WO2004060306A2 - Anti-inflammatory medicaments - Google Patents

Anti-inflammatory medicaments Download PDF

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Publication number
WO2004060306A2
WO2004060306A2 PCT/US2003/041449 US0341449W WO2004060306A2 WO 2004060306 A2 WO2004060306 A2 WO 2004060306A2 US 0341449 W US0341449 W US 0341449W WO 2004060306 A2 WO2004060306 A2 WO 2004060306A2
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group
phenyl
formula
compound
individually selected
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PCT/US2003/041449
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French (fr)
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WO2004060306A3 (en
Inventor
Daniel L. Flynn
Peter A. Petrillo
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Deciphera Pharmaceuticals, Llc
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Priority to MXPA05007236A priority Critical patent/MXPA05007236A/en
Priority to BR0317872-2A priority patent/BR0317872A/en
Priority to EP03808576A priority patent/EP1585734A4/en
Priority to AU2003303641A priority patent/AU2003303641A1/en
Priority to CA002513627A priority patent/CA2513627A1/en
Priority to JP2005508625A priority patent/JP2006514691A/en
Publication of WO2004060306A2 publication Critical patent/WO2004060306A2/en
Publication of WO2004060306A3 publication Critical patent/WO2004060306A3/en

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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/42One nitrogen atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/16Central respiratory analeptics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/06Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases.
  • This class of inhibitors binds to the ATP active site while also binding in a mode that induces movement ofthe kinase catalytic loop.
  • This class of inhibitors also interacts with the kinase at the ATP active site involving a concomitant movement ofthe kinase activation loop.
  • kinases utilize activation loops and kinase domain regulatory pockets to control their state of catalytic activity. This has been recently reviewed (see, e.g., M. Huse and J. Kuriyan, Cell (2002) 109:275).
  • the present invention is broadly concerned with new compounds for use in treating anti- inflammatory conditions and methods of treating such conditions.
  • the inventive compounds have the formula
  • R 1 is selected from the group consisting of aryls (preferably C 6 -C 18 , and more, preferably C 6 -C l2 ) and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NR 6 -,
  • alkynyls preferably C r C 18 , and more preferably C,-C 12
  • alkenyls preferably -C ⁇ , and more preferably C,-C 12
  • alkylenes preferably C,-C I8 , and more preferably C,-C ⁇ 2
  • one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH 2 ) h - the introduction ofthe side-chain oxo group does not form an ester moiety;
  • A is selected from the group consisting of aromatic (preferably C 6 -C 18 , and more preferably C 6 -C 12 ), monocycloheterocyclic, and bicycloheterocyclic rings;
  • D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl;
  • E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
  • Q is selected from the group consisting of
  • each R 4 group is individually selected from the group consisting of -H, alkyls (preferably
  • each R 5 is individually selected from the group consisting of -H, alkyls (preferably C r C 18 , and more preferably C]-C I2 ), alkoxyalkyls (preferably C r C 18 , and more preferably -C ⁇ ), aryls (preferably C 6 -C 18 , and more preferably C 6 -C 12 ), aralkyls (preferably C 6 -C 18 , and more preferably C 6 -C 12 and preferably C j -C j g, and more preferably C,-C 12 ), heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R 5 is individually selected from the group consisting of -H, alkyls (preferably C rc ,
  • heterocyclyls preferably C r C 18 , and more preferably C r
  • arylaminos preferably C 6 -C 18 , and more preferably C 6 -C I2
  • cyclo alkylaminos preferably C r C !8 , and more preferably C,-C I2
  • heterocyclylaminos hydroxys, alkoxys (preferably C r C 18 , and more preferably
  • each R 6 is individually selected from the group consisting of -H, alkyls (preferably C,-C 18 , and more preferably C r C 12 ), arylfhios (preferably C 6 -C 18 , and more preferably C 6 -C 12 ), cyanos, halogens, perfluoroalkyls (preferably C r C 18 , and more preferably C r C 12 ), alkylcarbonyls (preferably C r C 18 , and more preferably C r C 12 ), and nitros; each R 6 is individually selected from the group consisting of -H, alkyls (preferably C,-
  • cycloalkylaminos preferably C,-C 18 , and more preferably C,-C 12
  • heterocyclylaminos hydroxys, alkoxys (preferably C r C 18 , and more preferably
  • the compound has the structure of formula (I) except that: when Q is Q-3 or Q-4, then the compound of formula (I) is not
  • R80 is H, Me
  • R82 is substituted phenyl
  • R81 is substituted phenyl
  • R 10 alkyl, aryl, arylalkoxyalkyl, or arylalkyls
  • R! 1 H, alkyl, alkoxy, nitro, halogen
  • R12, R13 H, alkyl
  • R1 H, alkyl
  • allyl H
  • R15 H, alkyl
  • R 20 substituted phenyl
  • R 21 H, alkyl
  • fomiula (I) is not imidazophenyl; when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not
  • R :7 substituted phenyl, pyr idyl-arbonyl
  • R.j CN, metlioxyc-rbonyl n » 0 or 1 when Q is Q-16 and t is 0, then
  • R 29 alkyl
  • R 30 H, t-Bu, benzoyl
  • R 3 ⁇ substituted phenyl
  • each W is individually selected from the group consisting of -CH- and
  • each G is individually selected from the group consisting of -O-, -S-, and -N(R 4 )-;
  • each Z is individually selected from the group consisting of -O- and -N(R 4 )-; when Q is Q-31, then the compound of formula (I) is not
  • R 6 hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy
  • R.5 benzoyl, phenylalkylaminocarbonyl, substituted phenylaminocarbony! H, Br
  • R. 51 H, phenylsulfonyl, phenyl, benzyl
  • R 4 g H, alkyl, Br, substituted phenyl, benzoyl
  • R Et, i-Pr phenylsulfonyl
  • R 53 substituted phenyl, substituted benzyl
  • A is not phenyl; when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl; when Q is Q-32 and Y is an ether linlcage, then
  • R5S substituted alkylaminocarbonyl, plienylaminocarbonyl
  • R60 H
  • R59 H
  • R61 substituted phenyl, thienyl, Br
  • R62 H, alkyl, phenyl
  • R63 substituted phenyl when Q is Q-35 as shown
  • G is selected from the group consisting of-O-, -S-, -NR 4 -, and -CH 2 -, k is 0 or 1, and u is 1, 2, 3, or 4, then
  • R7 4 chlorophenyl
  • R is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls, and even more preferably, R j is selected from the group consisting of
  • each R 2 is individually selected from . the group consisting of -H, alkyls (preferably C,-C I8 , and more preferably C,-C I2 ), aminos, alkylaminos (preferably C,-C 18 , and more preferably C,-C 12 ), arylaminos (preferably C 6 -C ]8 , and more preferably C 6 -C 12 ), cycloalkylaininos (preferably C,-C 18 , and more preferably C,-C 12 ), heterocyclylaminos, halogens, alkoxys (preferably C,-C 18 , and more preferably C,-C ]2 ), and hydroxys; each R 3 is individually selected from the group consisting of -H, alkyls (preferably C,-C 18 , and more preferably C r C 12 ), alkylaminos (preferably C,-C 18 , and more preferably C j -C 12 ), arylaminos (preferably C 6 -C 18
  • V is selected from the group consisting of O and H 2 .
  • a as described above is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
  • each Wj is individually selected from the group consisting of -CH- and -N-.
  • the activation state of akinase is determined by the interaction of switch control ligands and complemental switch control pockets.
  • One conformation ofthe kinase may result from the switch control ligand's interaction with a particular switch control pocket while another conformation may result from the ligand's interaction with a different switch control pocket.
  • interaction ofthe ligand with one pocket, such as the "on" pocket results in the kinase assuming an active conformation wherein the kinase is biologically active.
  • an inactive conformation (wherein the kinase is not biologically active) is assumed when the ligand interacts with another of the switch control pockets, such as the "off pocket.
  • the switch control pocket can be selected from the group consisting of simple, composite and combined switch control pockets. Interaction between the switch control ligand and the switch control pockets is dynamic and therefore, the ligand is not always interacting with a switch control pocket. In some instances, the ligand is not in a switch control pocket (such as occurs when the protein is changing from an active conformation to an inactive conformation). In other instances, such as when the ligand is interacting with the environment surrounding the protein in order to determine with which switch control pocket to interact, the ligand is not in a switch control pocket. Interaction of the ligand with particular switch control pockets is controlled in part by the charge status ofthe amino acid residues ofthe switch control ligand.
  • the switch control ligand When the ligand is in a neutral charge state, it interacts with one ofthe switch control pockets and when it is in a charged state, it interacts with the other ofthe switch control pockets.
  • the switch control ligand may have a plurality of OH groups and be in a neutral charge state. This neutral charge state results in a ligand that is more likely to interact with one ofthe switch control pockets tlirough hydrogen boding between the OH groups and selected residues ofthe pocket, thereby resulting in whichever protein conformation results from that interaction.
  • the propensity ofthe ligand to interact with the other ofthe switch control pockets will increase and the ligand will interact with this other switch control pocket through complementary covalent binding between the negatively or positively charged residues ofthe pocket and ligand.
  • This will result in the protein assuming the opposite conformation assumed when the ligand was in a neutral charge state and interacting with the other switch control pocket.
  • the conformation ofthe protein determines the activation state ofthe protein and can therefore play a role in protein-related diseases, processes, and conditions. For example, if a metabolic process requires a biologically active protein but the protein' s switch control ligand remains in the switch control pocket (i.e.
  • One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 ⁇ -kinase and including both the consensus wild type sequence and disease polymorphs thereof.
  • the activation state is generally selected from an upregulated or downregulated state.
  • the method generally comprises the step of contacting the kinase with a molecule having the general fomiula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and a lesser propensity to interact with the occupied switch control pocket.
  • the protein will have a greater propensity to assume either an active or inactive conformation (and consequenctly be upregulated or downregulated), depending upon which ofthe switch control pockets is occupied by the molecule.
  • contacting the kinase with a molecule modulates that protein' s activation state.
  • the molecule can act as an antagonist or an agonist of either switch control pocket.
  • the contact between the molecule and the kinase preferably occurs at a region of a switch control pocket ofthe kinase and more preferably in an interlobe oxyanion pocket ofthe kinase.
  • the contact between the molecule and the pocket also results in the alteration ofthe conformation of other adjacent sites and pockets, such as an ATP active site.
  • an alteration can also effect regulation and modulation ofthe active state ofthe protein.
  • the region ofthe switch control pocket ofthe kinase comprises an amino acid residue sequence operable for binding to the Formula I molecule.
  • binding can occur between the molecule and a specific region ofthe switch control pocket with preferred regions including the -C helix, the oc-D helix, the catalytic loop, the activation loop, and the C-terminal residues or C-lobe residues (all residues located downstream (toward the C-end) from the Activation loop), and combinations thereof.
  • one preferred binding sequence in this helix is the sequence UXXKRXXREXXLLXXM, (SEQ ID NO. 2).
  • one preferred binding sequence in this loop is DIIHRD (SEQ ID NO. 3).
  • one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof.
  • one preferred binding sequence is WMHY (SEQ ID NO. 6).
  • the molecule will be administered to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft- versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
  • a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative se
  • the molecules of the present invention will be administerable in any conventional form including oral, parenteral, inhalation, and subcutaneous. It is preferred for the administration to be in the oral form.
  • Preferred molecules include the preferred compounds of fomiula (I), as discussed above.
  • Another aspect ofthe present invention provides a method of treating an inflammatory condition of an individual comprising the step of administering a molecule having the general formula (I) to the individual.
  • Such conditions are often the result of an overproduction of the biologically active fonn of a protein, including kinases.
  • the administering step generally includes the step of causing said molecule to contact a kinase involved with the inflammatory process, preferably p38 cc-kinase.
  • the contact preferably occurs in an interlobe oxyanion pocket ofthe kinase that includes an amino acid residue sequence operable for binding to the Fonnula I molecule.
  • Preferred binding regions ofthe interlobe oxyanion pocket include the ⁇ -C helix region, the ⁇ -D helix region, the catalytic loop, the activation loop, the C-tenninal residues, and combinations thereof.
  • the binding region is the ⁇ -C helix
  • one preferred binding sequence in this helix is the sequence IIXXKRXXREXXLLXXM, (SEQ ID NO. 2).
  • the binding region is the catalytic loop
  • one prefen-ed binding sequence in this loop is DIIHRD (SEQ ID NO. 3).
  • one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO.5), and combinations thereof.
  • DFGLARHTDD SEQ ID NO.4
  • EMTGYVATRWYR SEQ ID NO.5
  • Such a method pennits treatment of the condition by virtue of the modulation of the activation state of a kinase by contacting the kinase with a molecule that associates with the switch control pocket that nonnally leads to a biologically active fonn ofthe kinase when interacting with the switch control ligand.
  • the ligand cannot easily interact with the switch control pocket associated with or occupied by the molecule, the ligand tends to interact with the switch control pocket leading to the biologically inactive form ofthe protein, with the attendant result of a decrease in the amount of biologically active protein.
  • the inflammatory condition is selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
  • the molecules may be administered in any conventional fonn, with any convention excipients or ingredients. However, it is preferred to administer the molecule in an oral dosage form.
  • Preferred molecules are again selected from the group consisting ofthe prefened formula (I) compounds discussed above.
  • Figure 1 is a schematic representation of a naturally occurring mammalian protein in accordance with the invention including "on” and “off switch control pockets, a transiently modifiable switch control ligand, and an active ATP site;
  • Fig. 2 is a schematic representation ofthe protein of Fig. 1, wherein the switch control ligand is illustrated in a binding relationship with the off switch control pocket, thereby causing the protein to assume a first biologically downregulated confonnation;
  • Fig. 3 is a view similar to that of Fig. 1, but illustrating the switch control ligand in its charged-modified condition wherein the OH groups of certain amino acid residues have been phosphorylated;
  • Fig. 4 is a view similar to that of Fig. 2, but depicting the protein wherein the switch control ligand is in a binding relationship with the on switch control pocket, thereby causing the protein to assume a second biologically-active conformation different than the first conformation of Fig. 2;
  • Fig. 4a is an enlarged schematic view illustrating a representative binding between the phosphorylated residues of the switch control ligand, and complemental residues from the on switch control pocket;
  • Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic fonn possible small molecule compounds in a binding relationship with the on and off switch control pockets;
  • Fig. 6 is a schematic view ofthe protein in a situation where a composite switch control pocket is formed with portions ofthe switch control ligand and the on switch control pocket, and with a small molecule in binding relationship with the composite pocket;
  • Fig. 7 is a schematic view ofthe protein in a situation where a combined switch control pocket is formed with portions of the on switch control pocket, the switch control ligand sequence, and the active ATP site, and with a small molecule in binding relationship with the combined switch control pocket.
  • the present invention provides a way of rationally developing new small molecule modulators which interact with naturally occurring proteins (e.g., mammalian, and especially human proteins) in order to modulate the activity ofthe proteins.
  • Naturally occurring proteins e.g., mammalian, and especially human proteins
  • Novel protein-small molecule adducts are also provided.
  • the invention preferably makes use of naturally occurring proteins having a confomiational property whereby the proteins change their conformations in vivo with a conesponding change in protein activity.
  • a given enzyme protein in one conformation may be biologically upregulated, while in another confonnation, the same protein may be biologically downregulated.
  • the invention preferably makes use of one mechanism of confonnation change utilized by naturally occurring proteins, through the interaction of what are tenned "switch control ligands" and "switch control pockets" within the protein.
  • switch control ligand means a region or domain within a naturally occuning protein and having one or more amino acid residues therein which are transiently modified in vivo between individual states by biochemical modification, typically phosphorylation, sulfation, acylation or oxidation.
  • switch control pocket means a plurality of contiguous or non-contiguous amino acid residues within a naturally occurring protein and comprising residues capable of binding in vivo with transiently modified residues of a switch control ligand in one of the individual states thereof in order to induce or restrict the confonnation ofthe protein and thereby modulate the biological activity ofthe protein, and/or which is capable of binding with a non-naturally occurring switch control modulator molecule to induce or restrict a protein conformation and thereby modulate the biological activity ofthe protein.
  • a protein-modulator adduct in accordance with the invention comprises a naturally occurring protein having a switch control pocket with a non-naturally occun ⁇ ng molecule bound to the protein at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein.
  • the protein also has a conesponding switch control ligand, the ligand interacting in vivo with the pocket to regulate the confonnation and biological activity ofthe protein such that the protein will assume a first confonnation and a first biological activity upon the ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence ofthe ligand-pocket interaction.
  • a protein 100 is illustrated in schematic fonn to include an "on" switch control pocket 102, and "off switch control pocket 104, and a switch control ligand 106.
  • the schematically depicted protein also includes an ATP active site 108.
  • the ligand 106 has three amino acid residues with side chain OH groups 110.
  • the off pocket 104 contains corresponding X residues 112 and the on pocket 102 has Z residues 114.
  • the protein 100 will change its conformation depending upon the charge status ofthe OH groups 110 on ligand 106, i.e., when the OH groups are unmodified, a neutral charge is presented, but when these groups are phosphorylated a negative charge is presented.
  • the functionality of the pockets 102, 104 and ligand 106 can be understood from a consideration of Figs.2-4.
  • the ligand 106 is shown operatively interacted with the off pocket.104 such that the OH groups 110 interact with the X residues 112 fonning a part ofthe pocket 104.
  • Such interaction is primarily by virtue of hydrogen bonding between the OH groups 110 and the residues 112.
  • this ligand/pocket interaction causes the protein 100 to assume a conformation different from that seen in Fig. 1 and con-esponding to the off or biologically downregulated confonnation ofthe protein.
  • Fig. 3 illustrates the situation where the ligand 106 has shifted from the off pocket interaction conformation of Fig. 2 and the OH groups 110 have been phosphorylated, giving a negative charge to the ligand.
  • the ligand has a strong propensity to interact with on pocket 102, to thereby change the protein confonnation to the on or biologically upregulated state (Fig. 4).
  • Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted to positively charged residues 114 to achieve an ionic-like stabilizing bond. Note that in the on conformation of Fig. 4, the protein confonnation is different than the off confonnation of Fig.
  • Figs. 1 -4 illustrate a simple situation where the protein exhibits discrete pockets 102 and 104 and ligand 106. However, in many cases a more complex switch control pocket pattern is observed.
  • Fig.6 illustrates a situation where an appropriate pocket for small molecule interaction is formed from amino acid residues taken both from ligand 106 and, for example, from pocket 102. This is termed a "composite switch control pocket" made up of residues from both the ligand 106 and a pocket, and is refened to by the numeral 120.
  • a small molecule 122 is illustrated which interacts with the pocket 120 for protein modulation purposes.
  • FIG. 7 Another more complex switch pocket is depicted in Fig. 7 wherein the pocket includes residues from on pocket 102, and ATP site 108 to create what is ternied a "combined switch control pocket.”
  • Such a combined pocket is refened to as numeral 124 and may also include residues from ligand 106.
  • An appropriate small molecule 126 is illustrated with pocket 124 for protein modulation purposes.
  • BOC-group removal with acid preferably trifluoroacetic acid
  • base preferably triethylamine
  • intermediate 30 is treated with acid, preferably trifluoroacetic acid, to afford the N-unsubstituted sulfahydantoin 1-33.
  • Intemiediate 56 wherein M is a suitable leaving group, preferably bromine or chlorine, is partitioned to undergo a Heck reaction, giving 1-57; a Buchwald amination reaction , giving 1-59; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give 1-60.
  • the Heck reaction product 1-57 may be optionally hydrogenated to afford the saturated compound 1-58.
  • I 4 is methyl
  • compounds of formula 1-57, 1-58, 1-59, or 1-60 are treated with boron tribromide or lithium chloride to afford compounds of Fo ⁇ nula 1-61, wherein R- t is hydrogen.
  • Scheme 12 illustrates the further synthetic elaboration of intermediates 67. Removal ofthe silyl protecting group (TBS) is accomplished by treatment of 67 with flouride (tetra-n- butylammonium fluoride or cesium flouride) to give primary alcohols 68. Reaction of 68 with isocyanates 2 gives rise to compounds of Fomiula 1-69. Alternatively, reaction of 68 with [R 6 0 2 C(NH)p]q-D-E-M, wherein M is a suitable leaving group, affords compounds of Formula 1-70. Oxidation of 68 using the Dess-Martin periodinane (D. Dess, J. Martin, J. Am. Chem. Soc.
  • aldehydes 71 Reductive amination of 71 with amines 8 gives rise to compounds of Fomiula 1-72.
  • aldehydes 71 may be reacted with ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73. 5 Reaction of 73 with isocyanates 2 affords compounds of Formula 1-74.
  • Scheme 17.2 illustrates the synthetic sequences for converting intenriediates 104 to compounds of Fomiula I.
  • Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(O) catalyzed animation conditions affords compounds of Formulae 1-105.2 and 1-105.3.
  • Reaction of acetylene 104.4 with 26 under Sonogashira coupling conditions affords compounds of Formula 1-105.4.
  • 0 Compounds 1-105.4 may optionally be reduced to the corresponding satarated analogs J- 105.5 by standard hydrogenation.
  • Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117.
  • Treatment of 113 with aqueous copper oxide or an alkaline hydroxide affords compounds of Fomiula 1-115.
  • treatment of 113 with t- butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517.
  • Treating of the t-butyl sulfide 116 with acid affords the desired thiols of Fomiula 1-118.
  • 113 may be treated with excess ammonia under pressurized conditions to afford compound 117.
  • Scheme 19.3 illustrates the conversion of intemiediate 114 into compounds of Fomiula 1-119. 1-122. and 121, by analogy to the sequence described in Scheme 19.2.
  • intermediates 133 are reacted with alkenes under palladium(0)-catalyzed Heck reaction conditions to give compounds of Fomiula 1-136.
  • Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide.
  • amines 134c are available via the reduction of amides 134b as shown in Scheme 21.2.
  • the morpholine amide analogues 134d and morpholine analogues 134e are also available as shown in Scheme 21.2.
  • Intemiediate 145 is converted to the diesters 148 by reaction with an alkyl iodide in the presence of base, preferably potassium carbonate.
  • Intemiediates 146-148 are treated with HCl/dioxane to give the secondary amines 149-151, which are then condensed with acids 152 in the presence of PyBOP and di- isopropylethylamine to give compounds of Formula 1-153.
  • Compounds 1-163 or 1-164 are converted to the desired phosphonates 1-165 by an Arbuzov reaction sequence involving reduction of the esters to benzylic alcohols, conversion of the alcohols to the benzylic bromides, and treatment of the bromides with a tri-alkylphosphite.
  • phosphonates 1-165 are converted to the flourinated analogs 1-166 by treatment with diethylaminosulfur trifluoride (DAST).
  • DAST diethylaminosulfur trifluoride
  • Scheme 28.2 illustrates the conversion of intemiediate t-butylsulfides 172-175 to the sulfonic acids, employing a two step process involving acid-catalyzed deprotection of the t- butyl sulfide to the corresponding mercaptans, and subsequent peracid oxidation (preferably with peracetic acid or trifluoroperacetic acid) of the mercaptans to the desired sulfonic acids of Formula 1-176.
  • a hybrid p38-alpha kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety Ri-X-A.
  • alcohols 178 (X O) are reacted with with 177 under Buchwald copper(I)-catalyzed conditions to afford 179.
