US2007078121A1PendingUtilityA1
Enzyme modulators and treatments
Est. expiryDec 23, 2024(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/10A61P 37/06A61P 35/04A61P 7/08A61P 37/00A61P 9/00A61P 35/02A61P 31/04A61P 35/00A61P 29/00A61P 11/06C07D 401/12A61P 19/02A61P 15/00C07D 231/40C07D 403/04C07D 405/12C07D 403/14A61P 17/06A61P 19/08C07D 413/10A61P 17/02C07D 413/12C07D 409/14C07D 401/10C07D 471/04C07D 209/46C07D 403/10C07D 417/12C07D 231/38C07D 401/04C07D 409/04C07D 401/14C07D 409/12A61P 1/04C07D 417/14A61P 11/00C07D 417/04C07D 403/12
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Claims
Abstract
Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, immunological disorders, hyperproliferative diseases, cancer, and diseases characterized by hyper-vascularization are provided. In a preferred embodiment, modulation of the activation state of kinases, including p38 kinase protein, abl kinase protein, bcr-abl kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein, comprises the step of contacting said kinase protein with the novel compounds.
Claims
exact text as granted — not AI-modified1 . Compounds of the formula
wherein A2 is selected from the group consisting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with A1 and a distal ring attached to the proximal ring, and either the distal ring has a heteroatom in the ring structure thereof and/or the distal ring has Z2 or Z3 substituents;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
D comprises a member of the group consisting of Z5- or Z6-substituted mono- and poly-aryl, of Z5- or Z6-substituted mono- and poly-heteroaryl, of Z5- or Z6-substituted mono- and poly-heterocyclyl, of Z5- or Z6-substituted mono- and poly-arylalkyl, of Z5- or Z6-substituted mono- and poly-aryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heteroarylalkyl, of Z5- or Z6-substituted mono- and poly-heteroaryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heterocyclylalkyl, of Z5- or Z6-substituted mono- and poly-heterocyclyl branched alkyl, alkyl, and carbocyclyl moieties;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , —SO 2 R5-, —(CH 2 ) n N(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , —R8C(═O)—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3, moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
2 . The compounds of claim 1 wherein D is a moiety of the formula
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)—C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p —, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
and wherein the carbon atoms of —(CH 2 )n-, —(CH 2 )q-, —(CH 2 )p-, C2-C5alkenyl, and C2-C5alkynyl of X2 can be further substituted by one or more C1-C6alkyl;
and E2 is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
and n is 0-4; p is 1-4; q is 2-6.
3 . The compounds of claim 1 wherein D comprises carbocyclyls and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
4 . The compounds of claim 3 wherein the E2 ring is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
5 . The compounds of claim 1 wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein ----- indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 may be independently attached to either of the rings making up the foregoing bicyclic structures;
each R9 is independently and individually selected from the group consisting of H, F, C1-C6alkyl, branched C4-C7alkyl, carbocyclyl, phenyl, phenyl C1-C6alkyl, heterocyclyl and heterocyclylC1-C6alkyl;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH2) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
6 . The compounds of claim 5 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
7 . The compounds of claim 6 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
8 . The compounds of claim 2 wherein said A2 group is defined as set forth in claim 5 .
9 . The compounds of claim 8 wherein said A2 group is defined as set forth in claim 6 .
10 . The compounds of claim 8 wherein said A2 group is defined as set forth in claim 7 .
11 . The compounds of claim 3 wherein said A2 group is defined as set forth in claim 5 .
12 . The compounds of claim 11 wherein said A2 group is defined as set forth in claim 6 .
13 . The compounds of claim 11 wherein said A2 group is defined as set forth in claim 7 .
14 . The compounds of claims 1 , 5 , 8 or 11 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
15 . The compounds of claims 1 , 5 , 8 or 11 wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
16 . The compounds of claims 1 , 5 , 8 or 11 wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
17 . The compounds of claims 1 , 5 , 8 , 11 wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
18 . The compounds of claims 1 , 5 , 8 , 11 wherein W and Y are each NH and X═O.
