring independently of one another;
R15, R16, R17, R25, R31, R32 are H, (C independently of one another 1-C 6)-alkyl;
R18 is (C 1-C 6)-alkyl, CO (R33);
Perhaps
R17 forms 5-6 unit ring with R18 with the nitrogen-atoms that they were connected;
R33 is a phenyl, and can be replaced by following groups: F, Cl, (C 1-C 6)-alkyl;
R12 is OH, O-(C 1-C 6)-alkyl, CN, S-(C 1-C 6)-alkyl, COO (R80), CON (R81) (R82), saturated C 3-C 7The C of cycloalkyl, saturated or fractional saturation 7-C 10Bicyclic alkyl, phenyl, comprise 1 or 2 heteroatomic 5-10 unit monocycle or bicyclic heterocyclic radical that is selected from N, O and S, comprise 1-3 heteroatomic 5-6 unit heteroaryl that is selected from N, O and S, above-mentioned ring can comprise in addition and is selected from following substituting group: F, Cl, Br, CF 3, CN, oxo, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, N (R34) (R35), COCH=CH (R36), CO (C 1-C 6)-alkyl, COCOO (C 1-C 6)-alkyl, COO (R40), S (O) u(R41); 5 membered nitrogen-containing heteroaryl bases, (C 0-C 8) the alkylidene group phenyl;
U is 2;
R34, R35, R38 are (C independently of one another 1-C 8)-alkyl;
R36 is 5 yuan and contains the oxa-aromatic ring;
R40 is H, (C 1-C 8)-alkyl, (C 2-C 6)-alkenyl, (C 0-C 6)-alkylidene group-phenyl;
R78, R79 are H, (C independently of one another 1-C 8)-alkyl, hydroxyl-(C 1-C 4)-alkyl, OH;
R80, R81, R82 are (C independently of one another 1-C 8)-alkyl;
R10 is H, (C 1-C 8)-alkyl;
E is:
Figure C200480009860C00121
Figure C200480009860C00122
With
Figure C200480009860C00123
And can choose the substituting group with the following groups of being selected from: H, F, Cl, Br, OH, CF wantonly 3, NO 2, OCF 3, O-(C 1-C 6)-alkyl, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, N (R57) (R58), SO 2-CH 3, CO (R65);
R57, R58 are H independently of one another;
R65 is H, (C 1-C 8)-alkyl;
K is key, O, OCH 2, CH 2O, S, SO, SO 2, N (R66), N (R67) CO, CON (R68), (C (R69) (R70)) v, CO, C=C, C ≡ C, SCH 2, SO 2CH 2
V is 1;
R66, R67, R68, R69, R70 are H independently of one another;
R11 is H, (C 1-C 6)-alkyl, (C 1-C 4)-alkoxyl group-(C 1-C 4)-alkyl, (C 3-C 8)-alkenyl, C 3-C 7Cycloalkyl, 7-10 unit's three rings or spiro cycloalkyl group, C 3-C 7Cycloalkenyl group, phenyl, naphthyl, contain heteroatomic 5-6 unit heteroaryl that 1-3 is selected from N, S and O, contain 1 or 2 the heteroatomic 9 yuan of bicyclic heteroaryls that are selected from N, S and O, contain 1 or 2 heteroatomic 5-6 unit saturated heterocyclyl that is selected from N, S and O, described ring system can be replaced by following groups in addition: F, Cl, Br, CF 3, CN, (C 1-C 6)-alkyl, O-(C 1-C 8)-alkyl, phenyl, oxo, CO (R71), COO (R74), N (R75) CO (C 1-C 6)-alkyl, N (R76) are (R77) or SO 2CH 3
R71, R74, R75, R76, R77 are H, (C independently of one another 1-C 8)-alkyl;
Prerequisite is if K is a key, and R11 is not a hydrogen so.
6. pharmaceutical composition, this pharmaceutical composition contains claimed compounds among one or more claim 1-5.
7. produce the method contain the medicine of each one or more formula I compounds required for protection among the claim 1-5, described method comprises mixes above-mentioned activeconstituents and mixture is converted into a kind of form that is suitable for administration with appropriate carriers pharmaceutically.
8. each formula I compound required for protection is used for alleviating the purposes of the medicine of weight of mammal among the claim 1-5 in preparation.
9. each formula I compound required for protection is used for preventing or the purposes of the medicine of treatment of obesity in preparation among the claim 1-5.
10. each formula I compound required for protection is used for preventing or treating the purposes of the medicine of type ii diabetes among the claim 1-5 in preparation.
11. each arbitrary formula I compound required for protection is used for the treatment of disorder relevant with physiological period of healthy unbalance and other mental disorder, treatment and the purposes in the medicine drugs of addiction in preparation among the claim 1-5.
12. each formula I compound required for protection has purposes in the medicine of MCH-receptor antagonist activity in preparation among the claim 1-5.
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