  • esters 179 are converted to the acids 181 preferably under acidic conditions when R 6 is t-butyl.
  • Scheme 30 Another sequence for preparing amines 180 is illustrated in Scheme 30.
  • A-N0 2 went R 1 X-A-N0 2 ⁇ R 1 X-A-NH 2 heat or i s? Pd(0 h ) e c a a t t o a r lysis 183 180
  • hybrid inhibitors possessing oxyanion pocket-binding moiety Q and moiety R r X-A
  • hybrid inhibitors possessing oxyanion pocket-binding moiety Q and moiety R X-A
  • inhibitors of Formula I which contain an urea linkage NH-CO- NH- connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are shown in Scheme 33.
  • Treatment of amines 1-185 with p-nitrophenyl chlorofo ⁇ nate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I.
  • hybrid inhibitors possessing oxyanion pocket-binding moiety Q and moiety R r X-A
  • inhibitors of Fomiula I which contain an urea linkage NH-CO-NH- connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are prepared as shown in Scheme 33.
  • Treatment of amines 180 with p-nitrophenyl chlorofomiate and base affords carbamates 188.
  • Reaction of 188 with amines 1-185 gives ureas of Fomiula I.
  • a fluorescence binding assay is used to detect binding of inhibitors of Formula I with unphosphorylated p38-alpha kinase as previously described: see J. Regan et al, Journal of Medicinal Chemistiy (2002) 45:2994.
  • the binding affinity of an inhibitor for p38 kinase can be measured by its ability to decrease the fluorescence from SKF 86002.
  • the assay was performed in a 384 plate (Greiner uclear 384 plate) on a Polarstar Optima plate reader (BMG).
  • the reaction mixture contained 1 ⁇ M SKF 86002, 80 nM ⁇ 38 kinase and various concentrations of an inhibitor in 20 mM Bis-Tris Propane buffer, pH 7, containing 0.15 % (w/v) n-octylglucoside and 2 mM EDTA in a final volume of 65 ⁇ l.
  • the reaction was initiated by addition of the enzyme.
  • the plate was incubated at room temperature ( ⁇ 25 °C) for 2 hours before reading at emission of 420 nm and excitation at 340 nm.
  • rfu relative fluorescence unit
  • IC 50 value for the inhibitor was calculated from the % inhibition values obtained at a range of concentrations of the inhibitor using Prism.
  • time-dependent inhibition was assessed, the plate was read at multiple reaction times such as 0.5, 1, 2, 3, 4 and 6 hours. The IC 50 values were calculated at the each time point. An inhibition was assigned as time-dependent if the IC 50 values decrease with the reaction time (more than twofold in four hours).
  • Example A To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine (56 mL) and
  • Example C A solution of Example C (1.66 g, 4.0 mmol) and SOCl 2 (0.60 mL, 8.0 mmol) in CH 3 C1 (100 mL) was refluxed for 3 h and concentrated in vacuo to yield l- ⁇ 3-tert-butyl-l-[3- chloromethyl)phenyl]-lH-pyrazol-5-yl ⁇ -3-(naphthalen-l-yl)urea (1.68 g, 97%) was obtained as white powder.
  • Example H was dissolved in dry THF (10 mL) and added a THF solution (10 mL) of 1- isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) atRT. The reaction mixture was stirred for 3h, quenched with H 2 O (30 mL), the resulting precipitate filtered and washed with 1NHC1 and ether to yield l-[2-(3-azidomethyl-phenyl)-5-t-butyl-2H-pyrazol-3-yl]-
  • Example H To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H 2 O (30 mL) was added.
  • the c de product was purified by preparative HPLC t o y i e l d l - ( 3 - t e r t - b u t y l - l - [ [ 3 - N - [ [ ( l - pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-lH-pyrazol-5-yl)-3-(4- chlorophenyl)urea.
  • Example J (0.5 ⁇ ) ⁇ 0°C, was added Example J (97.3 mg, 0.25 mmol) at such a rate that the reaction solution temperature did not rise above 5 °C.
  • a solution of pyiTolidine (18.8 ⁇ L, 0.227 mmol) and Et 3 N (95 ⁇ L, 0.678 mmol) in CH 2 C1 2 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 °C.
  • the reaction solution was warmed to RT and stirred overnight.
  • Example I A mixture of Example I (41 mg, 0.1 mmol), Kemp acid anhydride (24 mg, 0.1 mmol) and Et 3 N (100 mg, 1 mmol) in anhydrous CH 2 C1 2 (2 mL) were sti ⁇ -ed overnight at RT, and concentrated in vacuo.
  • Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (64.2 mg, 0.15 mmol) were added HOBt (30 mg, 0.225 mmol), Example K (24 mg, 0.15 mmol) and 4- methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF (3 mL) and EDCI (43 mg, 0.225 mmol).
  • Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (0.642 g,
  • Example 21 The title compound was synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate (0.09 g, 0.6 mmol) to yield l- ⁇ 3- tert-butyl- 1 -[3 -(2-morpholino-2-oxoethyl)phenyl] - lH-pyrazol-5 -yl ⁇ -3 -(4-chlorophenyl)urea.
  • Example L (0.2 g, 0.58 mmol) and phenyhsocyanate (0.09 g, 0.6 mmol) to yield l- ⁇ 3-tert-butyl- l-[3-(2-mo ⁇ pholino-2-oxoethyl)phenyl]-lH-pyrazol-5-yl ⁇ -3-phenylurea.
  • Example 21 The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and l-isocyanato-4-methoxy-naphthalene to yield 1- (3-tert-butyl- l-[3-(2-morpholino-2-oxoethyl)phenyl]-lH- ⁇ yrazol-5-yl ⁇ -3-(l-metl ⁇ oxynaphthalen-4-yl)urea.
  • the reaction mixture was stirred at 0 °C for 3 h.
  • the pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate.
  • the combined organic extracts were concentrated in vacuo provided 2-(3- hydrazinophenyl)acetamide.
  • Example N A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH 2 C1 2 (4 ml) was stirred at RT under N 2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield l- ⁇ 3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-lH- ⁇ yrazol-5-yl ⁇ -3-(naphthalene-l-yl)urea as a white solid (0.22 g).
  • Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate (0.112 g, 0.73 mmol) to yield 1- ⁇ 3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-lH-pyrazol-5-yl ⁇ -3-(4-chloiOphenyl)urea as a white solid ( 0.28 g).
  • mp: 222 224
  • Example P A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19 g, 1.05 mmol) in dry CH 2 C1 2 (5 ml) was stirred at RT under N 2 for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc and dilute citric acid solution. The organic layer was dried (Na 2 SO 4 ), and the volatiles removed in vacuo.
  • Example Q Amixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13 g, 0.8 mmol) in dry C ⁇ 2 C1 2 (5 ml) was stirred at RT under N 2 for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3h at RT and diluted with EtOAc and diluted citric acid solution. The organic layer was dried (Na 2 SO 4 ), and the volatiles removed in vacuo.
  • Example Q (0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate (0.077 g, 0.5 mmol) to yield 3- ⁇ 4- [3-tert-butyl-5-(3-(4-chlo ⁇ henyl)ureido]-lH-pyrazol-l-yl ⁇ phenyl)propanonic acid acid (0.16 g, off-white solid), mp: 112 - 114 ; * ⁇ NMR (200M ⁇ z, CDC1 3 ): ⁇ 8.16 (s, IH), 7.56 (s, IH),
  • a 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with 3- nitrobiphenyl (20 g, 0.10 mol) dissolved in THF (-100 mL) and 10% Pd C (3 g).
  • the reaction vessel was charged with H 2 (g) and purged three times.
  • the reaction was charged with 40 psi H 2 (g) and placed on a Parr shaker hydrogenation apparatus and allowed to shake overnight at RT.
  • Example R (0.145 g; 0.50 mmol) was dissolved in 2 mL CH 2 C1 2 (anhydrous) followed by the addition of he-iylisocyanate (0.0544 mL; 0.50mmol;
  • Example C The title compound is synthesized in a manner analogous to Example C utilizing Example A and 4-fluorophenyl isocyanate yield ethyl 3-(3-tert-butyl-5-(3-(4- flurophenyl)ureido)- 1 H-pyrazol- 1 -yl)benzoate.
  • Example P (0.30g, 0.95 mmol) and 4-fluOrophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3- (3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-lH-pyrazol-l-yl)phenyl)propanoic acid.
  • Example N To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane- methylsulf ⁇ de (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCl was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-aminoethyl)phenyl]-lH-py ⁇ -azol-5 amine (0.9 g).
  • Example T A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate (0.123 g, 0.73 mmol) in dry CH 2 C1 2 (5 ml) was stirred at RT under N 2 for 48 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 1%> methanol in CH 2 Cl 2 as the eluent (0.15 g, off-white solid). The solid was then treated with TFA (0.2ml) for 5 min and diluted with EtOAc.
  • Example U In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0107 mol) was dissolved in CH 2 C1 2 (5 mL, anhydrous) followed by the addition of 1 -naphthylisocyanate (1.53 mL, 0.0107 mol, 1 eq.). The reaction was kept under Ar and stirred for 18 h.
  • Example U (3.82 g; 0.0156 mol) and j-?-chlorophenylisocyanate (2.39 g, 0.0156 mol, 1 eq.), purified by trituration with hexane/EtOAc (4:1) and filtered to yield 1 -[3 -tert-butyl- 1 -(3- methoxyphenyl)-lH-pyrazol-5-yl]-3-(4-chlorophenyl)urea (6.1 g, 98%).
  • Example 39 (2.07 g) was dissolved in CH 2 C1 2 (20 mL) and cooled to 0 °C with an ice bath. BBr 3 (1 M in CH 2 C1 2 ; 7.5 mL) was added slowly. The reaction mixture was allowed to warm warm to RT overnight. Additional BBr 3 (1 M in CH 2 C1 2 , 2 X 1 mL, 9.5 mmol total added) was added and the reaction was quenched by the addition of MeOH.
  • the starting material l-[4-(aminomethyl)phenyl]-3-tert-butyl-N-nitroso-lH-pyrazol-5- amine, was synthesized in a manner analogous to Example A utilizing 4-aminobenzamide and 4,4-dimefhyl-3-oxopentanenitrile.
  • a 40 mL vial was equipped with a stir bar, a septum, and a source of Ar.
  • the vial was charged with the crude material from the previous reaction (2 g, 8.2 mmol, 244.17 g/mol) and C ⁇ C1 3 (15 mL) were cooled to 0 under Ar and di-tert-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHC1 3 (5 mL) was added drop wise over a 2 min period.
  • the mixture was treated with IN KOH (2 mL), added over a 2h period.
  • the resulting emulsion was broken with the addition of saturated NaCl solution, the layers were separated and the aqueous phase extracted with CH 2 C1 2 (2 x 1.5 ml).
  • a 40 mL vial was equipped with a septum, a stir bar and a source of Ar, and charged with Example N (2 g, 5.81 mmol), flushed with Ar and dissolved in CHC1 3 (20 mL).
  • the solution was treated with 2-naphthylisocyanate (984 mg, 5.81 mmol) in CHC1 3 (5 mL) and added over 1 min The reaction was stirred for 8h, and additional 1 -naphthylisocyanate (81 mg) was added and the reaction stirred overnight.
  • Example 46 The title compound was synthesized in a mamier analogous to Example 47 utilizing Example 46 (260mg, 0.66 mmol) to yield l- ⁇ 3-tert-butyl-l-[4-(l,l-dioxothiomorpholin-4- yl)methylphenyl]-lH-pyrazol-5-yl ⁇ -3-(4-chlorophenyl)urea (180 mg).
  • Example X 1 g was dissolved in CH 2 C1 2 (100 mL). Saturated sodium bicarbonate (100 mL) was added and the mixture rapidly stirred, cooled in an ice bath and treated with diphosgene (1.45 g) and the heterogeneous mixture stirred for 1 h. The layers were separated and the CH 2 C1 2 layer treated with tert-butanol (1.07 g) and the solution stiired overnight at RT.
  • Example X (1.27 g) and l-isocyanato-4-methoxy-naphthalene (996 mg) to yield methyl 4- ⁇ 3- tert-butyl-5-[3-( 1 -methoxynaphthalen-4-yl)ureido]- IH-pyrazol- 1 -yl ⁇ benzoate as white crystals (845 mg, 36%).
  • Example 59 700 mg was added dropwise a solution of diisobutylaluminum hydride in toluene (IM in toluene, 7.5 mL) over 10 min.
  • IM diisobutylaluminum hydride in toluene
  • the reaction mixture was stirred for 30 min at -78 °C, and then 30 min at 0 °C.
  • the reaction mixture was concentrated in vacuo to dryness and treated with H 2 0.
  • the solid was filtered and treated with acetonitrile.
  • X or Y is O, S, NR6, -NR6S02-, NR6CO-, alkylene, 0-(CH2)n-, NR6-(CH2)n-, wherein one ofthe methylene units may be substituted with an oxo group, or X or Y is a direct bond; D is taken from the groups identified in Chart I:

Abstract

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.

Description

ANTI-INFLAMMATORY MEDICAMENTS
BACKGROUND OF THE INVENTION Related Applications This application claims the benefit of provisional applications entitled Process For
MODULATING PROTEIN FUNCTION, S/N 60/437,487 filed December 31, 2002, ANTI- CANCER MEDICAMENTS, S/N 60/437,403 filed December 31, 2002, ANTI- INFLAMMATORY MEDICAMENTS, S/N 60/437,415 filed December 31, 2002, ANTI- INFLAMMATORY MEDICAMENTS, S/N 60/437,304 filed December 31, 2002, and MEDICAMENTS FOR THE TREATMENT OFNEURODEGENERATIVE DISORDERS OR DIABETES, S/N 60/463,804 filed April 18, 2003. Each of these applications is incorporated by reference herein.
Field ofthe Invention
The present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases.
Description ofthe Prior Art Basic research has recently provided the life sciences community with an unprecedented volume of information on the human genetic code and the proteins that are produced by it. In 2001, the complete sequence of the human genome was reported (Lander, E.S. et al. Initial sequencing and analysis ofthe human genome. Nature (2001) 409:860; Venter, J.C. et al. The sequence of the human genome. Science (2001) 291:1304). Increasingly, the global research community is now classifying the 50,000+ proteins that are encoded by this genetic sequence, and more importantly, it is attempting to identify those proteins that are causative of major, under-treated human diseases.
Despite the wealth of information that the human genome and its proteins are providing, particularly in the area of confomiational control of protein function, the methodology and strategy by which the pharmaceutical industry sets about to develop small molecule therapeutics has not significantly advanced beyond using native protein active sites for binding to small molecule therapeutic agents. These native active sites are nonnally used by proteins to perfomi essential cellular functions by binding to and processing natural substrates or tranducing signals from natural ligands. Because these native pockets are used broadly by many other proteins within protein families, drugs which interact with them are often plagued by lack of selectivity and, as a consequence, insufficient therapeutic windows to achieve maximum efficacy. Side effects and toxicities are revealed in such small molecules, either during preclinical discovery, clinical trials, or later in the marketplace. Side effects and toxicities continue to be a major reason for the high attrition rate seen within the drug development process. For the kinase protein family of proteins, interactions at these native active sites have been recently reviewed: see J. Dumas, Protein Kinase Inhibitors : Emerging Pharmacophores 1997-2001, Expert Opinion on Therapeutic Patents (2001) 11 : 405-429; J. Dumas, Editor, New challenges in Protein Kinase Inhibition, in Current Topics in Medicinal Chemistry (2002) 2: issue 9.
It is known that proteins are flexible, and this flexibility has been reported and utilized with the discovery of the small molecules which bind to alternative, flexible active sites with proteins.
Figure imgf000003_0001
2, pp. 527- 541 (2003). See also, Wu et al, Structure, Vol. 11, pp. 399-410 (2003). However these reports focus on small molecules which bind only to proteins at the protein natural active sites. Peng et al, Bio. Organic and Medicinal Chemistry Ltrs., Vol. 13, pp. 3693-3699 (2003), and Schindler, et al., Science, Vol. 289, p. 1938 (2000) describe inhibitors of abl kinase. These inhibitors are identified in WO Publication No. 2002/034727. This class of inhibitors binds to the ATP active site while also binding in a mode that induces movement ofthe kinase catalytic loop. Pargellis et al., Nature Structural Biology, Vo\. 9, p. 268 (2002) reported inhibitors p38 alpha-kinase also disclosed in WO Publication No. 00/43384 and Regan et al., J. Medicinal Chemistry, Vol. 45, pp. 2994-3008 (2002). This class of inhibitors also interacts with the kinase at the ATP active site involving a concomitant movement ofthe kinase activation loop.
More recently, it has been disclosed that kinases utilize activation loops and kinase domain regulatory pockets to control their state of catalytic activity. This has been recently reviewed (see, e.g., M. Huse and J. Kuriyan, Cell (2002) 109:275).
SUMMARY OF THE INVENTION The present invention is broadly concerned with new compounds for use in treating anti- inflammatory conditions and methods of treating such conditions. In more detail, the inventive compounds have the formula
Figure imgf000004_0001
wherein:
R1 is selected from the group consisting of aryls (preferably C6-C18, and more, preferably C6-Cl2) and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-,
-NR6SO2-, -NR6CO-, alkynyls (preferably CrC18, and more preferably C,-C12), alkenyls (preferably -C^, and more preferably C,-C12), alkylenes (preferably C,-CI8, and more preferably C,-Cι2), -O(CH2)h-, and -NR6(CH2)h-, where eachh is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably CrC18, and more preferably C C,,), -O(CH2)h-, and
-NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction ofthe side-chain oxo group does not form an ester moiety; A is selected from the group consisting of aromatic (preferably C6-C18, and more preferably C6-C12), monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(O)- and -S(O)2-; j is 0 or 1 ; m is 0 or 1 ; n is 0 or 1 ; p is 0 or 1 ; q is O or l; t is 0 or 1 ; Q is selected from the group consisting of
Figure imgf000005_0001
each R4 group is individually selected from the group consisting of -H, alkyls (preferably
Cj-0,8, and more preferably CrC12), aminoalkyls (preferably C,-C18, and more preferably C]-CI2), alkoxyalkyls (preferably CrC18, and more preferably -C^), aryls (preferably C6-C18, and more preferably C6-C12), aralkyls (preferably C6-C18, and more preferably C6-C12 and preferably Cj-Cjg, and more preferably C,-C12), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R5 is individually selected from the group consisting of -H, alkyls (preferably Cr
C18, and more preferably C,-C12), aryls (preferably C6-C18, and more preferably
C6-C12), heterocyclyls, alkylaminos (preferably CrC18, and more preferably Cr
CI2), arylaminos (preferably C6-C18, and more preferably C6-CI2), cyclo alkylaminos (preferably CrC!8, and more preferably C,-CI2), heterocyclylaminos, hydroxys, alkoxys (preferably CrC18, and more preferably
C,-C12), aryloxys (preferably C6-C18, and more preferably C6-C12), alkylthios
(preferably C,-C18, and more preferably CrC12), arylfhios (preferably C6-C18, and more preferably C6-C12), cyanos, halogens, perfluoroalkyls (preferably CrC18, and more preferably CrC12), alkylcarbonyls (preferably CrC18, and more preferably CrC12), and nitros; each R6 is individually selected from the group consisting of -H, alkyls (preferably C,-
C18, and more preferably CrC12), allyls, and β-trimethylsilylethyl; each R8 is individually selected from the group consisting of alkyls (preferably C,-CI8, and more preferably C,-C12), aralkyls (preferably C6-C18, and more preferably C6- C12) preferably C,-C18, and more preferably C,-C12), heterocyclyls, and heterocyclylalkyls (preferably C,-C18, and more preferably CrC12); each R9 group is individually selected from the group consisting of -H, -F, and alkyls (preferably C,-CI8, and more preferably CrC12), wherein when two Rg groups are geminal alkyl group's, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; each Z is individually selected from the group consisting of -O- and -N(R4)-; and each ring of formula (I) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls (preferably C,-Cι8, and more preferably -C^), aryls (preferably C6-Cι8, and more preferably C6-CI2), heterocyclyls, alkylaminos (preferably Cj-C18, and more preferably C,-C12). arylaminos (preferably C6-Cl8, and more preferably C6-
CI2), cycloalkylaminos (preferably C,-C18, and more preferably C,-C12), heterocyclylaminos, hydroxys, alkoxys (preferably CrC18, and more preferably
C]-C12), aryloxys (preferably C6-C]8, and more preferably C6-C12), alkylthios
(preferably -C^, and more preferably C1-C12), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfmyls (preferably CrC18, and more preferably CrC12), alkylsulfonyls (preferably C,-Cl8, and more preferably -C^), aminosulfonyls, and perfluoroalkyls (preferably Cι-C18, and more preferably C1-C12).