19 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D is selected from the group consisting of 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-fluoro-5-cyanophenyl, 3-(R8SO 2 )-phenyl, 3-(hydroxyC1-C3alkyl)-phenyl, 3-(R3O—N═C(R6))-phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl,
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
and wherein the carbon atoms of —(CH 2 )n-, —(CH 2 )q-, —(CH 2 )p-, C2-C5alkenyl, and C2-C5alkynyl of X2 can be further substituted by one or more C1-C6alkyl;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, R13, Z2, Z3, Z4, Z5, or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
20 . Most preferred compounds from claim 19 are 1-(3-t-butyl-1-(1-(methanesulfonylureidoamidomethyl)naphthalen-3-yl)-1H-pyrazol-5-yl)3-(2,3-dichlorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(4-(2-aminoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, (3S)-6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-((1-amino-1-oxo-methylamino)methyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-((1-amino-1-oxo-methylamino)methyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3,5-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3,5-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,5-difluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(1,3-dihydroxypropan-2-ylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,5-difluorophenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-cyanophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-cyanophenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)phenyl)urea, 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(3-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-(2-aminoethylamino)quinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(dimethylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-aminoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 6-(3-t-butyl-5-(3-(4-(1-oxoisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(3-t-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea
21 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 1 .
22 . The method of claim 21 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
23 . The method of claim 21 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
24 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 19 .
25 . The method of claim 24 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
26 . The method of claim 24 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
27 . A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier.
28 . The composition of claim 27 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
29 . A pharmaceutical composition comprising a compound of claim 19 together with a pharmaceutically acceptable carrier.
30 . The composition of claim 29 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
31 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 1 .
32 . The method of claim 31 , said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
33 . The method of claim 31 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
34 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 19 .
35 . The method of claim 34 said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
36 . The method of claim 34 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
37 . An adduct comprising a compound of claim 1 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
38 . An adduct comprising a compound of claim 19 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
39 . A method of claim 21 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
40 . A method of claim 39 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
41 . A method of claim 40 , wherein the second site is an ATP cofactor site.
42 . A method of claim 39 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
43 . A method of claim 40 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
44 . A method of claim 41 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
45 . A method of claim 44 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
46 . A method of claim 24 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
47 . A method of claim 46 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
48 . A method of claim 47 , wherein the second site is an ATP cofactor site.
49 . A method of claim 46 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
50 . A method of claim 47 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
51 . A method of claim 48 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
52 . A method of claim 51 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-MO17); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
53 . A synthesis method comprising the steps of:
providing a ring compound of the formula wherein s is 3 or 4, the ring compound has two double bonds and one reactable ring NH moiety, Q is independently and individually selected from the group consisting of N and CR2, and R15 is selected from the group consisting of lower alkyl, branched lower alkyl, benzyl, substituted benzyl, or other suitable carboxylic acid protecting group; each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated; reacting said ring compound with a compound of the formula A3P-M In the presence of a transition metal catalyst; wherein A3P is a protected form of A3; wherein A3 comprises a member of the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly-heterocyclyl moieties, P is a protective group wherein A3 is chemically protected so as not to interfere with the reaction of A3P-M with wherein A3P-M is taken from the group consisting of A3P—B(OH) 2 , -A3P—B(OR16) 2 , -A3P—B(R17) 3 M2, -A3P—Si(R18) 3 , or A3P—Sn(R16) 3 , wherein R16 is taken from lower alkyl or branched lower alkyl, R17 is halogen, R18 is lower alkoxy, and M2 is Li, K, or Na, and from the formulae wherein v is 1 or 2; said reaction generating an intermediate compound of the formula converting said intermediate compound to the carboxylic acid form thereof subjecting said carboxylic acid to a Curtiuss rearrangement in the presence of a compound of formula D1-NH 2 , to yield a compound of the formula where D1 is selected from the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly-heterocyclyl.