I one preferred embodiment, the compound has the structure of formula (I) except that: when Q is Q-3 or Q-4, then the compound of formula (I) is not
Figure imgf000007_0001
when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl; when Q is Q-7, R5 is -OH, Y is -O-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, then the compound of formula (I) is not
Figure imgf000008_0001
R80 is H, Me
R82 is substituted phenyl
R81 is substituted phenyl
when Q is Q-8, then Y is not -CH2O-; when Q is Q-8, the compound of formula (I) is not
Figure imgf000008_0002
R10 = alkyl, aryl, arylalkoxyalkyl, or arylalkyls
when Q is Q-9, then the compound of formula (I) is not
Figure imgf000009_0001
R! 1 = H, alkyl, alkoxy, nitro, halogen
R12, R13 = H, alkyl R1 = H, alkyl, allyl, propargyl R15 = H, alkyl,
Figure imgf000009_0002
Figure imgf000009_0003
R17, RI 8 = alkyl R19 = H, alkyl
when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy; when Q is Q-10, then the compound of formula (I) is not
Figure imgf000009_0004
when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy; when Q is Q-11, then the compound of formula (I) is not
Figure imgf000010_0001
when Q is Q-15, then the compound of formula (I) is not
Figure imgf000010_0002
R20 = substituted phenyl, R21 = H, alkyl
when Q is Q-16 and Y is -NH-, then
Figure imgf000010_0003
of formula (I) is not biphenyl; when Q is Q-16 and Y is -S-, then
Figure imgf000010_0004
of formula (I) is notphenylsulfonylammophenyl or phenylcarbonylaminophenyl; when Q is Q-16 and Y is -SO2NH-, then the compound of formula (I) is not
Figure imgf000011_0001
R23 = OH, SH, NH2 when Q is R 4 = hydrogen or one or more methoxy, hydroxy, fluoro, chloro, nitro, dimethylamino, or furanyl Q-16 R25 = substituted phenyl, furanyl
R26 = OH or CI a n d X5 = O, NH;
Y is -CONH-, then
Figure imgf000011_0002
of fomiula (I) is not imidazophenyl; when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not
Figure imgf000011_0003
R:7 = substituted phenyl, pyr idyl-arbonyl R.j = CN, metlioxyc-rbonyl n » 0 or 1 when Q is Q-16 and t is 0, then
Figure imgf000012_0001
of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl; when Q is Q-17, then the compound of formula (I) is not
Figure imgf000012_0002
R29 = alkyl
R30 = H, t-Bu, benzoyl R3ι = substituted phenyl
when Q is Q-21, then the compound of formula (I) is not
Figure imgf000012_0003
when Q is Q-22, then the compound of foimula (I) is selected from the group consisting of
Figure imgf000013_0001
when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of
Figure imgf000013_0002
but excluding
Figure imgf000014_0001
when Q is Q-23, then the compound of fomiula (I) is not
Figure imgf000015_0001
Figure imgf000015_0002
when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of
Figure imgf000016_0001
wherein each W is individually selected from the group consisting of -CH- and
-N-; each G, is individually selected from the group consisting of -O-, -S-, and -N(R4)-; and
* denotes the point of attacliment to Q-24, Q-25, Q-26, or Q-31 as follows:
Figure imgf000016_0002
wherein each Z is individually selected from the group consisting of -O- and -N(R4)-; when Q is Q-31, then the compound of formula (I) is not
Figure imgf000017_0001
or
Figure imgf000017_0002
when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not
Figure imgf000017_0003
R 6 = hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy
when Q is Q-28 or Q-29 and Y is an ether linlcage, then the compound of formula (I) is not
Figure imgf000018_0001
or
Figure imgf000018_0002
when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not
Figure imgf000018_0003
when Q is Q-32, then
R, — x — A— j— L— ψj— D — E — Y-
is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; when Q is Q-32, Y is -CONH-, q is 0, m is 0, and
H N -L- A
of formula (I) is -CONH-, then A is not phenyl; when Q is Q-32, q is 0, m is 0, and
Figure imgf000019_0001
is -CONH-, then the compound of formula (I) is not
Figure imgf000019_0002
R.5 = benzoyl, phenylalkylaminocarbonyl, substituted phenylaminocarbony! H, Br
R 7 = alkyl, substituted phenyl, thienyl, phenacetyl 1-55 = CI, Br, SPh, benzoyl, phenylsulfonyl naphthyl R.51 = H, phenylsulfonyl, phenyl, benzyl R4g = H, alkyl, Br, substituted phenyl, benzoyl, R = Et, i-Pr phenylsulfonyl R53 = substituted phenyl, substituted benzyl R^ = H, alkyl, phenyl X, = O, N-Ph, N-alkyl, N-carbamoyl R50 = substituted phenyl Z, =N(R50), O when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone; when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then
A is not phenyl; when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl; when Q is Q-32 and Y is an ether linlcage, then
Figure imgf000020_0001
of formula (I) is not biphenyl or phenyloxazolyl; when Q is Q-32 and Y is -CH=CH-, then
Figure imgf000020_0002
of formula (I) is not phenylaminophenyl; when Q is Q-32, then the compound of formula (I) is not
Figure imgf000020_0003
d = 0-2
R5S = substituted alkylaminocarbonyl, plienylaminocarbonyl R60 = H, alkyl R59 = H, CI R61 = substituted phenyl, thienyl, Br
R62= H, alkyl, phenyl
R63 = substituted phenyl when Q is Q-35 as shown
Figure imgf000021_0001
wherein G is selected from the group consisting of-O-, -S-, -NR4-, and -CH2-, k is 0 or 1, and u is 1, 2, 3, or 4, then
R— X)-A NHL-(N)-: D — E — Y-
is selected from the group consisting of
Figure imgf000021_0002
Figure imgf000022_0001
except that the compound of fomiula (I) is not
azolyl
Figure imgf000023_0001
Figure imgf000023_0002
R74= chlorophenyl
Figure imgf000023_0003
, N(Et)2
Figure imgf000023_0004
Even more preferably, R, as discussed above is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls, and even more preferably, Rj is selected from the group consisting of
Figure imgf000024_0001
each R2 is individually selected from . the group consisting of -H, alkyls (preferably C,-CI8, and more preferably C,-CI2), aminos, alkylaminos (preferably C,-C18, and more preferably C,-C12), arylaminos (preferably C6-C]8, and more preferably C6-C12), cycloalkylaininos (preferably C,-C18, and more preferably C,-C12), heterocyclylaminos, halogens, alkoxys (preferably C,-C18, and more preferably C,-C]2), and hydroxys; each R3 is individually selected from the group consisting of -H, alkyls (preferably C,-C18, and more preferably CrC12), alkylaminos (preferably C,-C18, and more preferably Cj-C12), arylaminos (preferably C6-C18, and more preferably C6-C12), cycloalkylaininos (preferably C,-C]8, and more preferably CrC12), heterocyclylaminos, alkoxys (preferably C,-C18, and more preferably C,-C12), hydroxys, cyanos, halogens, perfluoroalkyls (preferably CrC]8, and more preferably C,-C12), alkylsulfmyls (preferably CrC18, and more preferably CrC12), alkylsulfonyls (preferably C,-C18, and more preferably C,-C12), R4NHS02-, and -NHSO2R4; and
V is selected from the group consisting of O and H2. Finally, in another preferred embodiment, A as described above is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
Figure imgf000025_0001
where each Wj is individually selected from the group consisting of -CH- and -N-.
With respect to the method of using the novel compounds, the activation state of akinase is determined by the interaction of switch control ligands and complemental switch control pockets. One conformation ofthe kinase may result from the switch control ligand's interaction with a particular switch control pocket while another conformation may result from the ligand's interaction with a different switch control pocket. Generally interaction ofthe ligand with one pocket, such as the "on" pocket, results in the kinase assuming an active conformation wherein the kinase is biologically active. Similarly, an inactive conformation (wherein the kinase is not biologically active) is assumed when the ligand interacts with another of the switch control pockets, such as the "off pocket. The switch control pocket can be selected from the group consisting of simple, composite and combined switch control pockets. Interaction between the switch control ligand and the switch control pockets is dynamic and therefore, the ligand is not always interacting with a switch control pocket. In some instances, the ligand is not in a switch control pocket (such as occurs when the protein is changing from an active conformation to an inactive conformation). In other instances, such as when the ligand is interacting with the environment surrounding the protein in order to determine with which switch control pocket to interact, the ligand is not in a switch control pocket. Interaction of the ligand with particular switch control pockets is controlled in part by the charge status ofthe amino acid residues ofthe switch control ligand. When the ligand is in a neutral charge state, it interacts with one ofthe switch control pockets and when it is in a charged state, it interacts with the other ofthe switch control pockets. For example, the switch control ligand may have a plurality of OH groups and be in a neutral charge state. This neutral charge state results in a ligand that is more likely to interact with one ofthe switch control pockets tlirough hydrogen boding between the OH groups and selected residues ofthe pocket, thereby resulting in whichever protein conformation results from that interaction. However, if the OH groups ofthe switch control ligand become charged through phosphorylation or some other means, the propensity ofthe ligand to interact with the other ofthe switch control pockets will increase and the ligand will interact with this other switch control pocket through complementary covalent binding between the negatively or positively charged residues ofthe pocket and ligand. This will result in the protein assuming the opposite conformation assumed when the ligand was in a neutral charge state and interacting with the other switch control pocket. Of course, the conformation ofthe protein determines the activation state ofthe protein and can therefore play a role in protein-related diseases, processes, and conditions. For example, if a metabolic process requires a biologically active protein but the protein' s switch control ligand remains in the switch control pocket (i.e. the "off pocket) that results in a biologically inactive protein, that metabolic process cannot occur at a normal rate. Similarly, if a disease is exacerbated by a biologically active protein and the protein's switch control ligand remains in the switch control pocket (i.e. the "on" pocket) that results in the biologically active protein conformation, the disease condition will be worsened. Accordingly, as demonstrated by the present invention, selective modulation ofthe switch control pocket and switch control ligand by the selective administration of a molecule will play an important role in the treatment and control of protein-related diseases, processes, and conditions.
One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 α-kinase and including both the consensus wild type sequence and disease polymorphs thereof. The activation state is generally selected from an upregulated or downregulated state. The method generally comprises the step of contacting the kinase with a molecule having the general fomiula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and a lesser propensity to interact with the occupied switch control pocket. As a result, the protein will have a greater propensity to assume either an active or inactive conformation (and consequenctly be upregulated or downregulated), depending upon which ofthe switch control pockets is occupied by the molecule. Thus, contacting the kinase with a molecule modulates that protein' s activation state. The molecule can act as an antagonist or an agonist of either switch control pocket. The contact between the molecule and the kinase preferably occurs at a region of a switch control pocket ofthe kinase and more preferably in an interlobe oxyanion pocket ofthe kinase. In some instances, the contact between the molecule and the pocket also results in the alteration ofthe conformation of other adjacent sites and pockets, such as an ATP active site. Such an alteration can also effect regulation and modulation ofthe active state ofthe protein. Preferably, the region ofthe switch control pocket ofthe kinase comprises an amino acid residue sequence operable for binding to the Formula I molecule. Such binding can occur between the molecule and a specific region ofthe switch control pocket with preferred regions including the -C helix, the oc-D helix, the catalytic loop, the activation loop, and the C-terminal residues or C-lobe residues (all residues located downstream (toward the C-end) from the Activation loop), and combinations thereof. When the binding region is the α-C helix, one preferred binding sequence in this helix is the sequence UXXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (SEQ ID NO. 3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. When the binding region is in the C-lobe residues, one preferred binding sequence is WMHY (SEQ ID NO. 6). When a biologically inactive protein conformation is desired, molecules which interact with the switch control pocket that nonnally results in a biologically active protein conformation (when interacting with the switch control ligand) will be selected. Similarly, when a biologically active protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically inactive protein conformation (when interacting with the switch control ligand) will be selected. Thus, the propensity of the protein to assume a desired conformation will be modulated by administration of the molecule. In prefen-ed forms, the molecule will be administered to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft- versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. In such forms, it will be desired to select molecules that interact with the switch control pocket that generally leads to a biologically active protein conformation so that the protein will have the propensity to assume the biologically inactive fonn and thereby alleviate the condition. It is contemplated that the molecules of the present invention will be administerable in any conventional form including oral, parenteral, inhalation, and subcutaneous. It is preferred for the administration to be in the oral form. Preferred molecules include the preferred compounds of fomiula (I), as discussed above.
Another aspect ofthe present invention provides a method of treating an inflammatory condition of an individual comprising the step of administering a molecule having the general formula (I) to the individual. Such conditions are often the result of an overproduction of the biologically active fonn of a protein, including kinases. The administering step generally includes the step of causing said molecule to contact a kinase involved with the inflammatory process, preferably p38 cc-kinase. When the contact is between the molecule and a kinase, the contact preferably occurs in an interlobe oxyanion pocket ofthe kinase that includes an amino acid residue sequence operable for binding to the Fonnula I molecule. Preferred binding regions ofthe interlobe oxyanion pocket include the α-C helix region, the α-D helix region, the catalytic loop, the activation loop, the C-tenninal residues, and combinations thereof. When the binding region is the α-C helix, one preferred binding sequence in this helix is the sequence IIXXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one prefen-ed binding sequence in this loop is DIIHRD (SEQ ID NO. 3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO.5), and combinations thereof. Such a method pennits treatment of the condition by virtue of the modulation of the activation state of a kinase by contacting the kinase with a molecule that associates with the switch control pocket that nonnally leads to a biologically active fonn ofthe kinase when interacting with the switch control ligand. Because the ligand cannot easily interact with the switch control pocket associated with or occupied by the molecule, the ligand tends to interact with the switch control pocket leading to the biologically inactive form ofthe protein, with the attendant result of a decrease in the amount of biologically active protein. Preferably, the inflammatory condition is selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. As with the other methods of the invention, the molecules may be administered in any conventional fonn, with any convention excipients or ingredients. However, it is preferred to administer the molecule in an oral dosage form. Preferred molecules are again selected from the group consisting ofthe prefened formula (I) compounds discussed above.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic representation of a naturally occurring mammalian protein in accordance with the invention including "on" and "off switch control pockets, a transiently modifiable switch control ligand, and an active ATP site; Fig. 2 is a schematic representation ofthe protein of Fig. 1, wherein the switch control ligand is illustrated in a binding relationship with the off switch control pocket, thereby causing the protein to assume a first biologically downregulated confonnation;
Fig. 3 is a view similar to that of Fig. 1, but illustrating the switch control ligand in its charged-modified condition wherein the OH groups of certain amino acid residues have been phosphorylated;
Fig. 4 is a view similar to that of Fig. 2, but depicting the protein wherein the switch control ligand is in a binding relationship with the on switch control pocket, thereby causing the protein to assume a second biologically-active conformation different than the first conformation of Fig. 2; Fig. 4a is an enlarged schematic view illustrating a representative binding between the phosphorylated residues of the switch control ligand, and complemental residues from the on switch control pocket;
Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic fonn possible small molecule compounds in a binding relationship with the on and off switch control pockets; Fig. 6 is a schematic view ofthe protein in a situation where a composite switch control pocket is formed with portions ofthe switch control ligand and the on switch control pocket, and with a small molecule in binding relationship with the composite pocket; and
Fig. 7 is a schematic view ofthe protein in a situation where a combined switch control pocket is formed with portions of the on switch control pocket, the switch control ligand sequence, and the active ATP site, and with a small molecule in binding relationship with the combined switch control pocket.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides a way of rationally developing new small molecule modulators which interact with naturally occurring proteins (e.g., mammalian, and especially human proteins) in order to modulate the activity ofthe proteins. Novel protein-small molecule adducts are also provided. The invention preferably makes use of naturally occurring proteins having a confomiational property whereby the proteins change their conformations in vivo with a conesponding change in protein activity. For example, a given enzyme protein in one conformation may be biologically upregulated, while in another confonnation, the same protein may be biologically downregulated. The invention preferably makes use of one mechanism of confonnation change utilized by naturally occurring proteins, through the interaction of what are tenned "switch control ligands" and "switch control pockets" within the protein.
As used herein, "switch control ligand" means a region or domain within a naturally occuning protein and having one or more amino acid residues therein which are transiently modified in vivo between individual states by biochemical modification, typically phosphorylation, sulfation, acylation or oxidation. Similarly, "switch control pocket" means a plurality of contiguous or non-contiguous amino acid residues within a naturally occurring protein and comprising residues capable of binding in vivo with transiently modified residues of a switch control ligand in one of the individual states thereof in order to induce or restrict the confonnation ofthe protein and thereby modulate the biological activity ofthe protein, and/or which is capable of binding with a non-naturally occurring switch control modulator molecule to induce or restrict a protein conformation and thereby modulate the biological activity ofthe protein.
A protein-modulator adduct in accordance with the invention comprises a naturally occurring protein having a switch control pocket with a non-naturally occunϊng molecule bound to the protein at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein. Preferably, the protein also has a conesponding switch control ligand, the ligand interacting in vivo with the pocket to regulate the confonnation and biological activity ofthe protein such that the protein will assume a first confonnation and a first biological activity upon the ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence ofthe ligand-pocket interaction.
The nature of the switch control ligand/switch control pocket interaction may be understood from a consideration of schematic Figs. 1-4. Specifically, in Fig. 1, a protein 100 is illustrated in schematic fonn to include an "on" switch control pocket 102, and "off switch control pocket 104, and a switch control ligand 106. h addition, the schematically depicted protein also includes an ATP active site 108. In the exemplary protein of Fig. 1, the ligand 106 has three amino acid residues with side chain OH groups 110. The off pocket 104 contains corresponding X residues 112 and the on pocket 102 has Z residues 114. In the exemplary instance, the protein 100 will change its conformation depending upon the charge status ofthe OH groups 110 on ligand 106, i.e., when the OH groups are unmodified, a neutral charge is presented, but when these groups are phosphorylated a negative charge is presented.
The functionality of the pockets 102, 104 and ligand 106 can be understood from a consideration of Figs.2-4. In Fig. 2, the ligand 106 is shown operatively interacted with the off pocket.104 such that the OH groups 110 interact with the X residues 112 fonning a part ofthe pocket 104. Such interaction is primarily by virtue of hydrogen bonding between the OH groups 110 and the residues 112. As seen, this ligand/pocket interaction causes the protein 100 to assume a conformation different from that seen in Fig. 1 and con-esponding to the off or biologically downregulated confonnation ofthe protein.
Fig. 3 illustrates the situation where the ligand 106 has shifted from the off pocket interaction conformation of Fig. 2 and the OH groups 110 have been phosphorylated, giving a negative charge to the ligand. In this condition, the ligand has a strong propensity to interact with on pocket 102, to thereby change the protein confonnation to the on or biologically upregulated state (Fig. 4). Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted to positively charged residues 114 to achieve an ionic-like stabilizing bond. Note that in the on conformation of Fig. 4, the protein confonnation is different than the off confonnation of Fig. 2, and that the ATP active site is available and the protein is functional as a kinase enzyme. Figs. 1 -4 illustrate a simple situation where the protein exhibits discrete pockets 102 and 104 and ligand 106. However, in many cases a more complex switch control pocket pattern is observed. Fig.6 illustrates a situation where an appropriate pocket for small molecule interaction is formed from amino acid residues taken both from ligand 106 and, for example, from pocket 102. This is termed a "composite switch control pocket" made up of residues from both the ligand 106 and a pocket, and is refened to by the numeral 120. A small molecule 122 is illustrated which interacts with the pocket 120 for protein modulation purposes.
Another more complex switch pocket is depicted in Fig. 7 wherein the pocket includes residues from on pocket 102, and ATP site 108 to create what is ternied a "combined switch control pocket." Such a combined pocket is refened to as numeral 124 and may also include residues from ligand 106. An appropriate small molecule 126 is illustrated with pocket 124 for protein modulation purposes.
It will thus be appreciated that while in the simple pocket situation of Figs.1-4, the small molecule will interact with the simple pocket 102 or 104, in the more complex situations of Figs. 6 and 7 the interactive pockets are in the regions of the pockets 120 orl24. Thus, broadly the the small molecules interact "at the region" ofthe respective switch control pocket.
MATERIALS AND METHODS General Synthesis of Compounds. In the synthetic schemes of this section, q is 0 or 1. When q = 0, the substituent is replaced by a synthetically non-interfering group R7. Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are prepared according to the synthetic route shown in Scheme 1.1. Reaction of isothiocyanate 1 with chlorine, followed by addition of isocyanate 2 affords 3-oxo-thiadiazolium salt 3. Quenching of the reaction with air affords compounds of Formula T . Alternatively, reaction of isothiocyanate 1 with isothiocyanate 5 under the reaction conditions gives rise to compounds of Fomiula __ _. See A. Martinez et al, Journal of Medicinal Chemistry (2002) 45: 1292.
Intermediates 1, 2 and 5 are commercially available or prepared according to Scheme 1.2. Reaction of amine 8 with phosgene or a phosgene equivalent affords isocyanate 2. Similarly, reaction of amine 8 with thiophosgene affords isothiocyanate 5. Amine 8 is prepared by palladium(0)-catalyzed amination of 9, wherein M is a group capable of oxidative insertion into palladium(O), according to methodology reported by S. Buchwald. See M. Wolter et al, Organic Letters (2002) 4:973; B.H. Yang and S. Buchwald, Journal of Organometallic Chemisty (1999) 576(1-2): 125. In this reaction sequence, P is a suitable amine protecting group. Use of and removal of amine protecting groups is accomplished by methodology reported in the literature (Protective Groups in Organic Synthesis, Peter G.M. Wutts, Theodora Greene (Editors) 3rd edition (April 1999) Wiley, John & Sons, Incorporated; ISBN: 0471160199). Starting compounds 9 are commercially available or readily prepared by one of ordinary skill in the art: See March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith & Jerry March (Editors) 5th edition (January 2001) Wiley John & Sons; ISBN : 0471585890.
Figure imgf000034_0001
3 1-4
Figure imgf000034_0002
Scheme 1.2 phosgene N=C=0
[R602C-(NH)p]q-D-E-Y/ 2 ~ [R602C-(NH)p]q-D-E-Y
Base 8 2
NH2 thiophosgene N=_c=s
[R602C-(NH)p]q-D-E-Y *- [R602C-(NH)p]q-D-E-Y
Base
R602C-NH2
10 R602C-NH-D-E-Y-NHP deProtection
M-D-E-Y NHP *
Pd(0) catalysis
11
9
R602C-NH-D-E-Y-NH2
8
Compounds of Fonnula I wherein Q is taken from Ql or Q-2 and Y is alkylene are also available via the synthetic route shown in Scheme 1.3. Reaction of amine 8 with isocyanate or isothiocyanate 2a yields the urea/thiourea 8a which can be cyclized by the addition of chlorocarbonyl sulfenyl chloride. See GB1115350 and US3818024, Revankar et. al US Patent 4,093,624, and Klayman et. al JOC 1972, 37(10), 1532 for further details. Where R-t is a readily removable protecting group (e.g. R = 3,4-d-nιethoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of 1-4 (X=0) and 1-7 (X=S).
Scheme 1.3
[R602C-(NH)P]q-D-E-Y
8 8a, X=0, S
Deprotection
Figure imgf000035_0002
1-4 X=0 1-7 x=s
Figure imgf000035_0003
1-4 X=0 1-7 X=S
1-7 is also available as shown in Scheme 1.4. Condensation of isocyanate or isothiocyanate 2a with amine R5NH2 yields urea/thiourea 2b, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2c. Where R-t is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of 2d. Reaction of 2d with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-4 (X=O) and ϊ-7 (X=S).
Scheme 1.4
Figure imgf000036_0001
2b 2c
[R602C-(NH)p]q-D-[ ≡-γ Y Y" X
1-4 x=o
Figure imgf000036_0002
1-7 X=S
Compounds of Fomiula I wherein Q is taken from Q-1 ' or Q-2' and Y is alkylene are available via the synthetic route shown in Scheme 1.3. Condensation of isocyanate or isothiocyanate 2a with ammonia yields urea/thiourea 2e, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2f. Reaction of 2f with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields yields 1-4' (X=0) and 1-7' (X=S).
Scheme 1.5
Figure imgf000036_0003
2e 2f
[R
Figure imgf000036_0004
1-4' X=0 8a 1-7' X=S
Compounds of Fomiula I wherein Q is taken from Q-3 or Q-4 and Y is alkylene, are prepared according to the synthetic route shown in Schemes 2.1 and 2.2, respectively. Reaction of 12, wherein M is a suitable leaving group, with the carbamate-protected hydrazine 13 affords intermediate 14. Reaction of 14 with an isocyanate gives rise to intermediate 15. Thermal cyclization of 15 affords 1,2,4-triazolidinedione of Formula 1-16. By analogy, scheme 2.2 illustrates the preparation of 3-thio-5-oxo-l,2,4-triazolidines of Formula 1-18 by reaction of intermediate 14 with an isothiocyanate and subsequent thermal cyclization.
Scheme 2.1
Figure imgf000037_0001
Figure imgf000037_0002
Intermediates 12 wherein p is 1 are readily available or are prepared by reaction of 19 with carbamates 10 under palladium(0)-catalyzed conditions. Mi is a group which oxidatively inserts palladium(O), preferably iodo or bromo, and is of greater reactivity than
M. Compounds 19 are either commercially available or prepared by one of ordinary skill in the art.
Scheme 2.3
R602C-NH2
10
R602C-NH . M
M^-^
Ύ D' 'Y
Pd(0) catalysis; Base
12
19
Compounds of Formula I wherein D is taken from Q-3 or Q-4 and Y is alkylene, are also prepared according to the synthetic route shown in Scheme 2.4. Oxidation of amine R4NH2 to the corresponding hydrazine, condensation with ethyl chloroformate subsequent heating yields 1,2,4-triazolidinedione 15a. After the action of NaH in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16 (X=0) and 1-18 (X=S).
Scheme 2.4
L aNOz II ° R-NCX
2. SnCI2 ci^OEt - * X=O. S heat
R4NH2 - R4NHNH2 Al A±→ R4NHNH OB -
2a
Figure imgf000038_0001
Compounds of Formula I wherein D is taken from D-3' or D-4' and Y is alkylene, are also prepared according to the synthetic route shown in Scheme 2.4. When R5 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA on 15a will reveal 1,2,4-triazolidinedione 15b. After deprotonahon of 15b by NaH in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16' (X=0) and 1-18' (X=S).
Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y is alkylene are prepared according to the synthetic route shown in Scheme 3. Reaction of hydrazine 20 with chlorosulfonylisocyanate and base, such as triethylamine, gives rise to a mixture of intermediates 21A and 21B which are not isolated but undergo cyclization in situ to afford compounds of Formulae I-22A and I-22B. Compounds I-22A and I-22B are separated by chromatography or fractional crystallization. Optionally, compounds I-22A and I-22B can undergo Mitsunobu reaction with alcohols RtOH to give compounds of Formulae I-23A and I-23B. Compounds 20 are prepared by acid-catalyzed deprotection of t-butyl carbamates of structure 14, wherein Rio is t-butyl.
Scheme 3
Figure imgf000040_0001
Figure imgf000040_0002
Ph3P Ph3P
Diethyl azodicarboxylate Diethyl azodicarboxylate
R4OH R4OH
Figure imgf000040_0003
-23A I-23B
Compounds of Formula I wherein Q is Q-7 and Y is alkylene are prepared as shown in Scheme 4. Reaction of amine 8 with maleimide 24, wherein M is a suitable leaving group, affords compounds of Fomiula 1-25. Reaction of compound 26, wherein M is a group which can oxidatively insert Pd(0), can participate in a Heck reaction with maleimide 27, affording compounds of Formula 1-28. Maleimides 24 and 27 are commercially available or prepared by one of ordinary skill in the art. Scheme 4
[R602C-(NH)p]q-D-
Figure imgf000041_0001
T-25
Figure imgf000041_0002
Compounds of Formula I wherein Q is Q-8 and Y is alkylene are prepared as shown in Scheme 5, according to methods reported by M. Tremblay et al, Journal of Combinatorial Chemistiy (2002) 4:429. Reaction of polymer-bound activated ester 29 (polymer linkage is oxime activated-ester) with chlorosulfonylisocyante and t-butanol affords N-BOC sulfonylurea 30. Subjection of 30 to the Mitsunobu reaction with R-iOH gives rise to 31. BOC-group removal with acid, preferably trifluoroacetic acid, and then treatment with base, preferably triethylamine, provides the desired sulfahydantoin 1-32. Optionally, intermediate 30 is treated with acid, preferably trifluoroacetic acid, to afford the N-unsubstituted sulfahydantoin 1-33.
Scheme 5
Figure imgf000042_0001
Figure imgf000042_0002
1-33
Compounds of Formula I wherein Q is Q-8 and Y is alkylene are also prepared as shown in Scheme 5a. Amine 8 is condensed with the glyoxal hemiester to yield 31a. Reaction of chlorosulphonyl isocyanate first with benzyl alcohol then 31a yields 31b, which after heating yields 1-32.
Scheme 5.1
[R602C-(NH)p]q-D-E-Y
Figure imgf000043_0001
Et
NaCHBH3 8 31a
Figure imgf000043_0002
31a
3. 5% Pd/C
Figure imgf000043_0003
I-32
Compounds of Formula I wherein Q is taken from Q-8', are prepared according to the synthetic route shown in Scheme 5.2. Formation of 31c by the method of Muller and DuBois JOC 1989, 54, 4471 and its deprotonation with NaH/DMF or NaH/DMF and subsequently alkylation wherein M is a suitable leaving group such as chloride, bromide or iodide yields I- 32'. Alternatively, 1-32' is also available as shown in Scheme 5.3. Mitsunobu reaction of boc-sulfamide amino ethyl ester with alcohol 8b (made by methods analogous to that for amine 8) yields 31c, which after Boc removal with 2N HCl in dioxane is cyclized by the action of NaH on 31d results in 1-32'.
Scheme
[R602C-
Figure imgf000043_0004
Scheme 5.3
OH
B-c-H&o ΓVWWPW^Y- |R,θ2C.(NH)Plq.D.E.Y--H 9 o
S"" 0 8b S O
HN HN,
X)Et
OEt DEADCAT, Ph3P 31 d
0-.ll ^S-NH neat , [R602C-(NH)p]q-D-E-Y" "
O I-32'
Compounds of Formula I_wherein Q is Q-9 and Y is alkylene are prepared as shown in Scheme 6. Reaction of polymer-bound amino acid ester 34 with an isocyanate affords intemiediate urea 35. Treatment of 35 with base, preferably pyridine or triethylamine, with optional heating, gives rise to compounds of Formula 1-36. Scheme 6
Figure imgf000044_0001
Figure imgf000044_0002
Compounds of Foπnula I_wherein Q is Q-9 and Y is alkylene are also prepared as shown in Scheme 6.1. Reaction of aldehyde 8c under reductive amination conditions with the t-butyl ester of glycine yields 35a. Isocyanate 2a is condensed with p-nitrophenol (or the corresponding R(NH2 amine is condensed with p-πitrophenyl chlorofomiate) to yield the carbamic acid p-nitrophenyl ester, which when reacted with deprotonated 35a and yields the urea that when deprotected with acid yields 35b. Formula 1-36 is directly available from 35b by the action of NaH and heat.
Scheme 6.1 o
O
X, H,N.
, - "O.-Bu
[Rs02C-(NH)p]q-D-E-Y H „. [R602C-(NH)p]q-D-E-Y' O.-Bu
NaCHBH3
8c 35a
[R602C-(NH)p]q-D-
Figure imgf000045_0001
1-36 35b
Compounds of Formula I wherein Q is taken from Q-9', are prepared according to the synthetic route shown in Scheme 6.2. Foπnation of 35c by the method described in JP10007804A2 and Zvilichovsky and Zucker, Israel Journal of Chemistry, 1969, 7(4), 547- 54 and its deprotonation with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide, yields 1-36'.
Scheme
[R602C-
Figure imgf000045_0002
Compounds of Formula I_wherein Q is Q-10 or Q-11, and Y is alkylene are prepared as shown in Schemes 7.1 and 7.2, respectively. Treatment of alcohol 37 (Z = O) or amine 37 (Z = NH) with chlorosulfonylisocyanate affords intermediate carbamate or urea of structure 38. Treatment of 38 with an amine of stracture HN(R4)2 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-39. Reaction of chlorosulonylisocyanate with an alcohol (Z = O) or amine (Z = NR4) 40 affords intermediate 41. Treatment of 41 with an amine 8 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-42. Scheme 7.1
[R602C-(NH)p]q-D-E
Figure imgf000046_0001
37 38
Figure imgf000046_0002
1-42
Compounds of Formula I wherein Q is taken from Q-12 are prepared according to the synthetic route shown in Scheme 8. Alkylation of pyridine 43, wherein TIPS is triisopropylsilyl, under standard conditions (K2C0 , DMF, Rφ-I or Mitsunobu conditions employing I i-OH) yields pyridine derivative 44 which is reacted with compound 12, wherein M is a suitable leaving group, to afford pyridones of formula 1-45.
Scheme 8
Figure imgf000047_0002
Figure imgf000047_0001
43 44
Figure imgf000047_0003
1-4S
Compounds of Formula I wherein Q is taken from Q-13 are prepared according to the synthetic route shown in Scheme 9. Starting from readily available pyridine 46, alkylation under standard conditions (K2C03, DMF, R^I or Mitsunobu conditions employing Ri-OH) yields pyridine derivative 47. N-alkylation with K2C03, DMF, R-t-I affords pyridones of formula 48. Intemiediate 48 is partitioned to undergo a Heck reaction, giving 1-49; a Buchwald amination reaction, giving 1-51; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give 1-52. The Heck reaction product 1-49 may be optionally hydrogenated to afford the saturated compound 1-50. Wherein the phenyl ether R-, group is methyl, compounds of formula 1-49. 1-50, 1-51, or 1-52 are treated with boron tribromide or lithium chloride to afford compounds of Formula 1-53, wherein R4 is hydrogen.
Scheme 9
Figure imgf000048_0001
Compounds of Fomiula I wherein Q is taken from Q-14 are prepared according to the synthetic route shown in Scheme 10. Starting from readily available pyridine 54, alkylation under standard conditions (K2C0 , DMF, R4-I or Mitsunobu conditions employing R-t-OH) yields pyridine derivative 55. N-alkylation with K2C03,. DMF, R-t-I affords pyridones of formula 56. Intemiediate 56, wherein M is a suitable leaving group, preferably bromine or chlorine, is partitioned to undergo a Heck reaction, giving 1-57; a Buchwald amination reaction , giving 1-59; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give 1-60. The Heck reaction product 1-57 may be optionally hydrogenated to afford the saturated compound 1-58. Wherein I 4 is methyl, compounds of formula 1-57, 1-58, 1-59, or 1-60 are treated with boron tribromide or lithium chloride to afford compounds of Foπnula 1-61, wherein R-t is hydrogen. Scheme 10
Figure imgf000049_0001
Compounds of Formula I wherein Q is taken from Q-15 are prepared according to the synthetic routes shown in Schemes 11 and 12. Starting esters 62 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions. Reaction of protected secoester 62 with Meerwin's salt produces the vinyl ether 63 as a pair of regioisomers. Alternatively, reaction of 62 with dimethylamine affords the vinylogous carbamate 64. Fomiation of the dihydropyrimidinedione 66 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione 66 may optionally be further substituted by Mitsunobu reaction with alcohols R^OH to give rise to compounds 67.
Scheme 12 illustrates the further synthetic elaboration of intermediates 67. Removal ofthe silyl protecting group (TBS) is accomplished by treatment of 67 with flouride (tetra-n- butylammonium fluoride or cesium flouride) to give primary alcohols 68. Reaction of 68 with isocyanates 2 gives rise to compounds of Fomiula 1-69. Alternatively, reaction of 68 with [R602C(NH)p]q-D-E-M, wherein M is a suitable leaving group, affords compounds of Formula 1-70. Oxidation of 68 using the Dess-Martin periodinane (D. Dess, J. Martin, J. Am. Chem. Soc. (1991) 113:7277) or tetra-n-alkyl pemthenate (W. Griffith, S. Ley, Aldrichimica Ada (1990) 23:13) gives the aldehydes 71. Reductive amination of 71 with amines 8 gives rise to compounds of Fomiula 1-72. Alternatively, aldehydes 71 may be reacted with ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73. 5 Reaction of 73 with isocyanates 2 affords compounds of Formula 1-74.
Scheme 11
Figure imgf000050_0001
67
Scheme 12
Figure imgf000051_0001
73 1-74
Compounds of Formula I wherein Q is taken from Q-16 are prepared according to the synthetic routes shown in Schemes 13 and 14. Starting esters 75 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions. Reaction of protected secoester 75 with Meerwin's salt produces the vinyl ether 76 as a pair of regioisomers. Alternatively, reaction of 75 with dimethylamine affords the vinylogous
10 carbamate 77. Fomiation of the dihydropyrimidinedione 78 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione 78 may optionally be further substituted by Mitsunobu reaction with alcohols tOH to give rise to compounds 79. Compounds of Formulae 1-81, 1-82, 1-84, and 1-86 are prepared as shown in Scheme 14 by analogy to the sequence previously described in Scheme 12.
15
Figure imgf000052_0001
79
Figure imgf000052_0002
Alkyl acetoacetates 87 are commercially available and are directly converted into the esters 88 as shown in Scheme 15. Treatment of 87 with NaHMDS in THF, followed by quench with formaldehyde and TBSC1 (n = 1) or Q-(CH2)n-OTBS (n = 2-4), gives rise to compounds 88.
Scheme 15
Figure imgf000053_0001
Compounds of Formula I wherein Q is taken from Q-17 are prepared according to the synthetic routes shown in Schemes 16.1 and 16.2, and starts with the BOC-protected hydrazine 13, which is converted to the 1,2-disubstituted hydrazine 89 by a reductive alkylation with a glyoxal derivative mediated by sodium cyanoborohydride and acidic workup. Condensation of 89 with diethyl malonate in benzene under reflux yields the heterocycle 90. Oxidation with N204 in benzene (see Cardillo, Merlini and Boeri Gazz. Cliim. Ital., (1966) 9:8) to the nitromalonohydrazide 91 and further treatment with P205 in benzene (see: Cardillo,G. et al, Gazz.Chim.Ital. (1966) 9:973-985) yields the tncarbonyl 92. Alternatively, treatment of 90 with Brederick's reagent (t-BuOCH(N(Me )2, gives rise to 93, which is subjected to ozonolysis, with a DMS and methanol workup, to afford the protected tricarbonyl 92. Compound 92 is readily deprotected by the action of CsF in THF to yield the primary alcohol 94. Alcohol 94 is optionally converted into the primary amine 95 by a sequence involving tosylate fomiation, azide displacement, and hydrogenation. Scheme 16.1
Figure imgf000054_0001
91 t-BuO-CH(NMe)2)2 P-A
Figure imgf000054_0002
CsF, THF
Figure imgf000054_0003
95
94
Reaction of 94 with (hetero)aryl halide 26, wherein M is iodo, bromo, or chloro, under copper(I) catalysis affords compounds 1-96. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Fomiula 1-98. By analogy, reaction of amine 95 with 26 under palladium(O) catalysis affords compounds of Formula 1-97. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Fomiula I; 99.
Scheme 16.2
Figure imgf000055_0001
94
Figure imgf000055_0002
Compounds of Formula I wherein Q is taken from Q-17 are also prepared according to the synthetic route shown in Scheme 16.3. Deprotonation of 4,4-dimethyl-3,5-dioxo- pyrazolidine (95a, prepared according to the method described in Zinner and Boese, D. Pharmazie 1970, 25(5-6), 309-12 and Bausch, M. J.et.al J. Org. Chem. 1991, 56(19), 5643) with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide yields I-99a.
Scheme
[R602C-
0
Figure imgf000055_0003
Compounds of Formula I wherein Q is taken from Q-18 are prepared as shown in Schemes 17.1 and 17.2. Aminoesters 100 are subjected to reductive alkylation conditions to give rise to intermediates 101. Condensation of amines 101 with carboxylic acids using an 5 acid activating reagent such as dicyclohexylcarbodiimide (DCC)/hydrpxybenzotriazole (HOBt) affords intermediate amides 102. Cyclization of amides 102 to tetramic acids 104 is mediated by Amberlyst A-26 hydroxide resin after happing of the in situ generated alkoxide 103 and submitting 103 to an acetic acid-mediated resin-release.
Figure imgf000056_0001
(CH2)3-; H2N-(CH2)4-; HC-=C-CH2-
Scheme 17.2 illustrates the synthetic sequences for converting intenriediates 104 to compounds of Fomiula I. Reaction of alcohol 104.1 with aryl or heteroaryl halide 26 (Q = halogen) under copper(I) catalysis gives rise to compounds of Fomiula 1-105.1. Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(O) catalyzed animation conditions affords compounds of Formulae 1-105.2 and 1-105.3. Reaction of acetylene 104.4 with 26 under Sonogashira coupling conditions affords compounds of Formula 1-105.4. 0 Compounds 1-105.4 may optionally be reduced to the corresponding satarated analogs J- 105.5 by standard hydrogenation.
Scheme 17.2
Figure imgf000057_0001
104.1 1-105.1
Figure imgf000057_0002
l-105.2, n = 3
104.2, n = 3 1-105.3, n = 4
104.3, n = 4
q[R602Cp
Figure imgf000057_0003
Figure imgf000057_0004
104.4 1-105.4 1-105.5
Compounds of Fomiula I wherein Q is taken from Q-19, Q-20, or Q-21 are prepared as illustrated in Scheme 18. Commercially available Kemp's acid 106 is converted to its anhydride 107 using a dehydrating reagent, preferably di-isopropylcarbodiimide (DIC) or 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Reaction of 107 with amines RtNH2 affords the intermediate amides which are cyclized to the imides 108 by reaction with DIC or EDC. Alternatively, 107 is reacted with amines 8 to afford amides of Fomiula 1-110. Amides 1-110 may optionally be further reacted with DIC or EDC to give rise to compounds of Formula Mil. Acid 108 is further reacted with amines 8 to give compounds of Fomiula 1-109. Scheme 18
Figure imgf000058_0001
Figure imgf000058_0002
1-110 1-111
Compounds of Fomiula I wherein Q is taken from Q-22 or Q-23 are prepared as shown in Schemes 19.1 through 19.3. Preparation of intermediates 113 and 114 are prepared as shown in Scheme 19.1 from di-halo(hetero)aryls 112, wherein M2 is a more robust leaving group than Mi. Reaction of 112 with amines 37 (Z = NH) either thermally in the presence of base or by palladium(O) catalysis in the presence of base and phosphine ligand affords compounds 113. Alternatively, reaction of 112 with alcohols 37 (X = O) either thermally in
10 the presence of base or by copper(I) catalysis in the presence of base affords compounds 114.
Scheme 19.1
Figure imgf000059_0001
112 113
Figure imgf000059_0002
Base 114
Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117. Treatment of 113 with aqueous copper oxide or an alkaline hydroxide affords compounds of Fomiula 1-115. Alternatively, treatment of 113 with t- butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517. Treataient of the t-butyl sulfide 116 with acid affords the desired thiols of Fomiula 1-118. Alternatively, 113 may be treated with excess ammonia under pressurized conditions to afford compound 117.
Figure imgf000060_0001
1-118
Scheme 19.3 illustrates the conversion of intemiediate 114 into compounds of Fomiula 1-119. 1-122. and 121, by analogy to the sequence described in Scheme 19.2.
Scheme 19.3
Figure imgf000061_0001
114
aq CuO t-BuSH excess NH3, or Cul base
KOH K2C03 ethylene glycol
OH StBu NH2 W "^ W W "^ W W ^ W 2C-(NH)p]q-D-E-Yv R602C-(NH)p]q-D-E-Ys R602C-(NH)p]q-D-E-Yv
O
1-119 120 121
Figure imgf000061_0002
1-122
Compounds of Formula I wherein q is taken from Q-24, Q-25, or Q-26 are prepared as shown in Scheme 20. Reaction of compounds 1-115 or 1-119 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R-t)2 gives rise to compounds of Formulae 1-123 or 1-124. Reaction of compounds 1-118 or 1-122 with a peracid, preferably peracetic acid or trifluoroperacetic acid, affords compounds of Fomiula I; 125 or 1-126. Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R )2 or alcohols R4OH, affords compounds of Formulae I; 127, 1-128. 1-129, or 1-130.
Figure imgf000062_0001
I-U5, Z = NH I:il8, Z = NH 117, Z = NH ΪTΪ9, Z= 0 M22, Z = 0 121, Z= 0
1) Chlorosulfonylisocyanate
Peracetic acid
2) HN(R4)2 or R4OH
Figure imgf000062_0002
Figure imgf000062_0003
Figure imgf000062_0004
U23, Z = NH 1-125, Z = NH I-127, Z = NH 1.124, Z = θ i;T26, Z = 0 • 28, Z = 0
Figure imgf000062_0005
1-129, Z= NH 30, Z^ θ
Compounds of Fomiula I wherein Q is taken from Q-27 are prepared as illustrated in Scheme.21. Reductive alkylation of thiomorpholine with aldehydes 131 affords benzylic amines 132, which are then subjected to peracid oxidation to give rise to the thiomorpholine sulfones 133 (see C. R. Johnson et al, Tetrahedron (1969) 25: 5649). Intermediates 133 are reacted with amines 8 (Z = NH2) under Buchwald palladium-catalyzed amination conditions to give rise to compounds of Fomiula 1-134. Alternatively, compounds 133 are reacted with alcohols 8 (Z = OH) under Buchwald copper(I) catalyzed conditions to afford compounds of Formula 1-135. Alternatively, intermediates 133 are reacted with alkenes under palladium(0)-catalyzed Heck reaction conditions to give compounds of Fomiula 1-136. Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide.
Figure imgf000063_0001
Compounds of Fomiula I wherein Q is taken from Q-27 are also prepared as illustrated in Scheme 21.1. Aldehyde 8c is reductively aminated with ammonia, and the resultant amine condensed with divinyl sulphone to yield 1-134. Intemiediate 134a is also available by reduction of amide 8d under a variety of standard conditions. Scheme 21.1
O
A NH3 [R602C-(NH)p]q-D-E-Y H [R602C-(NH)p]q-D-E-Y NH2
NaCHBH3
8c 134a
Figure imgf000063_0002
More generally, amines 134c are available via the reduction of amides 134b as shown in Scheme 21.2. The morpholine amide analogues 134d and morpholine analogues 134e are also available as shown in Scheme 21.2.
Scheme 21.2
0 o
R.,R2NH
[R602C-(NH )p]q-D-E-Y X OH [R602C-(NH) A.
DIC coupling 8e 134b
Figure imgf000064_0001
Amide reduction i.e. LAH
Figure imgf000064_0002
Compounds of Fomiula I wherein Q is taken from Q-28 or Q-29 are prepared according to the sequences illustrated in Scheme 22. Readily available amides 138 are reacted with chlorosulfonylisocyanate to give intemiediates 140, which are reacted in situ with amines HN(R )2 or alcohols RtOH to afford compounds of Formulae 1-141 or 1-142, respectively. Alternatively, amides 138 are reacted with sulfonylchlorides to give compounds of Fomiula 1-139.
Scheme 22
Figure imgf000065_0001
138 140
Figure imgf000065_0002
1-141 1-142
Figure imgf000065_0003
1-139
Compounds of Formula I wherein Q is taken from Q-30 are prepared as shown in Scheme 23. Readily available N-BOC anhydride 143 (see S. Chen et al, J. Am. Chem. Soc. (1996) 118:2567) is reacted with amines HN(R))2 or alcohols R6OH to afford acids 144 or 145, respectively. Intemiediates 144 or 145 are further reacted with amines HN(R-t)2 in the presence of an acid-activating reagent, preferably PyBOP and di-isopropylethylamine, to give diamides 146 or ester-amides 147. Intemiediate 145 is converted to the diesters 148 by reaction with an alkyl iodide in the presence of base, preferably potassium carbonate. Intemiediates 146-148 are treated with HCl/dioxane to give the secondary amines 149-151, which are then condensed with acids 152 in the presence of PyBOP and di- isopropylethylamine to give compounds of Formula 1-153. Sche
Figure imgf000066_0001
HCl, dioxane
PyBOP, i-Pr2NEt
Figure imgf000066_0003
Figure imgf000066_0002
Figure imgf000066_0004
Compounds of Fomiula I wherein Q is taken from Q-31 or Q-32 are prepared according to the sequences illustrated in Scheme 24. Treatment of readily available sulfenamides 154 with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = - CH=CH ), gives rise to compounds of Formula 1-155. Treataient of sulfenamides 1-155 with iodosobenzene in the presence of alcohols RβOH gives rise to the sulfonimidates of Fomiula 1-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively, compounds 1-155 (Z = -CH=CH) may be optionally reduced to the saturated analogs 1-156 (Z = CH2-CH2-), which are converted to the corresponding sulfonimidates 1-157.