54 . The synthesis method of claim 53 wherein
is preferably taken from
A3P-M is taken from A3P—B(OH) 2 , A3P—B(OR16) 2 , or boroxines (A3PBO) 3 ;
said reaction generating an intermediate compound of the formula
and being catalyzed by a copper(II) catalyst, in an inert solvent taken from the group consisting of dichloromethane, dichloroethane, and N-methylpyrrolidinone, in the presence of a base taken from the group consisting of triethylamine and pyridine, at temperatures ranging from ambient to about 130° C., wherein the reaction is exposed to an atmosphere containing oxygen;
Converting said intermediate compound to the carboxylic acid form thereof
and subjecting said acid form compound to a Curtiuss rearrangement in the presence of a compound of formula D1-NH 2 , such rearrangement mediated by the use of diphenylphosphoryl azidate in an inert solvent taken from the group consisting of toluene, tetrahydrofuran, and dimethoxyethane, and in the presence of a base taken from the group consisting of triethylamine, pyridine, and di-iso-propylethylamine, at temperatures ranging from 80° C. to 110° C. to yield a desired compound of the formula
55 . The synthesis method of claim 53 wherein
is taken from
A3P-M is taken from A3P—B(OH) 2 , A3P—B(OR15) 2 , or boroxines (A3PBO) 3 ;
said reaction generating an intermediate compound of the formula
said catalyst comprising copper(II) acetate, said reaction being carried in an inert solvent, selected from the group consisting of dichloromethane, dichloroethane, and N-methylpyrrolidinone, in the presence of a base from the group consisting of triethylamine and pyridine, and in the presence of 4 angstrom sieves at ambient temperature, wherein the reaction is exposed to air, to generate an intermediate compound of the formula
converting said intermediate compound to the carboxylic acid form thereof
subjecting said carboxylic acid form intermediate to a Curtiuss rearrangement in the presence of a compound of formula D1-NH 2 , such rearrangement mediated by the use of diphenylphosphoryl azidate in an inert solvent taken from the group consisting of toluene, and in the presence of triethylamine at temperatures ranging from 80° C. to 110° C. to yield a desired compound of the formula.
56 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z1-substituted phenyl, Z1-substituted pyridyl, Z1-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of moieties of the formula
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E2 is taken from the group consisting of poly-aryl, poly-heteroaryl, mono- and poly heterocyclyl, and carbocyclyl;
wherein E1 is taken from the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly heterocyclyl and carbocyclyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)—C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p —, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein either E1 or E2 is directly linked to the Y group of formula I;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
57 . The compounds of claim 56 wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein E2 comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
58 . The compounds of claim 56 wherein D comprises a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
59 . The compounds of claim 58 wherein the E2 ring is cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
60 . The compounds of claim 56 wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
61 . The compounds of claim 60 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
62 . The compounds of claim 61 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
63 . The compounds of claim 57 wherein said A2 group is defined as set forth in claim 60 .
64 . The compounds of claim 63 wherein said A2 group is defined as set forth in claim 61 .
65 . The compounds of claim 63 wherein said A2 group is defined as set forth in claim 62 .
66 . The compounds of claim 58 wherein said A2 group is defined as set forth in claim 60 .
67 . The compounds of claim 66 wherein said A2 group is defined as set forth in claim 61 .
68 . The compounds of claim 66 wherein said A2 group is defined as set forth in claim 62 .
69 . The compounds of claims 56 , 60 . 63 or 66 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
70 . The compounds of claims 56 , 60 , 63 or 66 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
71 . The compounds of claims 56 , 60 , 63 or 66 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
72 . The compounds of claims 56 , 60 , 63 or 66 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
73 . The compounds of claims 56 , 60 , 63 or 66 , wherein W and Y are each NH and X═O.
74 . Compounds of the formula
wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
75 . Most preferred compounds from claim 74 are 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(2-(3-(2-amino-2-oxoethylophenyl)-5-t-butylthiophen-3-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(4-(6-(thiazol-4-yl)pyrimidin-4-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(4-(isoxazol-4-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea
76 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 56 .
77 . The method of claim 76 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
78 . The method of claim 76 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
79 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 74 .
80 . The method of claim 79 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
81 . The method of claim 79 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
82 . A pharmaceutical composition comprising a compound of claim 56 together with a pharmaceutically acceptable carrier.
83 . The composition of claim 82 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
84 . A pharmaceutical composition comprising a compound of claim 74 together with a pharmaceutically acceptable carrier.
85 . The composition of claim 84 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
86 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 56 .
87 . The method of claim 86 , said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
88 . The method of claim 86 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
89 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 74 .
90 . The method of claim 89 said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
91 . The method of claim 89 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
92 . An adduct comprising a compound of claim 56 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
93 . An adduct comprising a compound of claim 74 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
94 . A method of claim 76 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
95 . A method of claim 94 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
96 . A method of claim 95 , wherein the second site is an ATP cofactor site.
97 . A method of claim 94 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
98 . A method of claim 95 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
99 . A method of claim 96 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
100 . A method of claim 99 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
101 . A method of claim 79 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
102 . A method of claim 101 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
103 . A method of claim 102 , wherein the second site is an ATP cofactor site.