Treatment of readily available sulfonylchlorides 154.1 with amines HN(R4)2 and base gives rise to compounds of Formula 1-154.2. Scheme 24
[R602C-(NH)p]q-D-E-Y
ZH
37, Z = NH
Figure imgf000067_0001
154.1 1-154.2
Compounds of Formula I wherein Q is taken from Q-33 are prepared as shown in Scheme 25. Readily available nitriles 158 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH2) to afford compounds of Fomiula 1-159. Compounds 1-159 (wherein Z = CH=CH-) are optionally reduced to their satarated. analogs 1-160 by standard catalytic hydrogenation conditions. Treatment of compounds 1-159 or 1-160 with a metal azide (preferably sodium azide or zinc azide) gives rise to tetrazoles of Fomiula 1-161.
Scheme 25
[R602C-(NH)p]q-D-E-Yv
"ZH 37, Z = NH
Figure imgf000068_0001
1-160
Compounds of Fomiula I wherein Q is taken from Q-34 are prepared as shown in Scheme 26. Readily available esters 162 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH2) to afford compounds of Fomiula 1-163. Compounds 1-163 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-164 by standard hydrogenation conditions. Compounds 1-163 or 1-164 are converted to the desired phosphonates 1-165 by an Arbuzov reaction sequence involving reduction of the esters to benzylic alcohols, conversion of the alcohols to the benzylic bromides, and treatment of the bromides with a tri-alkylphosphite. Optionally, phosphonates 1-165 are converted to the flourinated analogs 1-166 by treatment with diethylaminosulfur trifluoride (DAST).
Figure imgf000069_0001
1-166
Compounds of Fomiula I wherein Q is taken from Q-35 are prepared according to Scheme 27. Readily available acid chlorides 167 are reacted with oxazolidones in the presence of base to afford the N-acyl oxazolidinones 168. Intemiediate 168 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH2) to afford the N-acyl oxazolidinones of Fomiula 1-169. Compounds 1- 69 (wherein Z is -CH=CH-) are optionally converted to the satarated analogs 1-170 under standard hydrogenation conditions.
Scheme 27 [R602C-(NH)p]q-D-E-Yv 37, Z = NH "ZH
Figure imgf000070_0001
167 168
[R602C-(NH)p]q-D-E-Y- \ ZH
37, Z = CH=CH2 hydrogenation » (Z = CH=CH)
Pd(0), phosphine, base
{R602C-(NH)p]q-D-E-Y-
Figure imgf000070_0002
1-170
Compounds of Formula I wherein Q is taken from Q-35 are also prepared as illustrated in Scheme 27.1. Intermediate 8a, wherein M is a suitable leaving group such as chloride, bromide or iodide, is refluxed with triethyl phosphite and the resulting phosphoryl intermediate saponified under mild conditions to yield 1-165.
Scheme 27.1
[R602C-(NH)p]q-D-E-Y 8a
Figure imgf000070_0003
Compounds of Fomiula I wherein Q is taken from Q-36 are prepared as illustrated in
Schemes 28.1 and 28.2. Reductive alkylation of the t-butylsulfide substituted piperazines with the readily available aldehydes 131 gives rise to the benzyhc piperazines 171. Intemiediates 171 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH2) to give compounds 172, 173, or 174, respectively. Optionally, intermediates 174 are converted to the satarated analogs 175 under standard hydrogenation conditions. Scheme 28.1
Figure imgf000071_0001
-St-Bu
<EAA 174
Figure imgf000071_0002
(NH)p]q-D-E-Y reduction (hydrogenation or diimide)
Figure imgf000071_0003
Figure imgf000071_0004
Scheme 28.2 illustrates the conversion of intemiediate t-butylsulfides 172-175 to the sulfonic acids, employing a two step process involving acid-catalyzed deprotection of the t- butyl sulfide to the corresponding mercaptans, and subsequent peracid oxidation (preferably with peracetic acid or trifluoroperacetic acid) of the mercaptans to the desired sulfonic acids of Formula 1-176.
Scheme 28.2
Figure imgf000071_0005
172-175 1-176
Z = NH, O, CH=CH, CH2-CH2 In some instances a hybrid p38-alpha kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety Ri-X-A. The synthesis of functionalized intemiediates of fomiula Ri-X-A are accomplished as shown in Scheme 29. Readily available intemiediates 177, which contain a group M capable of oxidative addition to palladium(O), are reacted with amines 178 (X = NH) under Buchwald Pd(0) amination conditions to afford 179. Alternatively amines or alcohols 178 (X = NH or O) are reacted thermally with 177 in the presence of base under nuclear aromatic substitution reaction conditions to afford 179. Alternatively, alcohols 178 (X = O) are reacted with with 177 under Buchwald copper(I)-catalyzed conditions to afford 179. In cases where p = 1, the carbamate of 179 is removed, preferably under acidic conditions when R6 is t-butyl, to afford amines 180. In cases where p = 0, the esters 179 are converted to the acids 181 preferably under acidic conditions when R6 is t-butyl.
Scheme 29
R.,-XH
M-A-(NH)p-C02R6 117788
R1X-A-(NH)p-C02R6 heat or
177 Pd(0) catalysis 179
Figure imgf000072_0001
R-ιX-A-NH2 R1X-A-C02H
180 181
Another sequence for preparing amines 180 is illustrated in Scheme 30. Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 wherein M is a leaving group, preferably M is fluoride, or M is a group capable of oxidative insertion into palladium(O), preferably M is bromo, chloro, or iodo, gives intemiediates 183. Reduction of the nitro group under standard hydrogenation conditions or treatment with a reducing metal, such as stannous chloride, gives amines 180. Scheme 30
R.,-XH 178 reduction
A-N02 — „ R1X-A-N02 ^ R1X-A-NH2 heat or i s? Pd(0 h)e caattoarlysis 183 180
In instances when hybrid p38-alpha kinase inhibitors are prepared, compounds of Fomiula 1-184 wherein q is 1 may be converted to amines 1-185 (p = 1) or acids 1-186 (p = 0) by analogy to the conditions described in Scheme 29. Compounds of Fomiula 1-184 are prepared as illustrated in previous schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10, 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, or 28.2. Scheme 31
[R602C-(NH)p]q-D"E "Y''Q q = l
1-184
Figure imgf000073_0001
1-185 1-186
Compounds T-l 84 are taken from schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, 28.2
The preparation of inhibitors of Fomiula I which contain an amide linkage -CO-NH- connecting the oxyanion pocket binding moieties and Ri-X-A moieties are shown in Scheme 32. Treatment of acids 181 with an activating agent, preferably PyBOP in the presence of di- iso-propylethylamine, and amines 1-185 gives compounds of Fomiula I. Alternatively, retroamides of Fomiula I are formed by treatment of acids 1-186 with PyBOP in the presence of di-iso-propylethylamine and amines 180. Scheme 32
Co
Figure imgf000074_0001
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RrX-A)
H02C-D'
Figure imgf000074_0002
Compounds 1-186 taken Compounds 180 taken from from scheme 31 schemes 29 or 30 RetroamideForniula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety R X-A)
The preparation of inhibitors of Formula I which contain an urea linkage NH-CO- NH- connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are shown in Scheme 33. Treatment of amines 1-185 with p-nitrophenyl chlorofoπnate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I.
Scheme 33
Co
Figure imgf000074_0003
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety RrX-A)
Alternatively, inhibitors of Fomiula I which contain an urea linkage NH-CO-NH- connecting the oxyanion pocket binding moieties and the Ri-X-A moieties are prepared as shown in Scheme 33. Treatment of amines 180 with p-nitrophenyl chlorofomiate and base affords carbamates 188. Reaction of 188 with amines 1-185 gives ureas of Fomiula I.
Scheme 34
Com
Figure imgf000075_0001
188
O
R X' ^N D-E^Q
H H
Formula I
(hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety Rj-X-A)
AFFINITY AND BIOLOGICAL ASSESSMENT OF P38-ALPHA KINASE INHIBITORS A fluorescence binding assay is used to detect binding of inhibitors of Formula I with unphosphorylated p38-alpha kinase as previously described: see J. Regan et al, Journal of Medicinal Chemistiy (2002) 45:2994.
1. P38 MAP kinase binding assay The binding affinities of small molecule modulators for ρ38 MAP kinase were determined using a competition assay with SKF 86002 as a fluorescent probe, modified based on published methods (C. Pargellis, et al Nature Structural Biology (2002) 9, 268-272. J. Regan, et al J. Med. Chem. (2002) 45, 2994-3008). Briefly, SKF 86002, a potent inhibitor of p38 kinase (K_ = 180 nM), displays an emission fluorescence around 420 nm when excitated at 340 nm upon its binding to the kinase. Thus, the binding affinity of an inhibitor for p38 kinase can be measured by its ability to decrease the fluorescence from SKF 86002. The assay was performed in a 384 plate (Greiner uclear 384 plate) on a Polarstar Optima plate reader (BMG). Typically, the reaction mixture contained 1 μM SKF 86002, 80 nM ρ38 kinase and various concentrations of an inhibitor in 20 mM Bis-Tris Propane buffer, pH 7, containing 0.15 % (w/v) n-octylglucoside and 2 mM EDTA in a final volume of 65 μl. The reaction was initiated by addition of the enzyme. The plate was incubated at room temperature (~ 25 °C) for 2 hours before reading at emission of 420 nm and excitation at 340 nm. By comparison of rfu (relative fluorescence unit) values with that of a control (in the absence of an inhibitor), the percentage of inhibition at each concentration of the inhibitor was calculated. IC50 value for the inhibitor was calculated from the % inhibition values obtained at a range of concentrations of the inhibitor using Prism. When time-dependent inhibition was assessed, the plate was read at multiple reaction times such as 0.5, 1, 2, 3, 4 and 6 hours. The IC50 values were calculated at the each time point. An inhibition was assigned as time-dependent if the IC50 values decrease with the reaction time (more than twofold in four hours).
Figure imgf000076_0001
Figure imgf000077_0001
IC50 values obtained at 2 hours reaction time
Biological assessment of p38-alpha kinase inhibitors of Fomiula I is perfomied in a THP-1 cell assay, measuring inhibition of LPS-stimulated TNF-alpha production. See see J. Regan et al, Journal of Medicinal Chemistiy (2002) 45:2994.
EXAMPLES The following examples set forth preferred methods in accordance with the invention. It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope ofthe invention.
[Boc-sulfamide] aminoester (Reagent AA), l,5,7,-trimethyl-2,4-dioxo-3-aza- bicyclo[3.3.1 ]nonane-7-carboxylic acid (Reagent BB), and Kemp acid anhydride (Reagent CC) was prepared according to literature procedures. See Askew et. alJ. Am. Chem. Soc. 1989, 111, 1082 for further details.
EXAMPLE A
Figure imgf000078_0001
To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) in concentrated HCl was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mol) at 0 °C. The reaction mixture was stirred for 1 h and a solution of SnCl2 #2H2O (662 g, 2.92 mol) in concentrated HCl (2 L) was then added at 0 °C, and the reaction stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-hydrazino-benzoic acid hydrochloride as a white solid.
The crude material from the previous reaction (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo- pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) were heated to reflux overnight. The reaction solution was evaporated in vacuo and the residue purified by column chromatography to yield ethyl 3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)benzoate (Example A, 116 g, 40%) as a white solid together with 3-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)benzoic acid (93 g, 36%). 'HNMR (DMSO--?6): 8.09 (s, IH), 8.05 (brd, J= 8.0 Hz, IH), 7.87 (brd, J= 8.0 Hz, IH), 7.71 (t, J= 8.0 Hz, IH), 5.64 (s, IH), 4.35 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H), 1.28 (s, 9H).
EXAMPLE B
Figure imgf000079_0001
To a solution of 1 -naphthyl isocyanate (9.42 g, 55.7 mmol) and pyridine (44 mL) in THF (100 mL) was added a solution of Example A (8.0 g, 27.9 mmol) in THF (200 mL) at 0 °C. The mixture was stirred at RT for lh, heated until all solids were dissolved, stirred at RT for an additional 3h and quenched with H2O (200 mL). The precipitate was filtered, washed with dilute HCl and H2O, and dried in vacuo to yield ethyl 3-[3-t-butyl-5-(3-naphthalen-l-yl)ureido)-lH- pyrazol-l-yl]benzoate(12.0 g, 95%) as a white power. 'Η NMR (DMSO-<i6): 9.00 (s, 1 H), 8.83 (s, 1 TT), 8.25 7.42 (m, 11 H), 6.42 (s, 1 H), 4.30 (q, J= 7.2 Hz, 2 H), 1.26 (s, 9 H), 1.06 (t, J=
7.2 Hz, 3 H); MS (ESI) m/z: 457.10 (M+H+).
EXAMPLE C
Figure imgf000080_0001
To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine (56 mL) and
THF (30 mL) was added a solution of 4-nitrophenyl 4-chlorophenylcarbamate (10 g, 34.8 mmol) in THF (150 mL) at 0 °C. The mixture was stiπ-ed at RT for 1 h and heated until all solids were dissolved, and stirred at RT for an additional 3 h. H2O (200 mL) and CH2C12 (200 mL) were added, the aqueous phase separated and extracted with CH2C12 (2 x 100 mL). The combined organic layers were washed with IN NaOH, and 0.1N HCl, saturated brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield ethyl 3-{3-tert-butyl-5-[3-(4- chlorophenyl)ureido]-lH-pyrazol-l-yl}benzoate (8.0 g, 52%). Η NMR (DMSO- d6): δ 9.11 (s,
1Η), 8.47 (s, 1Η), 8.06 (m, 1Η), 7.93 (d, J= 7.6 Ηz, 1Η), 7.81 (d, J= 8.0 Ηz, 1Η), 7.65 (dd, J = 8.0, 7.6 Ηz, 1Η), 7.43 (d, J= 8.8 Ηz, 2Η), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, IH), 4.30 (q, J= 6.8 Hz, 2H), 1.27 (s, 9H), 1.25 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 441 (M++H).
EXAMPLE D
Figure imgf000080_0002
To a stirred solution of Example B (8.20 g, 18.0 mmol) in THF (500 mL) was added LiAlH4 powder (2.66 g, 70.0 mmol) at -10 °C under N2. The mixture was stirred for 2 h at RT and excess LiAlH4 destroyed by slow addition of ice. The reaction mixture was acidified to pH = 7 with dilute HCl, concentrated in vacuo and the residue extracted with EtOAc. The combined organic layers were concentrated in vacuo to yield 1 - {3 -tert-butyl- 1 - [3 -(hydroxymethyl)phenyl] - lH-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (7.40 g, 99%) as a white powder. Η NMR (DMSO- d6): 9.19 (s, 1 Η), 9.04 (s, 1 Η), 8.80 (s, 1 Η), 8.26-7.35 (m, 11 Η), 6.41 <s, 1 Η), 4.60 (s, 2 Η), 1.28 (s, 9 Η); MS (ESI) m/z: 415 (M+Η+).
EXAMPLE E
Figure imgf000081_0001
A solution of Example C (1.66 g, 4.0 mmol) and SOCl2 (0.60 mL, 8.0 mmol) in CH3C1 (100 mL) was refluxed for 3 h and concentrated in vacuo to yield l-{3-tert-butyl-l-[3- chloromethyl)phenyl]-lH-pyrazol-5-yl}-3-(naphthalen-l-yl)urea (1.68 g, 97%) was obtained as white powder. 'Η NMR (DMSO---/6): δ 9.26 (s, 1 H), 9.15 (s, 1 H), 8.42 - 7.41 (m, 11 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H). MS (ESI) m/z: 433 (M+H+).
EXAMPLE F
Figure imgf000082_0001
To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added LiAlH4 powder (413 mg, 10.9 mmol) at -10 °C under N2. The mixture was stirred for 2h and excess LiAlH4 was quenched by adding ice. The solution was acidified to pH = 7 with dilute HCl. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200 + 100 mL). The filtrate was concentrated to yield l-{3-tert-butyl-l-[3-hydroxymefhyl)phenyl]- lH-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.40 g, 97%). ]Η NMR (DMSO- d6): δ 9.11 (s, IH), 8.47 (s, IH), 7.47-7.27 (m, 8H), 6.35 (s, IH), 5.30 (t, J = 5.6 Hz, IH), 4.55 (d, J = 5.6 Hz, 2H),
1.26 (s, 9H); MS (ESI) m/z: 399 (M+H+).
EXAMPLE G
Figure imgf000082_0002
A solution of Example F (800 mg, 2.0 mmol) and SOCl2 (0.30 mL, 4 mmol) in CHC13
(30 mL) was refluxed gently for 3h. The solvent was evaporated in vacuo and the residue was taken up to in CH2C12 (2 x 20 mL). After removal of the solvent, l-{3-te7-t-butyl-l-[3- (chloiOmethyl)phenyl]-lH-pyrazol-5-yl}-3-(4-chloiOphenyl)urea (812 mg, 97%) was obtained as white powder. 'ΗNMR (DMSO- d6): δ 9.57 (s, 1Η), 8.75 (s, 1Η), 7.63 (s, 1Η), 7.50 - 7.26 (m, 7H), 6.35 (s, IH), 4.83 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 417 (M+H+).
EXAMPLE H
Figure imgf000083_0001
To a suspension of LiAlH4 (5.28 g, 139.2 mmol) in THF (1000 mL) was added Example
A (20.0 g, 69.6 mmol) in portions at 0 °C under N2. The reaction mixture was stiired for 5 h, quenched with 1 N HCl at 0 °C and the precipitate was filtered, washed by EtOAc and the filtrate evaporated to yield [3-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)phenyl]methanol (15.2 g, 89%).
'Η NMR (DMSO-J6): 7.49 (s, 1Η), 7.37 (m, 2Η), 7.19 (d, J = 7.2 Hz, IH), 5.35 (s, IH), 5.25 (t, J =5.6 Hz, IH), 5.14 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 1.19 (s, 9H); MS (ESI) m/z: 246.19
(M+H+).
The crude material from the previous reaction (5.0 g, 20.4 mmol) was dissolved in dry THF (50 mL) and SOCl2 (4.85 g, 40.8 mmol), stirred for 2h at RT, concentrated in vacuo to yield 3 -tert-butyl- 1 -(3 -chloromethylphenyl)- lH-pyrazol-5-amine (5.4 g), which was added to N3 (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixture was heated at 30 °C for 2 h, poured into
Η2O (50 mL), and extracted with CH2C12. The organic layers were combined, dried over MgSO4, and concentrated in vacuo to yield crude 3-te7-t-butyl-l-[3-(azidomethyl)phenyl]-lH-pyrazol-5- amine (1.50 g, 5.55 mmol).
EXAMPLE I
Figure imgf000084_0001
Example H was dissolved in dry THF (10 mL) and added a THF solution (10 mL) of 1- isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) atRT. The reaction mixture was stirred for 3h, quenched with H2O (30 mL), the resulting precipitate filtered and washed with 1NHC1 and ether to yield l-[2-(3-azidomethyl-phenyl)-5-t-butyl-2H-pyrazol-3-yl]-
3-naphthalen-l-yl-urea (2.4 g, 98%) as a white solid.
The crude material from the previous reaction and Pd/C (0.4 g) in THF (30 mL) was hydrogenated under 1 atm at RT for 2 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield l-{3-tert-butyl-l-[3-(amonomethyl)phenyl}-lH-pyrazol-5yl)-3- (naphthalene-l-yl)urea (2.2 g, 96%) as a yellow solid. Η NMR (DMSO-J6): 9.02 (s, 1Η), 7.91 (d, J= 7.2 Ηz, IH), 7.89 (d, J = 7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, IH), 3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H+).
EXAMPLE J
Figure imgf000084_0002
To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H2O (30 mL) was added. The precipitate was filtered and washed with IN HCl and ether to give l-{3-tert-butyl-l-[3- (amonomethyl)phenyl}-lH-pyrazol-5yl)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for next step without further purification. MS (ESI) m z: 424 (M+Η+).
EXAMPLE K
Figure imgf000085_0001
To a solution of benzyl amine (16.5g, 154 mmol) and ethyl bromoacetate (51.5g, 308 mmol) in ethanol (500 mL) was added K2CO3 (127.5g, 924 mmol). The mixture was stirred at
RT for 3h, was filtered, washed with EtOH, concentrated in vacuo and cliromatographed to yield
N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (29g, 67%). Η NMR (CDC13): δ 7.39-7.23 (m, 5H), 4.16 (q, J= 7.2 Hz, 4H), 3.91(s, 2H), 3.54 (s, 4H), 1.26 (t, J= 7.2 Hz, 6H);
MS (ESI): m/e: 280 (M++H).
A solution of N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (7.70g, 27.6 mmol) in methylamine alcohol solution (25-30%, 50 mL) was heated to 50°C in a sealed tube for 3h, cooled to RT and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-N- (phenylmethyl)-glycine methylamide in quantitative yield (7.63g). 'H NMR (CDC13): δ 7.35-
7.28 (m, 5H), 6.75 (br s, 2H), 3.71(s, 2H), 3.20 (s, 4H), 2.81 (d, J= 5.6 Hz, 6H); MS (ESI) m/e 250(M+H+).
The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide
(3.09g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40°C under 40 psi H2 for lOh, filtered and concentrated in vacuo to yield N-(2- methylamino-2-oxoethyl)-glycine methylamide in quantitative yield (1.76g). 'H NMR (CDC13): δ 6.95(br s, 2H), 3.23 (s, 4H), 2.79 (d, J-6.0, 4.8 Hz), 2.25(br s IH); MS (ESI) m/e 160(M+H+) EXAMPLE 1
Figure imgf000086_0001
To a solution of l-methyl-[l,2,4]triazolidine-3, 5-dione (188 mg, 16.4 mmol) and sodium hydride (20 mg, 0.52 mmol) in DMSO (1 mL) was added Example E (86 mg, 0.2 mmol). The reaction was stirred at RT overnight, quenched with H2O (10 mL), extracted with CH2C12, and the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to yield l-(3-tert-butyl-l-{3-[(l-methyl- 3,5-dioxo-l,2,4-triazolidin-4-yl)methyl]phenyl}-lH-pyrazol-5-yl)-3-(naphthalene-l-yl)urea (Example 1, 14 mg). 'ΗNMR (CD3OD): 67.88-7.86 (m, 2Η), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, IH), 4.85 (s, IH), 1.34 (s, 9H), 1.27 (s, 6H); MS (ESI) m/z: 525
(M+H+).
EXAMPLE 2
Figure imgf000087_0001
The title compound was synthesized in a manner analogous to Example 1, utilizing Example G to yield l-(3-tert-butyl-l-{3-[(l-methyl-3,5-dioxo-l,2,4-triazolidin-4- yl)methyl]phenyl}-lH-pyrazol-5-yl)-3-(4-chloroρhenyl)urea 1Η NMR (CD3OD): δ 7.2-7.5 (m, 7H), 6.40 (s IH), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, IH), 1.50 (m, IH), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H+).
EXAMPLE 3
Figure imgf000087_0002
A mixture of compound l,l-Dioxo-[l,2,5]thiadiazolidin-3-one (94 mg, 0.69 mmol) and NaH (5.5 mg, 0.23 mmol) in THF (2 mL) was stirred at -10 °C under N2 for lh until all NaH was dissolved. Example E (100 mg, 0.23 mmol) was added and the reaction was allowed to stir at RT overnight, quenched with H2O, and extracted with CH2C12. The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC to yield l-(3-tert-butyl- l-{[3-(l,l,3-trioxo-[l,2,5]thiadiazolidin-2-yl)methyl]phenyl}-lH-pyrazol-5-yl)-3-(naphthalen-l- yl)urea (18 mg) as a white powder. 'Η NMR (CD3OD): δ 7.71 - 7.44 (m, 11 Η), 6.45 (s, 1 Η), 4.83 (s, 2 H), 4.00 (s, 2 H), 1.30 (s, 9 H). MS (ESI) m/z: 533.40 (M+H+).
EXAMPLE 4
Figure imgf000088_0001
The title compound was obtained in a manner analogous to Example 3 utilizing Example G. to yield l-(3-tert-butyl-l-{[3-(l,l,3-trioxo-[l,2,5]thiadiazolidin-2-yl)methyl]phenyl}-lH- pyrazol-5-yl)-3-(4-chlorophenyl)urea. ΗNMR (CD3OD): δ 7.38 - 7.24 (m, 8 Η), 6.42 (s, 1 Η),
4.83 (s, 2 Η), 4.02 (s, 2 Η), 1.34 (s, 9 Η); MS (ESI) m/z: 517 (M+Η+).
EXAMPLE 5
Figure imgf000088_0002
To a stirred solution of chlorosulfonyl isocyanate (19.8 μL, 0.227 mmol) in CH2C12 (0.5 mL) at 0°C was added pyrrolidine (18.8 μL, 0.227 mmol) at such a rate that the reaction solution temperature did not rise above 5 °C. After stirring for 1.5 h, a solution of Example J (97.3 mg,
0.25 mmol) and Et3N (95 μL, 0.678 mmol) in CH2C12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 °C. When the addition was completed, the reaction solution was warmed to RT and stirred ovemight. The reaction mixture was poured into 10% HCl, extracted with CH2C12, the organic layer washed with saturated NaCl, dried over MgSO4, and filtered. After removal ofthe solvents, the c de product was purified by preparative HPLC t o y i e l d l - ( 3 - t e r t - b u t y l - l - [ [ 3 - N - [ [ ( l - pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-lH-pyrazol-5-yl)-3-(4- chlorophenyl)urea. Η NMR(CD3OD): δ 7.61 (s, 1 Η), 7.43 -7.47 (m, 3 Η), 7.23 - 7.25 (dd, J =6.8 Ηz, 2 Η), 7.44 (dd, J=6.8 Ηz, 2 Η), 6.52 (s, 1 Η), 4.05 (s, 2 Η), 3.02 (m, 4 Η), 1.75 (m, 4 Η), 1.34 (s, 9 Η); MS (ESI) m/z: 574.00 (M+Η+).
EXAMPLE 6
Figure imgf000089_0001
The title compound was made in a manner analogous to Example 5 utilizing Example I to yield 1 -(3 -te/-t-butyl- 1 - [ [3 -N-[ [( 1 -pyιτolidinylcarbonyl)amino] sulphonyl]aminomethyl]- phenyl]-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea. 'ΗNMR CDCLV. δ 7.88 (m, 2Η), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, 1 H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H+).
EXAMPLE 7
Figure imgf000089_0002
To a stirred solution of chlorosulfonyl isocyanate (19.8 μΛ, 0.227 μμoλ) iv
Figure imgf000090_0001
(0.5 μΛ) ατ 0°C, was added Example J (97.3 mg, 0.25 mmol) at such a rate that the reaction solution temperature did not rise above 5 °C. After being stirred for 1.5 h, a solution of pyiTolidine (18.8 μL, 0.227 mmol) and Et3N (95 μL, 0.678 mmol) in CH2C12 (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 °C. When addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCl, extracted with CH2C12, the organic layer was washed with saturated NaCl, dried over Mg2SO4, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC to yield 1 - (3 - tert-b uty 1 - 1 - [ [ 3 -N- [ [ ( 1 - pyrrolidinylsulphonyl)amino] carbonyl] aminomethyl]phenyl]-lH-pyrazol-5-yl)-3-(4- chlorophenyl)urea. 'ΗNMR (CDC13): δ 7.38 (m, 1 Η), 7.36 - 7.42 (m, 3 Η), 7.23 (d, J= 8.8 Ηz, 2 Η), 7.40 (d, J= 8.8 Ηz, 2 Η), 6.43 (s, 1 Η), 4.59 (s, 1 Η), 4.43 (s, 2 Η), 1.81 (s, 2 Η), 1.33 (s, 9 TT); MS (ESI) m/z: 574.10 (M+Ε ).
EXAMPLE 8
Figure imgf000090_0002
The title compound was made in a manner analogous to Example 7 utilizing Example I to yield l-(3-tert-butyl-l-[[3-N-[[(l-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]- phenyl]-lH-pyrazol-5-yl)-3-(naphthalen-l-yl)urea. 'ΗNMR (CDC13): δ 7.88 (m, 2 Η), 7.02 - 7.39
(m, 2 Η), 7.43 - 7.50 (m, 7 Η), 6.48 (s, 1 Η), 4.45 (s, 1 Η), 3.32 - 3.36 (m, 4 Η), 1.77-1.81 (m,
4 Η), 1.34 (s,9 Η); MS (ESI) m/z: 590.03 (M+Η+).
EXAMPLE 9
Figure imgf000091_0001
To a solution of Reagent BB (36 mg, 0.15 mmol), Example I (62 mg, 0.15 mmol), HOBt
(40 mg, 0.4 mmol) and NMM (0.1 mL, 0.9 mmol) in DMF (10 mL) was added EDCI (58 mg, 0.3 mmol). After being stin-ed ovemight, the mixture was poured into water (15 mL) and extracted with EtOAc (3 5 mL). The organic layers were combined, washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to yield l,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]nonane-7-carboxylic acid 3-[3-t-butyl-5-(3- naphthalen-l-yl-ureido)-pyrazol-l-yl]benzylamide (22 mg). 'H NMR (CDC13): δ 8.40 (s, IH), 8.14 (d, J= 8.0 Hz, 2H), 7.91 (s, IH), 7.87 (s, IH), 7.86 (d, J= 7.2 Hz, IH), 7.78 (d, J= 7.6 Hz, IH), 7.73 (d, J= 8.4 Hz, IH), 7.69 (d, J= 8.4 Hz, IH), 7.57-7.40 (m, 4H), 7.34 (d, J= 7.6 Hz, IH), 6.69 (s, IH), 6.32 (t, J= 5.6 Hz, IH), 5.92 (brs, IH), 4.31 (d, J= 5.6 Hz, 2H), 2.37 (d, J= 14.8 Hz, 2H), 1.80 (d, J= 13.2 Hz, IH), 1.35 (s, 9H), 1.21 (d, J= 13.2 Hz, IH), 1.15 (s, 3H),
1.12 (d, J= 12.8 Hz, 2H), 1.04 (s, 6H); MS (ESI) m/z: 635 (M+H+).
EXAMPLE 10
Figure imgf000092_0001
The title compound, was synthesized in a manner analogous to Example 9 utilizing Example J to yield l,5,7-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3. l]nonane-7-carboxylic acid 3-{3- t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyι-azol-l-yl}benzylamide. 'H MR (CDC13): δ 8.48 (s, IH), 7.78 (s, IH), 7.75 (d, J= 8.0 Hz, IH), 7.69 (s, IH), 7.53 (t, J= 8.0 Hz, IH), 7.48 (d, J= 8.8
Hz, 2H), 7.26 (m, 3H), 6.62 (s, IH), 6.35(t, J= 6.0 Hz, IH), 5.69 (brs, IH), 4.26 (d, J= 6.0 Hz, 2H), 2.48 (d,J= 14.0 Hz, 2H), 1.87 (d, J= 13.6 Hz,lH), 1.35 (s, 9H), 1.25 (m, 6H), 1.15 (s, 6H); MS (ESI) m/z: 619 (M+H+).
EXAMPLE 11
Figure imgf000093_0001
A mixture of Example I (41 mg, 0.1 mmol), Kemp acid anhydride (24 mg, 0.1 mmol) and Et3N (100 mg, 1 mmol) in anhydrous CH2C12 (2 mL) were stiπ-ed overnight at RT, and concentrated in vacuo. Anhydrous benzene (20 mL) was added to the residue, the mixture was refluxed for 3h, concentrated in vacuo and purified by preparative HPLC to yield 3-{3-[3-t- butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-l-yl]-benzyl}-l,5-di-methyl-2,4-dioxo-3-aza- bicyclo[3.3.1]nonane-7-carboxylic acid (8.8 mg, 14%). !H NMR (CD3OD): δ 7.3 - 7.4 (m, 2H), 7.20 (m, 2H), 7.4 - 7.6 (m, 7H), 6.50 (m, IH), 4.80 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m,
IH), 1.40 (m, IH), 1.30 (m, 2H), 1.20 (s, 3H), 1.15 (s, 6H); MS (ESI) m/z: 636 (M+H+).
EXAMPLE 12
Figure imgf000093_0002
The title compound, was synthesized in a manner analogous to Example 11 utilizing Example j to yield 3-{3-[3-t-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-l-yl]-benzyl}-l,5- dimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid. Η NMR (CD3OD): δ 7.2 - 7.5 (m, 7H), 6.40 (s IH), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, IH), 1.50 (m, IH), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H+).
EXAMPLE 13
Figure imgf000094_0001
The title compound was synthesized in a manner analogous to Example 1 utilizing Example E and 4,4-dimethyl-3,5-dioxo-pyrazolidiιιe to yield l-(3-tert-butyl-l-{3-[(4,4-dimethyl- 3,5-dioxopyrazolidin- 1 -yl)methyl]phenyl} - lH-pyrazol-5-yl)-3-(naphthalen-l -yl)urea. Η MR (CD3OD): δ 7.88 - 7.86 (m, 2Η), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42.(m, 5H), 6.49 (s, IH), 4.85 (s, IH), 1.34 (s, 9H), 1.27 (s, 6H); MS (ESI) m/z: 525 (M+H+).
EXAMPLE 14
Figure imgf000095_0001
The title compound was synthesized in a manner analogous to Example 1 utilizing Example G and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield l-(3-tert-butyl-l-{3-[(4,4- dimethyl-3,5-dioxopyrazolidin-l-yl)methyl]phenyl}-lH-pyrazol-5-yl)-3-(4-chlorophenyl)urea. 'Η NMR (CD3OD): δ 7.60 - 7.20 (m, 8Η), 6.43 (s, IH), 4.70 (s, IH), 1.34 (s, 9H), 1.26 (s, 6H); MS (ESI) m/z: 509, 511 (M+H+).
EXAMPLE 15
Figure imgf000095_0002
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (64.2 mg, 0.15 mmol) were added HOBt (30 mg, 0.225 mmol), Example K (24 mg, 0.15 mmol) and 4- methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF (3 mL) and EDCI (43 mg, 0.225 mmol).
The reaction mixture was stirred at RT overnight and poured into H2O (3mL), and a white precipitate collected and further purified by preparative HPLC to yield l-[l-(3- {bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-tert-butyl-lH-pyrazol-5-yl]-3-(naphthalen- l-yl)urea (40 mg). Η NMR (CDC13): δ 8.45 (brs, 1Η), 8.10 (d, J= 7.6 Ηz, 1Η), 7.86-7.80 (m, 2Η), 7.63-7.56 (m, 2H), 7.52 (s, IH), 7.47-7.38 (m, 3H), 7.36-7.34 (m, IH), 726 (s, IH), 7.19- 7.17 (m, 2H), 6,60 (s, IH), 3.98 (s, 2H), 3.81 (s, 3H), 2.87 (s, 3H), 2.63 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z: 570 (M+H+).
EXAMPLE 16
Figure imgf000096_0001
The title compound was synthesized in a mamier analogous to Example 15 utilizing Example C (37 mg) and Example K to yield l-[l-(3- {bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-te7-t-butyl-lH-pyrazol-5-yl]-3-(4- chlorophenyl)urea. Η NMR (CD3OD): δ 8.58 (brs, 1Η), 8.39 (brs, 1Η), 7.64 - 7.62 (m, 3Η), 7.53-7.51 (m,lH), 7.38 (d,J= 9.2 Hz, 2H), 7.25 (d,J= 8.8 Hz, 2H), 6.44 (s, IH), 4.17 (s, 2H), 4.11 (s, 2H), 2.79 (s, 3H), 2.69 (s, 3H), 1.34-1.28 (m, 12H); MS (ESI) m/z: 554 (M+lT).
EXAMPLE 17
Figure imgf000097_0001
Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (0.642 g,
1.5 mmol) in dry THF (25 mL) at -78 °C were added freshly distilled triethylamine (0.202 g, 2.0 mmol) and pivaloyl chloride (0.216 g,1.80 mmol) with vigorous stiiτing. After stirring at -78 °C for 1 min and at 0 °C for 45 min, the mixture was again cooled to -78 °C and then transferred into the THF solution of lithium salt of D-4-phenyl-oxazolidin-2-one [*: The lithium salt ofthe oxazolidinone regeant was previously prepared by the slow addition of n-BuLi (2.50M in hexane, 1.20 mL, 3.0 mmol) into THF solution of D- 4-phenyl-oxazoldin-2-one at -78 °C], The reaction solution was stirred at -78 °C for 2 h and RT overnight, and then quenched with aq. ammonium chloride and extracted with dichloromethane (100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC to yield D-l-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H- pyrazol-3-yl}-3-(naphthalen-l-yl)urea (207 mg, 24%). 'ΗNMR (CDC13): δ 8.14 - 8.09 (m, 2Η),
8.06 (s,lH), 7.86 - 7.81 (m, 4H), 7.79 (s, IH), 7.68 - 7.61 (m, 2H), 7.51 - 7.40 (m, 9H), 6.75 (s, IH), 5.80 (t, J=9.2, 7.6 Hz, IH), 4.89 (t, J= 9.2 Hz, IH), 4.42 (dd, J=9.2, 7.6 Hz, IH), 1.37 (s,
9H); MS (ESI) m/z: 574 (M+H+). EXAMPLE 18
Figure imgf000098_0001
The title compound was synthesized in a manner analogous to Example 17 utilizing Example B and L-4-phenyl-oxazolidin-2-one to yield L-l-{5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-l-yl)urea 'Η NMR (CDC13): δ 8.14 - 8.09 (m, 2Η), 8.06 (s,lH), 7.86 - 7.81 (m, 4H), 7.79 (s, IH), 7.68 - 7.61 (m, 2H), 7.51 - 7.40 (m, 9H), 6.75 (s, IH), 5.80 (t, J=9.2, 7.6 Hz, IH), 4.89 (t, J= 9.2 Hz, IH), 4.42 (dd, J=9.2, 7.6 Hz, IH), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H+)
EXAMPLE 19
Figure imgf000098_0002
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and D-4-phenyl-oxazolidin-2-one to yield D-l-{5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(4-chlorophenyl)urea. !Η NMR (CDC13): δ 7.91 (s, IH), 7.85 (d, J= 8.0 Hz, IH), 7.79 (d, J= 7.6 Hz, IH), 7.71 (m, IH), 7.65 (m, IH), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, IH), 5.77 (dd, J= 8.8, 8.0 Hz, IH), 4.96 (t, 8.8 Hz, IH), 4.44 (dd, J= 8.8, 8.0 Hz, IH), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+If)
EXAMPLE 20
Figure imgf000099_0001
The title compound was synthesized in a manner analogous to Example 17 utilizing Example C and L-4-phenyl-oxazolidin-2-one to yield L-l-{5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2H-pyι-azol-3-yl}-3-(4-chlorophenyl)urea. Η NMR (CDC13): δ 7.91 (s, 1Η), 7.85 (d, J= 8.0 Ηz, 1Η), 7.79 (d, J= 7.6 Ηz, 1Η), 7.71 (m, 1Η), 7.65 (m, 1Η), 7.49 - 7.40 (m, 8Η), 7.26 - 7.24 (m, 2H), 6.68 (s, IH), 5.77 (dd, J= 8.8, 8.0 Hz, IH), 4.96 (t, 8.8 Hz, IH), 4.44 (dd, J= 8.8, 8.0 Hz, IH), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H+)
EXAMPLE L
Figure imgf000100_0001
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2C12 (40 ml, with a catalytic amount of DMF) at 0 °C under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield l-morpholin-4- yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1 -mo holin-4-yl-2-(3-nitro-pheny)- ethanone (2 g) and 10 % Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3h and filtered over Celite. Removal ofthe volatiles in vacuo provided 2-(3-amino- phenyl)- 1 -morpholin-4-yl-efhanone ( 1.7 g) . A solution of 2-(3-amino-phenyl)- 1 -morpholin-4-yl- ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0 °C, and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-l- morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-l-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for lh and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide
2-[3-(3-tert-butyl-5-amino-lH-pyι-azol-l-yl)phenyl]-l-morpholinoethanone (4 g), which was used without further purification. EXAMPLE 21
Figure imgf000101_0001
A mixture ofExampleL (0.2 g, 0.58 mmol) and l-naρhthylisocyanate (0.10 g, 0.6 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2Cl2 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield l-{3-tert-butyl-l-[3-(2-morpholino-2- oxoethyl)phenyl]-lH-pyrazol-5-yl}-3-(naphthalene-l-yl)urea. mp: 194 - 196 ; !Η NMR (200MHz, DMSO- d): δ 9.07 (IH, s), 8.45 (s, IH), 8.06 - 7.93 (m, 3H), 7.69 - 7.44 (m, 7H), 7.33 - 7.29 (d, 6.9 Hz, IH), 6.44 (s, IH), 3.85 (m, 2H), 3.54 - 3.45 (m, 8H), 1.31 (s, 9H); MS:
EXAMPLE 22
Figure imgf000101_0002
The title compound was synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate (0.09 g, 0.6 mmol) to yield l-{3- tert-butyl- 1 -[3 -(2-morpholino-2-oxoethyl)phenyl] - lH-pyrazol-5 -yl} -3 -(4-chlorophenyl)urea. mp: 100 104 ; Η NMR (200MΗz, DMSO-d6): δ 9.16 (s, IH), 8.45 (s, IH), 7.52-7.30 (m, 8H), 6.38 (s, IH), 3.83 (m, IH), 3.53 - 3.46 (m, 8H), 1.30 (s, 9H); MS:
EXAMPLE 23
Figure imgf000102_0001
The title compound is synthesized in a manner analogous to Example 21 utilizing
Example L (0.2 g, 0.58 mmol) and phenyhsocyanate (0.09 g, 0.6 mmol) to yield l-{3-tert-butyl- l-[3-(2-moιpholino-2-oxoethyl)phenyl]-lH-pyrazol-5-yl}-3-phenylurea.
EXAMPLE 24
Figure imgf000102_0002
The title compound is synthesized in a manner analogous to Example 21 utilizing Example L (0.2 g, 0.58 mmol) and l-isocyanato-4-methoxy-naphthalene to yield 1- (3-tert-butyl- l-[3-(2-morpholino-2-oxoethyl)phenyl]-lH-ρyrazol-5-yl}-3-(l-metlιoxynaphthalen-4-yl)urea.
EXAMPLE M
Figure imgf000103_0001
The title compound is synthesized in a manner analogous to Example C utilizing Example A and phenyhsocyanate to yield ethyl 3-(3-tert-butyl-5-(3-phenylureido)- lΗ-pyrazol- 1 - yl)benzoate.
EXAMPLE N
Figure imgf000103_0002
A solution of (3-nitrophenyl)acetic acid (23 g, 127 mmol) in methanol (250 ml) and a catalytic amount of concentrated in vacuo Η2S04 was heated to reflux for 18 h. The reaction mixture was concentrated in vacuo to a yellow oil. This was dissolved in methanol (250 ml) and stirred for 18 h in an ice bath, whereupon a slow flow of ammonia was charged into the solution. The volatiles were removed in vacuo. The residue was washed with diethyl ether and dried to afford 2-(3-nitrophenyl)acetamide (14 g, off-white solid). Η NMR (CDC13): δ 8.1 (s, IH), 8.0
(d, IH), 7.7 (d, IH), 7.5 (m, IH), 7.1 (bd s, IH), 6.2 (brs, IH), 3.6 (s, 2H).
The crude material from the previous reaction (8 g) and 10 % Pd on activated carbon (1 g) in ethanol (100 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-aminophenyl)acetamide (5.7 g). A solution of this material (7 g, 46.7 mmol) was dissolved in 6 N HCl (100 ml), cooled to 0 °C, and vigorously stirred. Sodium nitrite (3.22 g, 46.7 mmol) in water (50 ml) was added. After 30 min, tin (II) chloride dihydrate (26 g) in 6 N HCl (100 ml) was added. The reaction mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo provided 2-(3- hydrazinophenyl)acetamide.
The crude material from the previous reaction (ca. 15 mmol) and 4,4-dimethyl-3- oxopentanenitrile ( 1.85 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1.5 ml) was refluxed for
1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue, which was extracted with ethyl acetate. The solvent was removed in vacuo to provide 2-[3-(3- tert-butyl-5 -amino- lH-pyrazol-l-yl)phenyl]acetamide as a white solid (3.2 g), which was used without further purification.
EXAMPLE 25
Figure imgf000104_0001
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2C12 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield l-{3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-lH-ρyrazol-5-yl}-3-(naphthalene-l-yl)urea as a white solid (0.22 g). mp: 230 (dec); Η NMR (200MΗz, DMSO- d6): δ 9.12 (s, IH), 8.92 (s, IH), 8.32 - 8.08 (m, 3H), 7.94 - 7.44 (m, 8H), 6.44 (s, IH), 3.51 (s, 2H), 1.31 (s, 9H); MS:
EXAMPLE 26
Figure imgf000106_0001
The title compound was synthesized in a manner analogous to Example 23 utilizing
Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate (0.112 g, 0.73 mmol) to yield 1- {3-tert-butyl-l-[3-(carbamoylmethyl)phenyl)-lH-pyrazol-5-yl}-3-(4-chloiOphenyl)urea as a white solid ( 0.28 g). mp: 222 224 . (dec); 'ΗNMR (200MΗz, DMSO- d6); δ 9.15 (s, IH), 8.46 (s, IH), 7.55 - 7.31 (m, 8H), 6.39 (s, IH), 3.48 (s, 2H), 1.30 (s, 9H); MS:
EXAMPLE O
Figure imgf000107_0001
The title compound is synthesized in a manner analogous to Example C utilizing Example A and l-isocyanato-4-methoxy-naphthaleneto yield ethyl 3-(3-tert-butyl-5-(3-(l- methoxynaphthalen-4-yl)ureido)- 1 H-pyrazol- 1 -yl)benzoate.
EXAMPLE 27
Figure imgf000107_0002
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and D-4-phenyl-oxazolidin-2-one to yield D-l-{5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3 -carbonyl)phenyl] -2H-pyrazol-3 -yl} -3 -phenylurea. EXAMPLE 28
Figure imgf000108_0001
The title compound is synthesized in a manner analogous to Example 17 utilizing Example M and and L-4-phenyl-oxazolidin-2-one to yield L-l-{5-tert-butyl-2-[3-(2-oxo-4- phenyl-oxazolidinyl-3 -carbonyl)phenyl] -2H-pyrazol-3 -yl} -3 -phenylurea.
EXAMPLE P
Figure imgf000109_0001
A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10 % Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30 psi for 18Λ and filtered over Celite. Removal of the volatiles in vacuo provided 3-(3-amino-phenyl)propionic acid methyl ester (6 g).