104 . A method of claim 101 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
105 . A method of claim 102 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
106 . A method of claim 103 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
107 . A method of claim 106 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
108 . Compounds of the formula
wherein A2 is selected from the group consisting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with A1 and a distal ring attached to the proximal ring, and either the distal ring has a heteroatom in the ring structure thereof and/or the distal ring has Z2 or Z3 substituents;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
D comprises a member of the group consisting of Z5- or Z6-substituted mono- and poly-aryl, of Z5- or Z6-substituted mono- and poly-heteroaryl, of Z5- or Z6-substituted mono- and poly-heterocyclyl, of Z5- or Z6-substituted mono- and poly-arylalkyl, of Z5- or Z6-substituted mono- and poly-aryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heteroarylalkyl, of Z5- or Z6-substituted mono- and poly-heteroaryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heterocyclylalkyl, of Z5- or Z6-substituted mono- and poly-heterocyclyl branched alkyl, alkyl, and carbocyclyl moieties;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)—(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , —SO 2 R5-, —(CH 2 ) n N(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3, moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
109 . The compounds of claim 108 wherein D is a moiety of the formula
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)—C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
and E2 is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
and n is 0-4; p is 1-4; q is 2-6.
110 . The compounds of claim 108 wherein D comprises carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
111 . The compounds of claim 110 wherein the E2 ring is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
112 . The compounds of claim 108 wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
each R9 is independently and individually selected from the group consisting of H, F, C1-C6alkyl, branched C4-C7alkyl, carbocyclyl, phenyl, phenyl C1-C6alkyl, heterocyclyl and heterocyclylC1-C6alkyl;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
113 . The compounds of claim 112 , wherein A2 is selected from the group consisting of
and wherein the symbol (*) is the point of attachment to the A1 ring for formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
114 . The compounds of claim 113 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
115 . The compounds of claim 109 wherein said A2 group is defined as set forth in claim 112 .
116 . The compounds of claim 115 wherein said A2 group is defined as set forth in claim 113 .
117 . The compounds of claim 115 wherein said A2 group is defined as set forth in claim 114 .
118 . The compounds of claim 110 wherein said A2 group is defined as set forth in claim 112 .
119 . The compounds of claim 118 wherein said A2 group is defined as set forth in claim 113 .
120 . The compounds of claim 118 wherein said A2 group is defined as set forth in claim 114 .
121 . The compounds of claims 108 , 112 , 115 or 118 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
122 . The compounds of claims 108 , 112 , 115 or 118 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
123 . The compounds of claims 108 , 112 , 115 or 118 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
124 . The compounds of claims 108 , 112 , 115 or 118 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
125 . The compounds of claims 108 , 112 , 115 or 118 , wherein W and Y are each NH and X═O.
126 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
wherein the symbol (*) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-(R8SO 2 )— phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl,
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S. NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —N—(CH 2 ) q —O—, —O—(CH 2 )q-NR3-, N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)—C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, R13, Z2, Z3, Z4, Z5, or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8 aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
127 . Most preferred compounds from claim 126 are 1-(3-t-butyl-1-(1-methyl-1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)naphthalen-1-yl)acetic acid, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-carbamimidoyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,5-difluorophenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)phenyl)urea, 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(3-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(1-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-(2-aminoethylamino)quinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-13-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(dimethylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-aminoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 6-(3-t-butyl-5-(3-(4-(1-oxoisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6-(3-t-butyl-5-(3-(4-(1-oxoisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
128 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 108 .
129 . The method of claim 128 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
130 . The method of claim 128 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
131 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 126 .
132 . The method of claim 131 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
133 . The method of claim 131 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
134 . A pharmaceutical composition comprising a compound of claim 108 together with a pharmaceutically acceptable carrier
135 . The composition of claim 134 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
136 . A pharmaceutical composition comprising a compound of claim 126 together with a pharmaceutically acceptable carrier
137 . The composition of claim 136 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
138 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 108 .
139 . The method of claim 138 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
140 . The method of claim 138 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
141 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 126 .
142 . The method of claim 141 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
143 . The method of claim 141 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
144 . An adduct comprising a compound of claim 108 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
145 . An adduct comprising a compound of claim 126 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
146 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z1-substituted phenyl, Z1-substituted pyridyl, Z1-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of the formula
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E2 is taken from the group consisting of poly-aryl, poly-heteroaryl, mono- and poly heterocyclyl, and carbocyclyl;
wherein E1 is taken from the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly heterocyclyl and carbocyclyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p —, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein either E1 or E2 is directly linked to the Y group of formula I;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
147 . The compounds of claim 146 wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein E2 is comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
148 . The compounds of claim 146 wherein D comprises a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
149 . The compounds of claim 148 wherein the E2 ring is non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
150 . The compounds of claim 146 wherein A2 is selected from the group consisting of
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)—(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
151 . The compounds of claim 150 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
152 . The compounds of claim 151 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
153 . The compounds of claim 147 wherein said A2 group is defined as set forth in claim 150 .
154 . The compounds of claim 153 wherein said A2 group is defined as set forth in claim 151 .
155 . The compounds of claim 153 wherein said A2 group is defined as set forth in claim 152 .
156 . The compounds of claim 148 wherein said A2 group is defined as set forth in claim 150 .
157 . The compounds of claim 156 wherein said A2 group is defined as set forth in claim 151 .
158 . The compounds of claim 156 wherein said A2 group is defined as set forth in claim 152 .
159 . The compounds of claims 146 , 150 , 153 , 156 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
160 . The compounds of claims 146 , 150 , 153 , 156 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
161 . The compounds of claims 146 , 150 , 153 , 156 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
162 . The compounds of claims 146 , 150 , 153 , 156 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
163 . The compounds of claims 146 , 150 , 153 , 156 , wherein W and Y are each NH and X═O.
164 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p —, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z I moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
165 . Most preferred compounds from claim 164 are: 1-(1-(3-(1-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(6-(thiazol-4-yl)pyrimidin-4-yloxy)phenyl)urea, 1-(2-(3-(2-amino-2-oxoethyl)phenyl)-5-t-butylthiophen-3-yl)-3-(4-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(4-(isoxazol-4-yl)pyrimidin-2-yl)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea
166 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 146 .
167 . The method of claim 166 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
168 . The method of claim 166 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
169 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 164 .
170 . The method of claim 169 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
171 . The method of claim 169 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
172 . A pharmaceutical composition comprising a compound of claim 146 together with a pharmaceutically acceptable carrier
173 . The composition of claim 172 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
174 . A pharmaceutical composition comprising a compound of claim 164 together with a pharmaceutically acceptable carrier
175 . The composition of claim 174 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
176 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 146 .
177 . The method of claim 176 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
178 . The method of claim 176 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
179 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 164 .
180 . The method of claim 179 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
181 . The method of claim 179 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
182 . An adduct comprising a compound of claim 146 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
183 . An adduct comprising a compound of claim 164 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
184 . Compounds of the formula
wherein A2 is selected from the group consisting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with A1 and a distal ring attached to the proximal ring, and either the distal ring has a heteroatom in the ring structure thereof and/or the distal ring has Z2 or Z3 substituents;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
D comprises a member of the group consisting of Z5- or Z6-substituted mono- and poly-aryl, of Z5- or Z6-substituted mono- and poly-heteroaryl, of Z5- or Z6-substituted mono- and poly-heterocyclyl, of Z5- or Z6-substituted mono- and poly-arylalkyl, of Z5- or Z6-substituted mono- and poly-aryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heteroarylalkyl, of Z5- or Z6-substituted mono- and poly-heteroaryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heterocyclylalkyl, of Z5- or Z6-substituted mono- and poly-heterocyclyl branched alkyl, alkyl, and carbocyclyl moieties;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , —SO 2 R5, —(CH 2 ) n N(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3, moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
185 . The compounds of claim 184 wherein D is a moiety of the formula
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
and E2 is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
and n is 0-4; p is 1-4; q is 2-6.
186 . The compounds of claim 184 wherein D comprises carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
187 . The compounds of claim 186 wherein the E2 ring is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
188 . The compounds of claim 184 wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
each R9 is independently and individually selected from the group consisting of H, F, C1-C6alkyl, branched C4-C7alkyl, carbocyclyl, phenyl, phenyl C1-C6alkyl, heterocyclyl and heterocyclylC1-C6alkyl;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
189 . The compounds of claim 188 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
190 . The compounds of claim 189 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
191 . The compounds of claim 185 wherein said A2 group is defined as set forth in claim 188 .
192 . The compounds of claim 191 wherein said A2 group is defined as set forth in claim 189 .
193 . The compounds of claim 191 wherein said A2 group is defined as set forth in claim 190 .
194 . The compounds of claim 186 wherein said A2 group is defined as set forth in claim 188 .
195 . The compounds of claim 194 wherein said A2 group is defined as set forth in claim 189 .
196 . The compounds of claim 194 wherein said A2 group is defined as set forth in claim 190 .