A vigorously stirred solution ofthe crude material from the previous reaction (5.7 g, 31.8 mmol) dissolved in 6 N HCl (35 ml) was cooled to 0 °C, and sodium nitrite (2.2 g) in water (20 ml) was added. After lh, tin (II) chloride dihydrate (18 g) in 6 N HCl (35 ml) was added. And the mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided methyl 3-(3-hydrazino-phenyl)propionate (1.7 g). A stirred solution ofthe crude material from the previous reaction (1.7 g, 8.8 mmol) and
4,4-dimethyl-3-oxopentanenitrile ( 1.2 g, 9.7 mmol) in ethanol (30 ml) and 6 N HCl (2 ml) was refluxed for 18 h and cooled to RT. The volatiles were removed in vacuo and the residue dissolved in EtOAc and washed with 1 N aqueous NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo and the residue was purified by column chromatography using 30 % ethyl acetate in hexane as the eluent to provide methyl 3-[3-(3-tert-butyl-5-amino-lH-pyrazol
-l-yl)phenyl]propionate (3.2 g), which was used without further purification EXAMPLE 29
Figure imgf000110_0001
A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19 g, 1.05 mmol) in dry CH2C12 (5 ml) was stirred at RT under N2 for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc and dilute citric acid solution. The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column cliromatography using 3 % methanol in CH2C12 as the eluent to yield 3-(3-{3-tert-butyl-5-[3-(naphthalen-l-yl)ureido]-lH-pyrazol-l- yl)phenylpropionic acid (0.22 g, brownish solid), mp: 105-107 ; 'Η NMR (200MΗz, CDC13): δ 7.87 - 7.36 (m, 10H), 7.18 - 7.16 (m, IH), 6.52 (s, IH), 2.93 (t, J= 6.9 Hz, 2H), 2.65 (t, J= 7.1 Hz, 2H), 1.37 (s, 9H); MS
EXAMPLE 30
Figure imgf000111_0001
The title compound was synthesized in a manner analogous to Example 29 utilizing
Example P (0.30g, 0.95 mmol) and 4-chlorophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3-
{3-tert-butyl-5-[3-(4-chloropnehyl)ureido]-lH-pyrazol-l-yl)phenyl)propionic acid (0.05 g, white solid). mp:85 87 ; ΗNMR (200MΗz, CDC13): δ 8.21 (s, IH), 7.44 - 7.14 (m, 7H), 6.98 (s, IH),
6.55 (s, IH), 2.98 (t, J= 5.2 Hz, 2H), 2.66 (t, J= 5.6 Hz, 2H), 1.40 (s, 9H); MS
EXAMPLE Q
Figure imgf000111_0002
A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal ofthe volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
A solution of the crude material from the previous reaction (1.5 g, 8.4 mmol) was dissolved in 6 N HCl (9 ml), cooled to 0 °C, and vigorously stirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After lh, tin (TT) chloride dihydrate (5 g) in 6 N HCl (10 ml) was added. The reaction mixture was stirred at 0 °C for 3h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc The combined organic extracts were concentrated in vacuo provided ethyl 3-(4-hydrazino-phenyl)-propionate(l g).
The crude material from the previous reaction (1 g, 8.8 mmol) and 4,4-dimethyl-3- oxopentanenitrile ( 0.7 g) in ethanol (8 ml) and 6 N HCl (1 ml) was refluxed for 18h and cooled to RT. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column cliromatography using 0.7 % methanol in CH2C12 as the eluent to provide ethyl 3-{4-[3-tert-butyl-5-(3-(naphthalene-l- yl)ureido]-lH-pyrazol-l-yl}phenyl)prpanoate (0.57 g).
EXAMPLE 31
Figure imgf000112_0001
Amixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13 g, 0.8 mmol) in dry CΗ2C12 (5 ml) was stirred at RT under N2 for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3h at RT and diluted with EtOAc and diluted citric acid solution. The organic layer was dried (Na2SO4), and the volatiles removed in vacuo. The residue was purified by column chromatography using 4 % methanol in CH2Cl2as the eluent to yield 3- {4-[3- tert-butyl-5-(3-(naphthalene-l-yl)ureido]-lH-pyrazol-l-yl}phenyl)propanonic acid (0.18 g, off- white solid), mp: 120 122 ; "Η NMR (200MΗz, CDC13): δ 7.89 - 7.06 (m, 11H), 6.5 (s, IH), 2.89 (m, 2H), 2.61 (m, 2H), 1.37 (s, 9H); MS EXAMPLE 32
Figure imgf000113_0001
The title compound was synthesized in a maimer analogous to Example 31 utilizing
Example Q (0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate (0.077 g, 0.5 mmol) to yield 3-{4- [3-tert-butyl-5-(3-(4-chloφhenyl)ureido]-lH-pyrazol-l-yl}phenyl)propanonic acid acid (0.16 g, off-white solid), mp: 112 - 114 ; *Η NMR (200MΗz, CDC13): δ 8.16 (s, IH), 7.56 (s, IH),
7.21 (s, 2H), 7.09 (s, 2H), 6.42 (s, IH), 2.80 (m, 2H), 2.56 (m, 2H), 1.32 (s, 9H); MS
EXAMPLE R
Figure imgf000114_0001
A 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with 3- nitrobiphenyl (20 g, 0.10 mol) dissolved in THF (-100 mL) and 10% Pd C (3 g). The reaction vessel was charged with H2 (g) and purged three times. The reaction was charged with 40 psi H2 (g) and placed on a Parr shaker hydrogenation apparatus and allowed to shake overnight at RT. HPLC showed that the reaction was complete thus the reaction mixture was filtered through a bed of Celite and evaporated to yield the amine: 16.7g (98% yield) h a 250 mL Erlenmeyer flask with a magnetic stir bar, the crude material from the previous reaction (4.40 g, 0.026 mol) was added to 6 N HCl (40 mL) and cooled with an ice bath to ~ 0 °C. A solution of NaNO2 (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 L) was added drop wise. After 30 min, SnCl2'2H2O (52.0 g, 0.23 mol, 8.86 eq.) in 6N HCl (100 mL) was added and the reaction mixture was allowed to stir for 3h, then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for 4h, concentrated in vacuo and the residue extracted with EtOAc (2x100 mL). The residue was purified by column chromatograph using hexane/ EtOAc/Et3N (8:2:0.2) to yield 0.53g of Example R. Η NMR (CDC13): δ 7.5 (m, 18H), 5.8 (s, IH), 1.3 (s, 9H). EXAMPLE 33
Figure imgf000115_0001
In a dry vial with a magnetic stir bar, Example R (0.145 g; 0.50 mmol) was dissolved in 2 mL CH2C12 (anhydrous) followed by the addition of he-iylisocyanate (0.0544 mL; 0.50mmol;
1 eq.). The reaction was kept under argon and stiired for 17h. Evaporation of solvent gave a crystalline mass that was triturated with hexane/EtOAc (A: 1 ) and filtered to yield 1 -(3-tert-butyl- l-(3-phenylphenyl)-lH-ρyrazol-5-yl)-3-phenylurea (0.185 g, 90%). ΗPLC purity: 96%; mp: 80 84 ; 'Η MR (CDCLV. δ 7.3 (m, 16 Η), 6.3 (s, 1Η), 1.4 (s,.9Η).
EXAMPLE 34
Figure imgf000115_0002
The title compound was synthesized in a manner analogous to Example 33 utilizing Example R (0.145 g; 0.50 mmol) andjo-chlorophenylisocyanate (0.0768 g, 0.50 mmol, 1 eq.) to yield l-(3-tβrt-butyl-l-(3-phenylphenyl)-lH-pyrazol-5-yl)-3-(4-chlorophenyl)urea (0.205 g, 92%). HPLC purity: 96.5%; mp: 134 136 ; 'HNMR (CDC13): δ 7.5 (m, 14H), 7.0 (s, IH), 6.6 (s,lH), 6.4(s. lH),1.4(s,9H).
EXAMPLE S
Figure imgf000117_0001
The title compound is synthesized in a manner analogous to Example C utilizing Example A and 4-fluorophenyl isocyanate yield ethyl 3-(3-tert-butyl-5-(3-(4- flurophenyl)ureido)- 1 H-pyrazol- 1 -yl)benzoate.
EXAMPLE 35
Figure imgf000117_0002
The title compound is synthesized in a manner analogous to Example 17 utilizing
Example M and D-4-phenyl-oxazolidin-2-one to yield D-1 - {5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2H-pyfazol-3-yl}-3— (naphthalen-l-yl)urea. EXAMPLE 36.
Figure imgf000118_0001
The title compound is synthesized in a mamier analogous to Example 29 utilizing Example P (0.30g, 0.95 mmol) and 4-fluOrophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3- (3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-lH-pyrazol-l-yl)phenyl)propanoic acid.
EXAMPLE T
Figure imgf000119_0001
To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane- methylsulfϊde (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCl was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-l-[3-(2-aminoethyl)phenyl]-lH-pyι-azol-5 amine (0.9 g).
A mixture ofthe crude material from the previous reaction (0.8 g, 3.1 mmol) and di-tert- butylcarbonate (0.7 g, 3.5 mmol) and catalytically amount of DMAP in dry CΗ2C12 (5 ml) was stirred at RT under N2 for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using 1 % methanol in CH2C12 as the eluent to yield tert- butyl 3-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)phenylcaι-bamate (0.5 g).
EXAMPLE 37
Figure imgf000120_0001
A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate (0.123 g, 0.73 mmol) in dry CH2C12 (5 ml) was stirred at RT under N2 for 48 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 1%> methanol in CH2Cl2as the eluent (0.15 g, off-white solid). The solid was then treated with TFA (0.2ml) for 5 min and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield l-{3-tert-butyl-l-[3-(2- Aminoethyl)phenyl]-lH-pyrazol-5-yl} -3-(naphthalen-l-yl)urea as a solid (80 mg). mp: 110- 112 ; 'ΗNMR (200MHz, DMSO-d6): δ 9.09 (s, IH), 8.90 (s, IH), 8.01 - 7.34 (m, 1 IH), 6.43 (s, IH), 3.11 (m, 2H), 2.96 (m, 2H), 1.29 (s, 9H); MS
EXAMPLE 38
Figure imgf000120_0002
The title compound was synthesized in a manner analogous to Example 37 utilizing Example T (0.15 g, 0.42 mmol) and 4-chlorophenylisocyanate (0.065 g, 0.42 mmol) to yield 1- {3-tert-butyl-l-[3-(2-Aminoethyl)phenyl]-lH-pyrazol-5-yl}-3-(4-chlorophenyl)urea as an off- white solid (20 mg). mp:125-127 ; 'Η NMR (200MΗz, CDC13): δ 8.81 (s, IH), 8.66 (s, IH), 7.36 - 7.13 (m, 8H), 6.54 (s, IH), 3.15 (brs, 2H), 2.97 (brs, 2H), 1.32 (s, 9H); MS
EXAMPLE U
Figure imgf000121_0001
In a 250 mL Erlenmeyer flask with a magnetic stir bar, m-anisidine (9.84 g, 0.052 mol) was added to 6 N HCl (80 mL) and cooled with an ice bath to 0 °C. A solution of NaNO2 (4.22 g, 0.0612 mol, 1.18 eq.) in water (10 mL) was added drop wise. After 30 min, SnCl2-2H2O (104.0 g, 0.46 mol, 8.86 eq.) in 6 N HCl (200 mL) was added and the reaction mixture was allowed to stir for 3 h., and then subsequently transferred to a 1000 mL round bottom flask. To this, 4,4- dimethyl-3 -oxopentanenitrile (8.00 g, 0.064 mol) and EtOH (200 mL) were added and the mixture refluxed for 4 h, concentrated in vacuo and the residue recrystallized from CH2C12 to yield 3-tert-butyl-l-(3-methoxyphenyl)-lH-pyrazol-5-amine as the ΗC1 salt (13.9 g).
The crude, material from the previous reaction (4.65 g, 0.165 mol) was dissolved in 30 mL of CΗ2C12 with Et3N (2.30 mL, 0.0165 mol, 1 eq.) and stirred for 30 min Extraction with water followed by drying ofthe organic phase with Na2SO4 and concentration in vacuo yielded a brown syrup that was the free base, 3-tert-butyl-l-(3-methoxyphenyl)-lH-pyrazol-5-amine (3.82 g, 94.5%o), which was used without further purification.
EXAMPLE 39
Figure imgf000122_0001
In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0107 mol) was dissolved in CH2C12 (5 mL, anhydrous) followed by the addition of 1 -naphthylisocyanate (1.53 mL, 0.0107 mol, 1 eq.). The reaction was kept under Ar and stirred for 18 h. Evaporation of solvent followed by column chromatography with EtOAc/hexane/Et3N (7:2:0.5) as the eluent yielded l-[3-tert- butyl-l-(3-methoxyphenyl)-lH-pyrazol-5-yl]-3-(naphthalen-l-yl)urea(3.4g, 77%). HPLC: 97%; mp: 78 - 80; 'H NMR (CDC13): δ 7.9 - 6.8 (m, 15H), 6.4 (s, IH), 3.7 (s, 3H), 1.4 (s, 9H).
EXAMPLE 40
Figure imgf000122_0002
The title compound was synthesized in a manner analogous to Example 39 utilizing
Example U (3.82 g; 0.0156 mol) and j-?-chlorophenylisocyanate (2.39 g, 0.0156 mol, 1 eq.), purified by trituration with hexane/EtOAc (4:1) and filtered to yield 1 -[3 -tert-butyl- 1 -(3- methoxyphenyl)-lH-pyrazol-5-yl]-3-(4-chlorophenyl)urea (6.1 g, 98%). ΗPLC purity: 95%; mp: 158 - 160 ; 'Η NMR (CDC13): δ 7.7 (s, 1Η); δ 7.2 6.8 (m, 8Η), 6.4 (s, IH), 3.7 (s, 3H), 1.3 (s, 9H).
EXAMPLE 41
Figure imgf000123_0001
In a 100 ml round bottom flask equipped with a magnetic stir bar, Example 39 (2.07 g) was dissolved in CH2C12 (20 mL) and cooled to 0 °C with an ice bath. BBr3 (1 M in CH2C12; 7.5 mL) was added slowly. The reaction mixture was allowed to warm warm to RT overnight. Additional BBr3 (1 M in CH2C12, 2 X 1 mL, 9.5 mmol total added) was added and the reaction was quenched by the addition of MeOH. Evaporation of solvent led to a crystalline material that was cliromatographed on silica gel (30 g) using CH2Cl2/MeOH (9.6:0.4) as the eluent to yield l-[3-tert-butyl-l-(3-hydiOxyphenyl)-lH-pyrazol-5-yl]-3-(naphthalene-l-yl)urea (0.40g, 20%). Η NMR (DMSO-- 6): δ 9.0 (s, lΗ), 8.8 (s, 1Η), 8.1 - 6.8 (m, 11Η), 6.4 (s, 1Η), 1.3 (s, 9Η). MS (ESI) m/z: 401 (M+H+).
EXAMPLE 42
Figure imgf000123_0002
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 40 (2.00 g, 5 mmol) that resulted in a crystalline material that was filtered and washed with MeOH to yield l-[3-tert-butyl-l-(3-hydroxyphenyl)-lH-pyrazol-5-yl]-3-(4- chlorophenyl)urea (1.14 g, 60%). ΗPLC purity: 96%; mp: 214 - 216 ; Η NMR (CDCL : δ 8.4
(s, 1Η), 7.7 (s, 1Η), 7.4 - 6.6 (m, 9Η), 1.3 (s, 9H).
EXAMPLE V
Figure imgf000124_0001
The starting material, l-[4-(aminomethyl)phenyl]-3-tert-butyl-N-nitroso-lH-pyrazol-5- amine, was synthesized in a manner analogous to Example A utilizing 4-aminobenzamide and 4,4-dimefhyl-3-oxopentanenitrile.
A I L four-necked round bottom flask was equipped with a stir bar, a source of dry Ar, a heating mantle, and a reflux condenser. The flask was flushed with Ar and charged with the crude material from the previous reaction (12 g, 46.5 mmol; 258.1 g/mol) and anhydrous TΗF
(500 ml). This solution was treated cautiously with LiAlΗ4 (2.65 g, 69.8 mmol) and the reaction was stirred overnight. The reaction was heated to reflux and additional LiAlH4 was added complete (a total of 8.35 g added). The reaction was cooled to 0 and H2O (8.4 ml), 15% NaOH (8.4 ml) and H2O (24 ml) were added sequentially; The mixture was stirred for 2h, the solids filtered tlirough Celite, and washed extensively with THF, the solution was concentrated in vacuo to yield l-(4-(aminomethyl-3-methoxy)phenyl)-3-tert-butyl-lH-pyrazol-5-amine (6.8 g) as an oil.
A 40 mL vial was equipped with a stir bar, a septum, and a source of Ar. The vial was charged with the crude material from the previous reaction (2 g, 8.2 mmol, 244.17 g/mol) and CΗC13 (15 mL) were cooled to 0 under Ar and di-tert-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHC13 (5 mL) was added drop wise over a 2 min period. The mixture was treated with IN KOH (2 mL), added over a 2h period. The resulting emulsion was broken with the addition of saturated NaCl solution, the layers were separated and the aqueous phase extracted with CH2C12 (2 x 1.5 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated in vacuo to yield tert-butyl [4-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)-2- methoxybenzylcarbamate (2.23 g, 79%) as a light yellow solid. Η NMR (CDC13): δ 7.4 (m,
5Η), 5.6 (s, IH), 4.4 (d, 2H), 1.5 (s, 9H), 1.3 (s, 9H).
EXAMPLE 43
Figure imgf000126_0001
A 40 mL vial was equipped with a septum, a stir bar and a source of Ar, and charged with Example N (2 g, 5.81 mmol), flushed with Ar and dissolved in CHC13 (20 mL). The solution was treated with 2-naphthylisocyanate (984 mg, 5.81 mmol) in CHC13 (5 mL) and added over 1 min The reaction was stirred for 8h, and additional 1 -naphthylisocyanate (81 mg) was added and the reaction stirred overnight. The solid was filtered and washed with CH2Cl2to yield tert-butyl 4-[3- tert-butyl-5-(3-naphthalen-l-yl)ureido)-lH-pyrazol-l-yl]benzylcarbamate (1.2 g). ΗPLC purity: 94.4 %; 'Η ΝMR (DMSO-d6): δ 9.1 (s, 1Η), 8.8 (s, 1Η), 8.0 (m, 3Η), 7.6 (m, 9H), 6.4 (s, IH),
4.2 (d, 2H , 1.4 (s, 9H), 1.3 (s, 9H).
EXAMPLE 44
Figure imgf000126_0002
The title compound was synthesized in a manner analogous to Example 43 utilizing Example N (2.0 g, 5.81 mmol) and p-chlorophenylisocyanate (892 mg) to yield tert-butyl 4-[3- tert-butyl-5-(3-(4-chloropnehyl)ureido)-lH-pyι-azol-l-yl]benzylcarbamate (1.5 g). ΗPLC purity: 97%; 'ΗΝMR (DMSO-d6): δ 9.2 (s, 1Η), 8.4 (s, 1Η), 7.4 (m, 8Η), 6.4 (s, IH), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
EXAMPLE 45
Figure imgf000128_0001
A 10 mL flask equipped with a stir bar was flushed with Ar and charged with Example
43 (770 mg, 1.5 mmol) and CH2C12 (1 ml) and 1 :1 CH2C12:TFA (2.5 L). After 1.5 h, reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (15 mL), washed with saturated NaHCO3 (10 mL) and saturated NaCl (10 mL). The organic layers was dried, filtered and concentrated in vacuo to yield 1- {3-tert-butyl-l-[4-(aminomethyl)phenyl]-lH-pyrazol-5-yl}- 3-(naphthalen-l-yl)urea (710mg). ΗNMR(DMSO-J6): δ 7.4 (m, HΗ), 6.4 (s, lH), 3.7 (s, 2H),
1.3 (s, 9H).
EXAMPLE 46
Figure imgf000128_0002
The title compound was synthesized in a manner analogous to Example 45 utilizing Example 44 (1.5g, 1.5 mmol) to yield 1- {3 -tert-butyl- 1 -[4-(aminomethyl)phenyl]- lH-pyrazo 1-5- yl}-3-(4-chlorophenyl)urea (1.0 g). HPLC purity: 93.6%; mp: 100 - 102 ; 'H NMR (CDC13): δ 8.6 (s, IH), 7.3 (m, 8H), 6.3 (s, IH), 3.7 (brs, 2H), 1.3 (s, 9H).
EXAMPLE 47
Figure imgf000129_0001
A 10 ml vial was charged with Example 45 (260 mg, 63 mmol) and absolute EtOH (3 mL) under Ar. Divmylsulfone (63 uL, 74 mg, .63 mmol) was added drop wise over 3 min and the reaction was stirred at RT for 1.5 h. and concentrated in vacuo to yield a yellow solid, which was purified via preparative TLC, developed in 5% MeOH:CH2Cl2. The predominant band was cut and eluted off the silica with 1 : 1 EtOAcMeOH, filtered and concentrated in vacuo to yield l- {3-tert-butyl-l-[4-(l,l-dioxothiomorpholin-4-yl)methylphenyl]-lH-pyrazol-5-yl}-3- (naphthalen-l-yl)urea (150 g). ΗPLC purity: 96%; 'Η NMR (DMSO- ^): δ 9.1 (s, 1Η), 9.0
(s, 1Η), 7.9 (m, 3Η), 7.5 (m, 8H), 6.4 (s, IH), 3.1 (brs, 4H), 2.9 (brs, 4H), 1.3 (s, 9H).
EXAMPLE 48
Figure imgf000130_0001
The title compound was synthesized in a mamier analogous to Example 47 utilizing Example 46 (260mg, 0.66 mmol) to yield l-{3-tert-butyl-l-[4-(l,l-dioxothiomorpholin-4- yl)methylphenyl]-lH-pyrazol-5-yl}-3-(4-chlorophenyl)urea (180 mg). ΗPLC purity: 93%; mp: 136 - 138 ; 'Η NMR (DMSO-d6): δ 9.2 (s, 1Η), 8.5 (s, 1Η), 7.4 (m, 9Η), 6.4 (s, IH), 3.1 (brs, 4H), 3.0 (brs, 4H). 1.3 (s, 9H).
EXAMPLE 49
Figure imgf000131_0001
To a stirring solution of chlorosulfonyl isocyanate (0.35g , 5 mmol) in CH2C12 (20 mL) at 0 °C was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5 °C. After stirring for 2h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylmine (0.46 g, 9 mmol) in CH2C12 (20 mL) was added. When the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCl (10 mL) saturated with NaCl , the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo, purified by preparative HPLC to yield (pyπOlidine-l-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(3-naphthalen-l-yl-ureido)-pyrazol-l-yl]phenyl ester (40 mg). Η NMR (CDC13): δ 9.12 (brs, IH), 8.61 (brs, IH), 7.85 - 7.80 (m, 3H), 7.65 (d, J = 8.0 Hz, 2H), 7.53 -
7.51 (m, IH), 7.45 - 7.25 (m, 5H), 6.89 (s, 4H), 3.36 - 3.34 (brs, IH), 3.14 - 3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H+).