197 . The compounds of claims 184 , 188 , 191 or 194 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
198 . The compounds of claims 184 , 188 , 191 or 194 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
199 . The compounds of claims 184 , 188 , 191 or 194 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
200 . The compounds of claims 184 , 188 , 191 or 194 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
201 . The compounds of claims 184 , 188 , 191 or 194 , wherein W and Y are each NH and X═O.
202 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, cyclohexyl,
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5 alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, R13, Z2, Z3, Z4, Z5, or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH2) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
203 . Most preferred compounds from claim 202 are 1-(3-t-butyl-1-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-methyl-1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(indolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(1-acetylindolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-((1-methylsulfonylamino-1-oxo-methylamino)methyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)naphthalen-1-yl)acetic acid, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, (3S)-6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-carbamimidoyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-oxo-3,4-dihydroquinazolin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-((1-amino-1-oxo-methylamino)methyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-((3S)-3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,5-trifluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3,5-difluorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,4-difluorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4-difluorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-fluorophenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-phenoxyphenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-phenoxyphenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-(2-aminoethylamino)quinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(dimethylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(2-aminoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea.
204 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 184 .
205 . The method of claim 204 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
206 . The method of claim 204 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
207 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 202 .
208 . The method of claim 207 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
209 . The method of claim 207 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
210 . A pharmaceutical composition comprising a compound of claim 184 together with a pharmaceutically acceptable carrier
211 . The composition of claim 210 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
212 . A pharmaceutical composition comprising a compound of claim 202 together with a pharmaceutically acceptable carrier
213 . The composition of claim 212 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
214 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, or diseases characterized angiogenesis, comprising the step of administering to such individual a compound of claim 184 .
215 . The method of claim 214 , said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
216 . The method of claim 214 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
217 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 202 .
218 . The method of claim 217 said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
219 . The method of claim 217 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
220 . An adduct comprising a compound of claim 184 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
221 . An adduct comprising a compound of claim 202 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
222 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z1-substituted phenyl, Z1-substituted pyridyl, Z1-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from the formula
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E2 is taken from the group consisting of poly-aryl, poly-heteroaryl, mono- and poly heterocyclyl, and carbocyclyl;
wherein E1 is taken from the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly heterocyclyl and carbocyclyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5 alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein either E1 or E2 is directly linked to the Y group of formula I;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8 aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
223 . The compounds of claim 222 wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein E2 comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
224 . The compounds of claim 222 wherein D comprises a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
225 . The compounds of claim 224 wherein the E2 ring is non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
226 . The compounds of claim 222 wherein A2 is selected from the group consisting of
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
227 . The compounds of claim 226 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
228 . The compounds of claim 227 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
229 . The compounds of claim 223 wherein said A2 group is defined as set forth in claim 226 .
230 . The compounds of claim 229 wherein said A2 group is defined as set forth in claim 227 .
231 . The compounds of claim 229 wherein said A2 group is defined as set forth in claim 228 .
232 . The compounds of claim 224 wherein said A2 group is defined as set forth in claim 226 .
233 . The compounds of claim 232 wherein said A2 group is defined as set forth in claim 227 .
234 . The compounds of claim 232 wherein said A2 group is defined as set forth in claim 228 .
235 . The compounds of claims 222 , 226 , 229 , 232 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
236 . The compounds of claims 222 , 226 , 229 , 232 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
237 . The compounds of claims 222 , 226 , 229 , 232 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
238 . The compounds of claims 222 , 226 , 229 , 232 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
239 . The compounds of claims 222 , 226 , 229 , 232 , wherein W and Y are each NH and X═O.
240 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 ) n —N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
241 . Most preferred compounds from claim 240 are 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(2-(3-(2-amino-2-oxoethyl)phenyl)-5-t-butylthiophen-3-yl)-3-(4-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-(6-(thiazol-4-yl)pyrimidin-4-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(4-(pyridin-3-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(4-(isoxazol-4-yl)pyrimidin-2-ylamino)phenyl)urea
242 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 222 .
243 . The method of claim 242 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
244 . The method of claim 242 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
245 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 240 .
246 . The method of claim 245 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
247 . The method of claim 245 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
248 . A pharmaceutical composition comprising a compound of claim 222 together with a pharmaceutically acceptable carrier
249 . The composition of claim 248 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
250 . A pharmaceutical composition comprising a compound of claim 250 together with a pharmaceutically acceptable carrier
251 . The composition of claim 250 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
252 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, or diseases characterized angiogenesis, comprising the step of administering to such individual a compound of claim 222 .
253 . The method of claim 252 , said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
254 . The method of claim 252 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
255 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, or diseases characterized angiogenesis, comprising the step of administering to such individual a compound of claim 240 .
256 . The method of claim 255 , said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
257 . The method of claim 255 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
258 . An adduct comprising a compound of claim 222 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
259 . An adduct comprising a compound of claim 240 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
260 . Compounds of the formula
wherein A2 is selected from the group consisting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with A1 and a distal ring attached to the proximal ring, and either the distal ring has a heteroatom in the ring structure thereof and/or the distal ring has Z2 or Z3 substituents;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
D comprises a member of the group consisting of Z5- or Z6-substituted mono- and poly-aryl, of Z5- or Z6-substituted mono- and poly-heteroaryl, of Z5- or Z6-substituted mono- and poly-heterocyclyl, of Z5- or Z6-substituted mono- and poly-arylalkyl, of Z5- or Z6-substituted mono- and poly-aryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heteroarylalkyl, of Z5- or Z6-substituted mono- and poly-heteroaryl branched alkyl, of Z5- or Z6-substituted mono- and poly-heterocyclylalkyl, of Z5- or Z6-substituted mono- and poly-heterocyclyl branched alkyl, alkyl, and carbocyclyl moieties;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , —SO 2 R5-, —(CH 2 ) n N(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z2 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3, moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
261 . The compounds of claim 260 wherein D is a moiety of the formula
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
and E2 is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
and n is 0-4; p is 1-4; q is 2-6.
262 . The compounds of claim 260 wherein D is a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
263 . The compounds of claim 262 wherein the E2 ring is selected from the group comprising cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fused bicyclic rings comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
264 . The compounds of claim 260 wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein ----- indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
each R9 is independently and individually selected from the group consisting of H, F, C1-C6alkyl, branched C4-C7alkyl, carbocyclyl, phenyl, phenyl C1-C6alkyl, heterocyclyl and heterocyclylC1-C6alkyl;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
265 . The compounds of claim 264 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
266 . The compounds of claim 265 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.
267 . The compounds of claim 261 wherein said A2 group is defined as set forth in claim 264 .
268 . The compounds of claim 267 wherein said A2 group is defined as set forth in claim 265 .
269 . The compounds of claim 267 wherein said A2 group is defined as set forth in claim 266 .
270 . The compounds of claim 262 wherein said A2 group is defined as set forth in claim 264 .
271 . The compounds of claim 270 wherein said A2 group is defined as set forth in claim 265 .
272 . The compounds of claim 270 wherein said A2 group is defined as set forth in claim 266 .
273 . The compounds of claims 260 , 264 , 267 or 270 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
274 . The compounds of claims 260 , 264 , 267 or 270 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
275 . The compounds of claims 260 , 264 , 267 or 270 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
276 . The compounds of claims 260 , 264 , 267 or 270 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
277 . The compounds of claims 260 , 264 , 267 or 270 , wherein W and Y are each NH and X═O.
278 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2,3,4-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-phenoxyphenyl, 4 phenoxyphenyl, 1-naphthyl-2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen 1-yl, benzo[d][1,3]dioxol-5-yl or benzo[d][1,3]dioxol-4-yl,
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, R13, Z2, Z3, Z4, Z5, or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH2) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
each R14 is independently and respectively selected from the group consisting of H and C1-C6alkyl;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8 aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF 3 , (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , R8CO—, (R4) 2 N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , —SO 2 R3, SOR3, (R4) 2 NSO 2 , —SO 2 R4, —SOR4, —(CH 2 ) n N(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z3 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
V, V1, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
279 . Most preferred compounds from claim 278 are 1-(3-t-butyl-1-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(indolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)naphthalen-1-yl)acetic acid, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(1-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(indolin-6-yl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea, 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea,
280 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 260 .
281 . The method of claim 280 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
282 . The method of claim 280 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
283 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 278 .
284 . The method of claim 283 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
285 . The method of claim 283 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
286 . A pharmaceutical composition comprising a compound of claim 260 together with a pharmaceutically acceptable carrier
287 . The composition of claim 286 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
288 . A pharmaceutical composition comprising a compound of claim 278 together with a pharmaceutically acceptable carrier
289 . The composition of claim 288 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
290 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 260 .