EXAMPLE 50
Figure imgf000132_0001
The title compound was synthesized in a manner analogous to Example 49 utilizing Example 42 to yield (pyrrolidine-l-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(4-chlorophenyl-l- yl-ureido)pyrazol-l-yl]phenyl ester. MS (ESI) m/z: 561 (M+H+).
EXAMPLE W
Figure imgf000132_0002
Solid 4-methoxyplιenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100. mL) and treated with triethylamine (20.2 g). The mixture was stirred, at RT for .30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight.
The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert- butyl-l-(4-methoxyphenyl)-lH-pyrazol-5-amine (25 g, 70%). Η NMR (DMSO-Jd): δ 7.5 (d,
2Η), 7.0 (d, IH), 6.4 (s, IH), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H). EXAMPLE 51
Figure imgf000133_0001
To a solution of 1 -isocyanato-4-methoxy-naphthalene (996 mg) in anhydrous CH2C12 (20 mL) of was added Example W (1.23 g). The reaction solution was stirred for 3 h, the resulting white precipitate filtered, treated with 10% HCl and recrystallized from MeOH, and dried in vacuo to yield 1 - [3 -tert-butyl- 1 -(4-methoxyphenyl)- lH-pyrazol-5 -yl] -3 -( 1 -methoxynaphthalen- 4-yl-urea as white crystals (900 mg, 40%). ΗPLC purity: 96%; mp: 143 - 144 ; Η NMR (DMSO-^): δ 8.8 (s, 1Η), 8.5 (s, 1Η), 8.2 (d, 1Η), 8.0 (d, 1Η), 7.6 (m, 5Η), 7.1 (d, 2H), 7.0 (d, IH), 6.3 (s, IH), 4.0 (s, 3H), 3.9 (s, 3H); 1.3 (s, 9H).
EXAMPLE 52
Figure imgf000133_0002
The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and jϋ-bromophenylisocyanate (990mg) to yield l-{3-tert-butyl-l-(4- methoxyphenyl)-lH-pyrazol-5-yl}-3-(4-bromophenyl)urea as off-white crystals (1.5g, 68%). ΗPLC purity: 98%; mp: 200 - 201 ; Η NMR (DMSO-^): δ 9.3 (s, 1Η), 8.3 (s, 1Η), 7.4 (m.6Η), 7.0 (d, 2H), 6.3 (s, IH), 3.8 (s, 3H), 1.3 (s, 9H).
EXAMPLE 53
Figure imgf000134_0001
The title compound was synthesized in a manner analogous to Example 51 utilizing Example W and p-chlorophenylisocyanate (768 mg) into yield l-{3-tert-butyl-l-(4- methoxyphenyl)-lH-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (1.3g, 65%). ΗPLC purity: 98%; mp: 209 - 210 ; 'Η NMR (DMSO-^): δ 9.1 (s, 1Η), 8.3 (s, 1Η), 7.4 (m, 4Η), 7.3
(d, 2H), 7.1 (d, 2H), 6.3 (s, IH), 3.8 (s, 3H), 1.3 (s, 9H).
EXAMPLE 54
Figure imgf000134_0002
The title compound was synthesized in a manner analogous to Example 41 utilizing Example 53 (500 mg) to yield l-{3-tert-butyl-l-(4-hydroxyphenyl)-lH-pyrazol-5-yl}-3-(4- chlorophenyl)urea as white crystals (300 mg, 62%). ΗPLC purity: 94%; mp: 144 - 145 ; 'Η
NMR (DMSO--ffi): δ 9.7 (s, 1Η), 9.1 (s, 1Η), 8.3 (s, 1Η), 7.4 (d, 2Η), 7.3 (m, 4H); 6.9 (d, 2H), 6.3 (s, IH), 1.3 (s, 9H)
EXAMPLE 55
Figure imgf000135_0001
The title compound was synthesized in a manner analogous to Example 41 utilizing Example
52 (550 mg) to yield l-{3-tert-butyl-l-(4-hydroxyphenyl)-lH-pyrazol-5-yl}-3-(4- bromophenyl)urea as a white crystalline solid (400 mg, 70%). ΗPLC purity: 93%; mp: 198 200 ; 'Η NMR (DMSO-^): δ 9.7 (s, 1Η), 9.2 (s, 1Η), 8.3 (s, 1Η), 7.4 (d, 4Η), 7.2 (m, 2H), 6.9 (d, 2H), 6.3 (s, IH), 1.3 (s, 9H).
EXAMPLE X
Figure imgf000135_0002
Methyl 4-(3-tert-butyl-5-amino-lH-pyrazol-l-yl)benzoate (3.67 mmol) was prepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., A5, 2994 (2002). EXAMPLE 56
Figure imgf000136_0001
A 500mL round bottom flask was equipped with a magnetic stir bar and an ice bath. The flask was charged with Example X (1 g) and this was dissolved in CH2C12 (100 mL). Saturated sodium bicarbonate (100 mL) was added and the mixture rapidly stirred, cooled in an ice bath and treated with diphosgene (1.45 g) and the heterogeneous mixture stirred for 1 h. The layers were separated and the CH2C12 layer treated with tert-butanol (1.07 g) and the solution stiired overnight at RT. The solution was washed with H2O (2 l50 mL), dried (Na2SO4), filtered, concentrated in vacuo, and purified by flash cliromatography using 1 :2 ethyl acetate: hexane as the eluent to yield tez-t-bufhyl l-(4-(methoxycarbonyl)phenyl)-3-tert-butyl-lH-pyrazol-5- ylcarbamate (100 mg) as an off-white solid. 'Η NMR (DMSO-Jό): δ 9.2 (s, 1Η), 8.1 (d, 2Η), 7.7 (d, 2H), 6.3 (s, IH), 3.3 (s, 3H), 1.3 (s, 18H).
EXAMPLE 57
Figure imgf000137_0001
The title compound was synthesized in a manner analogous to Example 41 utilizing Example X (1.37 g) and -chlorophenylisocyanate (768 mg) to yield methyl 4- {3-tert-butyl-5-[3-(4- chlorophenyl)ureido]-lH-pyrazol-l-yl}benzoate as white crystals (1.4 g 66%). ΗPLC purity:
98%; mp: 160 - 161 ; 'Η NMR (DMSO--?tf): δ 9.2 (s, 1Η), 8.6 (s, 1Η), 8.1 (d, 2Η), 7.8 (d, 2H),
7.5 (d, 2H), 7.3 (d, 2H), 6.4 (s, IH), 3.9 (s, 3H), 1.3 (s, 9H).
EXAMPLE 58
Figure imgf000137_0002
The title compound was synthesized in a manner analogous to Example 41 utilizing
Example X (1.27 g) and l-isocyanato-4-methoxy-naphthalene (996 mg) to yield methyl 4-{3- tert-butyl-5-[3-( 1 -methoxynaphthalen-4-yl)ureido]- IH-pyrazol- 1 -yl}benzoate as white crystals (845 mg, 36%). ΗPLC purity: 98%; mp: 278 280 ; 'ΗNMR (DMSO- 6): δ 8.76 (s, 1Η), 8.73 (s, IH), 8.1 (m, 3H), 7.9 (d, IH), 7.7 (d, 2H), 7.6 (m, 3H), 7.0 (d, IH), 7.0 (d, IH), 6.3 (s, IH), 4.0 (s, 3H), 3.9 (s, 3H),1.3 (s, 9H).
EXAMPLE 59
Figure imgf000138_0001
The title compound was synthesized in a manner analogous to Example 41 utilizing
Example X (1.37 g) and -bromophenylisocyanate (990 mg) to yield methyl 4-{3-tert-butyl-5-[3- (4-bromophenyl)ureido]-lH-pyι-azol-l-yl}benzoateaswhitecrystals (1.4g, 59%). ΗPLCpuiϊty:
94%; mp: 270 272 ; Η NMR (DMSO-Jtf): δ 9.2 (s, 1Η), 8.6 (s, 1Η), 8.1 (d, 2Η), 7.7 (d, 2H),
7.4 (d, 4H), 6.4 (s, IH), 3.9 (s, 3H), 1.3 (s, 9H).
EXAMPLE 60
Figure imgf000138_0002
To a solution of Example 59 (700 mg) in 30 mL of toluene at -78 °C, was added dropwise a solution of diisobutylaluminum hydride in toluene (IM in toluene, 7.5 mL) over 10 min. The reaction mixture was stirred for 30 min at -78 °C, and then 30 min at 0 °C. The reaction mixture was concentrated in vacuo to dryness and treated with H20. The solid was filtered and treated with acetonitrile. The solution was evaporated to dryness and the residue was dissolved in ethyl acetate, and precipitated by hexanes to afford yellow solid which was dried under vacuum to give l-[3-tert-butyl-l-(4-hydroxymethyl)phenyl)-lH-pyrazol-5-yl]urea (400 mg, 61%). ΗPLC purity: 95%; 'HNMR (DMSO-J6): δ 9.2 (s, IH), 8.4 (s, IH), 7.5 (m, 8H), 6.4 (s, IH), 5.3 (t, IH),
4.6 (d, 2H), 1.3 (s, 9H).
1.38
Figure imgf000140_0001
Example 4
Figure imgf000140_0002
Figure imgf000140_0003
Example 6
Figure imgf000140_0004
Figure imgf000140_0005
Wherein Y is O, S, NR6, -NR6S02-, NR6CO-, alkylene, 0-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or Y is a direct bond; D is taken from the groups identified in Chart I: Chart 1
Figure imgf000141_0001
Example 7
Figure imgf000142_0002
Figure imgf000142_0001
Example 9 Example 10
Figure imgf000142_0003
Exam le 11
Figure imgf000142_0004
Figure imgf000143_0001
Example 15
Example 16
Figure imgf000143_0002
Figure imgf000143_0003
Example 19
Figure imgf000144_0002
Figure imgf000144_0001
Example 22
Figure imgf000144_0004
Example 24
Figure imgf000144_0003
Figure imgf000144_0005
Figure imgf000145_0001
Example 27
Example 28
Figure imgf000145_0002
Figure imgf000145_0003
Example 30
Figure imgf000145_0004
Figure imgf000145_0005
Example 31
Figure imgf000146_0002
Figure imgf000146_0001
Example 33 Example 34
Figure imgf000146_0003
Exam le 35
Figure imgf000146_0004
Figure imgf000147_0001
Example 39
Example 40
Figure imgf000147_0002
Figure imgf000147_0003
Example 42
Figure imgf000147_0004
Example 43
Figure imgf000148_0001
Figure imgf000148_0002
Example 45 Example 46
Figure imgf000148_0003
Exam le 47
Figure imgf000148_0004
Figure imgf000149_0001
Example 51
Example 52
Figure imgf000149_0002
Figure imgf000149_0003
Example 54
Figure imgf000149_0004
Figure imgf000149_0005
Example 55
Figure imgf000150_0002
Figure imgf000150_0001
Example 57 Example 58
Figure imgf000150_0003
Example 60
Exam le 59
Figure imgf000150_0004
Figure imgf000151_0001
Figure imgf000151_0002
Figure imgf000151_0003
Figure imgf000152_0001
Example 69
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000153_0001
Figure imgf000153_0002
Example 78
Figure imgf000153_0003
Figure imgf000153_0004
wherein X or Y is O, S, NR6, -NR6S02-, NR6CO-, alkylene, 0-(CH2)n-, NR6-(CH2)n-, wherein one ofthe methylene units may be substituted with an oxo group, or X or Y is a direct bond; D is taken from the groups identified in Chart I:
Chart 1
Figure imgf000154_0001
Specific examples ofthe present invention are illustrated by their structural formulae below:
Figure imgf000155_0001
Figure imgf000155_0002
Example 83 Example 84
Figure imgf000155_0003
Figure imgf000156_0001
Figure imgf000157_0001
Example 96
Example 95
Figure imgf000157_0002
Figure imgf000158_0001
Example 102
Figure imgf000158_0002
Figure imgf000158_0003
Figure imgf000159_0001
Example 108
Figure imgf000159_0002
Figure imgf000159_0003
Figure imgf000160_0001
Example 1 13 Example 1 14
Figure imgf000160_0002
Figure imgf000161_0001
Example 120
Figure imgf000161_0002
Figure imgf000161_0003
Figure imgf000162_0001
Example 125
Example 126
Figure imgf000162_0002
Figure imgf000163_0001
Example 132
Figure imgf000163_0002
Figure imgf000163_0003
Example 133
Figure imgf000164_0001
Figure imgf000164_0002
Figure imgf000164_0003
Example 138
Example 137
Figure imgf000164_0004
Figure imgf000165_0001
Example 144
Figure imgf000165_0002
Figure imgf000165_0003
All of the references above identified are incorporated by reference herein. In addition, two simultaneously applications are also incorporated by reference, namely
Modulation of Protein Functionalities, S/N , filed December , 2003, and
Anti-Cancer Medicaments, S/N filed December , 2003.
165

Claims

We Claim:
A compound having the formula
Figure imgf000167_0001
wherein: R1 is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-,
-NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and
-NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH2)h- the introduction ofthe side-chain oxo group does not fonn an ester moiety; A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(O)- and -S(O)2-; j is 0 or 1 ; m is 0 or 1 ; n is 0 or 1 ; p is 0 or 1 ; q is O or l; t is 0 or 1 ; Q is selected from the group consisting of
Figure imgf000168_0001
each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaininos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R6 is individually selected from the group consisting of -H, alkyls, allyls, and β-trimethylsilylethyl; each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each R, group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups maybe cyclized to fonn a 3-6 membered ring; and each Z is individually selected from the group consisting of -O- and -N(R4)-; each ring of formula (I) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; except that: when Q is Q-3 or Q-4, then the compound of fomiula (I) is not
Figure imgf000169_0001
when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl; when Q is Q-7, R5 is -OH, Y is -O-, -S-, or -CO-, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, R5 is -OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, then the compound of formula (I) is not
Figure imgf000170_0001
R80 is H, Me
R82 is substituted phenyl
R81 is substituted phenyl
when Q is Q-8, then Y is not -CH2O-; when Q is Q-8, the compound of formula (I) is not
Figure imgf000170_0002
R10 = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not
Figure imgf000171_0001
Figure imgf000171_0002
Figure imgf000171_0003
R17, RI 8 = alkyl R19 = H, alkyl
when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy; when Q is Q-10, then the compound of formula (I) is not
Figure imgf000171_0004
when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy; when Q is Q-ll, then the compound of fonnula (I) is not
Figure imgf000172_0001
when Q is Q-15, then the compound of formula (I) is not
Figure imgf000172_0002
R2o = substituted phenyl, R2] = H, alkyl
when Q is Q-16 and Y is -NH-, then
Figure imgf000172_0003
of formula (I) is not biphenyl; when Q is Q-16 and Y is -S-, then
Figure imgf000172_0004
of formula (I) is not phenylsulfonylammophenyl or phenylcarbonylaminophenyl; when Q is Q-16 and Y is -SO2NH-, then the compound of formula (I) is not
Figure imgf000173_0001
R23 = OH, SH, NH2
R24 = hydrogen or one or more methoxy, hydroxy, fluoro, chloro, nitro, dimethylamino, or furanyl
R25 = substituted phenyl, furanyl
R26 = OH or CI
X5 = O, NH;
when Q is Q-16 and Y is -CONH-, then
H H
R, Xf— A— rNf-L—VNf-D — E
' m
of formula (I) is not imidazophenyl; when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not
Figure imgf000173_0002
R27 = substituted phenyl, pyridylcarbonyl R2n = CN, nietlioxycarbonyl n = 0 or 1 when Q is Q-16 and t is 0, then
Figure imgf000174_0001
of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl; when Q is Q-17, then the compound of formula (I) is not
Figure imgf000174_0002
R2g = alkyl
R30 = H, t-Bu, benzoyl phenyl
when Q is Q-21, then the compound of fomiula (I) is not
Figure imgf000174_0003
when Q is Q-22, then the compound of fomiula (I) is selected from the group consisting of
172
Figure imgf000175_0001
when Q is Q-22 and q is 0, then the compound of fonnula (I) is selected from the 15 group consisting of
Figure imgf000175_0002
but excluding
Figure imgf000176_0001
when Q is Q-23, then the compound of formula (I) is not
Figure imgf000176_0002
Figure imgf000177_0001
when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of fomiula (I) is selected from the group consisting of
Figure imgf000177_0002
wherein each W is individually selected from the group consisting of
-CH- and -N-; each G] is individually selected from the group consisting of-O-, -S-, and
-N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
Figure imgf000178_0001
wherein each Z is individually selected from the group consisting of -O- and -N(R4>; when Q is Q-31, then the compound of fonnula (I) is not
Figure imgf000178_0002
or
Figure imgf000178_0003
when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not
Figure imgf000179_0001
R46 = hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy
when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not
Figure imgf000179_0002
or
Figure imgf000179_0003
when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not
Figure imgf000179_0004
when Q is Q-32, then
Figure imgf000180_0001
is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; when Q is Q-32, Y is -CONH-, q is 0, m is 0, and
Figure imgf000180_0002
of formula (I) is -CONH-, then A is not phenyl; when Q is Q-32, q is 0, m is 0, and
Figure imgf000180_0003
is -CONH-, then the compound of formula (I) is not
Figure imgf000180_0004
R54 = benzoyl, phenylalkylaminocarbonyl, substituted phenylaminocarbonyl H, Br
1^7 = alkyl, substituted phenyl, thienyl, phenacetyl R55 = CI, Br, SPh, benzoyl, phenylsulfonyl naphthyl R51 = H, phenylsulfonyl, phenyl, benzyl Rj = H, alkyl, Br, substituted phenyl, benzoyl, Rs = Et, i-Pr phenylsulfonyl R53 = substituted phenyl, substituted benzyl R49 = H, alkyl, phenyl X] = O, N-Ph, N-alkyl, N-carbamoyl 50 = substituted phenyl Z, =N(R50), O when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone; when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is
0, then A is not phenyl; when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and. m is 0, then A is not phenyl; when Q is Q-32 and Y is an ether linlcage, then
Figure imgf000181_0001
of fonnula (I) is not biphenyl or phenyloxazolyl; when Q is Q-32 and Y is -CH=€H-, then
Figure imgf000181_0002
of formula (I) is not phenylaminophenyl; when Q is Q-32, then the compound of formula (I) is not
Figure imgf000182_0001
when Q is Q-35 as shown
Figure imgf000183_0001
wherein G is selected from the group consisting of-O-, -S-, -NR4-, and CH2-, k is 0 or 1, and u is 1, 2, 3, or 4, then
Figure imgf000183_0002
is selected from the group consisting of
Figure imgf000183_0003
Figure imgf000184_0001
except that the compound of fonnula (I) is not
azolyl
Figure imgf000185_0001
Figure imgf000185_0002
R74= chlorophenyl
Figure imgf000185_0003
Figure imgf000185_0004
2. The compound of claim 1, wherein Rj is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls.
The compound of claim 2, where Rj is selected from the group consisting of
Figure imgf000186_0001
each R2 is individually selected from the group consisting of -H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys; each R3 is individually selected from the group consisting of -H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfmyls, alkylsulfonyls, R4NHSOr, and -NHSO2R4; and N is selected from the group consisting of O and H2.
4. The compound of claim 1 , wherein A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzo furanyl, benzothienyl, pyrazolylpyrimidmyl, imidazopyrimidinyl, purinyl, and
Figure imgf000187_0001
where each W, is individually selected from the group consisting of -CH- and -N-
5. A method of modulating the activation state of p38 α-kinase comprising the step of contacting said kinase with a molecule having the formula
Figure imgf000188_0001
wherein:
R1 is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-,
-NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side- chain oxo group except that where -O(CH2)h- the introduction ofthe side-chain oxo group does not fonn an ester moiety; A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(O)- and -S(O)2-; j is 0 or 1 ; m is 0 or 1 ; n is 0 or 1 ; p is 0 or 1 ; q is 0 or 1 ; t is O or 1; Q is selected from the group consisting of
Figure imgf000189_0001
each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R5 is individually selected from the group consisting of -H. alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R6 is individually selected from the group consisting of -H, alkyls, allyls, and β- trimethylsilylethyl; each Rg is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each Rg group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and each Z is individually selected from the group consisting of-O- and -N(R4)-; and each ring of formula (II) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, amino sulfonyls, and perfluoroalkyls, and thereby causing modulation of said activation state.
6. The method of claim 5, said contacting step occurring at the region of a switch control pocket of said kinase.
7. The method of claim 6, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Fomiula (TT) molecule.
8. The method of claim 6, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
9. The method of claim 8, said region being selected from the group consisting of the α-C helix, the α-D helix, the catalytic loop, the switch control ligand sequence, and the C- lobe residues and combinations thereof.
10. The method of claim 9, said α-C helix including SEQ ID NO. 2.
11. The method of claim 9, said catalytic loop including SEQ ID NO. 3.
12. The method of claim 9, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
13. The method of claim 9, said C-lobe residues including SEQ ID NO. 6.
14. The method of claim 5, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
15. The method of claim 5, said activation state being selected from the group consisting ofthe upregulated and downregulated states.
16. The method of claim 5, said molecule being an antagonist ofthe on switch control pocket for said kinase.
17. The method of claim 5, said molecule being an agonist ofthe off switch control pocket for said kinase.
18. The method of claim 5, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arfhritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft- versus-host reaction, Cl ron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
19. The method of claim 18, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
20. The method of claim 5, said molecule having the structure ofthe compound of claim 1.
21. An adduct comprising a molecule binding with a kinase, said molecule having the formula
Ri 5ζ -ANTA-H-NI -D XX (HI)
wherein:
R1 is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NR6-, -NR6SO2-, -NR6CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR6(CH2)h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR6(CH2)h-, one of the methylene groups present therein may be optionally double-bonded to a side- chain oxo group except that where -O(CH2)h- the introduction ofthe side-chain oxo group does not fomi an ester moiety;
A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicyclohetero cyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pynolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(O)- and -S(O)2-; j is 0 or 1 ; m is 0 or 1; n is 0 or 1 ; p is 0 or 1; q is 0 or 1 ; t is O or l;
Q is selected from the group consisting of
Figure imgf000194_0001
each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R4 groups are bonded with the same atom, the two R4 groups optionally fonn an alicyclic or heterocyclic 4-7 membered ring; each R5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R6 is individually selected from the group consisting of -H, alkyls, allyls, and β- trimethylsilylethyl; each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each Rg group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; each Z is individually selected from the group consisting of-O- and -N(R4)-; and each ring of formula (III) optionally includes one or more of R7, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfmyls, alkylsulfonyls, amino sulfonyls, and perfluoroalkyls.
22. The adduct of claim 21, said molecule binding at the region of a switch control pocket of said kinase.
23. The adduct of claim 22, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Fonnula (III) molecule.
24. The adduct of claim 22, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
25. The adduct of claim 24, said region being selected from the group consisting of the α-C helix, the α-D helix, the catalytic loop, the switch control ligand sequence, and the C- terminal residues and combinations thereof.
26. The adduct of claim 25, said α-C helix including SEQ ID NO. 2.
27. The adduct of claim 25, said catalytic loop including SEQ ID NO. 3.
28. The adduct of claim 25, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 5, SEQ ID NO. 6, and combinations. thereof.
29. The adduct of claim 25, said C-lobe residues including W197, M198, H199,
Y200.
. 30. The adduct of claim 21, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
31. The adduct of claim 21 said molecule having the structure ofthe compound of claim 1.
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US20090137021A1 (en) 2009-05-28
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