291 . The method of claim 290 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
292 . The method of claim 290 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
293 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 278 .
294 . The method of claim 293 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
295 . The method of claim 293 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
296 . An adduct comprising a compound of claim 260 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
297 . An adduct comprising a compound of claim 278 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
298 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z1-substituted phenyl, Z1-substituted pyridyl, Z1-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4′ may cyclize to form a C3-C7 heterocyclyl ring;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of the formula
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E2 is taken from the group consisting of poly-aryl, poly-heteroaryl, mono- and poly heterocyclyl, and carbocyclyl;
wherein E1 is taken from the group consisting of mono- and poly-aryl, mono- and poly-heteroaryl, mono- and poly heterocyclyl and carbocyclyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein either E1 or E2 is directly linked to the Y group of formula I;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
299 . The compounds of claim 298 wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein E2 comprises the group consisting of cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
300 . The compounds of claim 298 wherein D comprises a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2 is directly linked to the Y group of formula I.
301 . The compounds of claim 300 wherein the E2 ring is cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl, pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl, oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
302 . The compounds of claim 298 wherein A2 is selected from the group consisting of
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
303 . The compounds of claim 302 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
304 . The compounds of claim 303 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
305 . The compounds of claim 299 wherein said A2 group is defined as set forth in claim 302 .
306 . The compounds of claim 305 wherein said A2 group is defined as set forth in claim 303 .
307 . The compounds of claim 305 wherein said A2 group is defined as set forth in claim 304 .
308 . The compounds of claim 300 wherein said A2 group is defined as set forth in claim 302 .
309 . The compounds of claim 308 wherein said A2 group is defined as set forth in claim 303 .
310 . The compounds of claim 308 wherein said A2 group is defined as set forth in claim 304 .
311 . The compounds of claims 298 , 302 , 305 , 308 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
312 . The compounds of claims 298 , 302 , 305 , 308 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
313 . The compounds of claims 298 , 302 , 305 , 308 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
314 . The compounds of claims 298 , 302 , 305 , 308 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
315 . The compounds of claims 298 , 302 , 305 , 308 , wherein W and Y are each NH and X═O.
316 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of
wherein E1 is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8 aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
317 . Most preferred compounds from claim 316: 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea, 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea
318 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 298 .
319 . The method of claim 318 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
320 . The method of claim 318 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
321 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 316 .
322 . The method of claim 321 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
323 . The method of claim 321 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
324 . A pharmaceutical composition comprising a compound of claim 298 together with a pharmaceutically acceptable carrier
325 . The composition of claim 324 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
326 . A pharmaceutical composition comprising a compound of claim 316 together with a pharmaceutically acceptable carrier
327 . The composition of claim 326 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
328 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 298 .
329 . The method of claim 328 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
330 . The method of claim 328 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
331 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 316 .
332 . The method of claim 331 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
333 . The method of claim 331 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
334 . An adduct comprising a compound of claim 298 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
335 . An adduct comprising a compound of claim 316 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
336 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 and Z7 moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E1A is taken from the groups consisting of carbocyclyl, mono- and poly-heterocyclyl and mono- and poly-heteroaryl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group consisting of naphthyl, a 5-membered ring heteroaryl, or a fused bicyclic heteroaryl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1A or E1B ring and the E2A or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1A or E1B or E2A or E2B are directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
and cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
337 . The compounds of claim 336 wherein E1A is selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
E2A is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl.
338 . The compounds of claim 336 wherein D comprises a moiety taken from the group consisting of carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2A or E2B is directly linked to the Y group of formula I.
339 . The compounds of claim 338 wherein the E2A ring is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is selected from the group consisting of phenyl, pyridyl and pyrimidyl.
340 . The compounds of claim 336 wherein A2 is selected from the group consisting of
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
341 . The compounds of claim 340 , wherein A2 is selected from the group consisting of
wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
342 . The compounds of claim 341 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
343 . The compounds of claim 337 wherein said A2 group is defined as set forth in claim 340 .
344 . The compounds of claim 343 wherein said A2 group is defined as set forth in claim 341 .
345 . The compounds of claim 343 wherein said A2 group is defined as set forth in claim 342 .
346 . The compounds of claim 338 wherein said A2 group is defined as set forth in claim 340 .
347 . The compounds of claim 346 wherein said A2 group is defined as set forth in claim 341 .
348 . The compounds of claim 346 wherein said A2 group is defined as set forth in claim 342 .
349 . The compounds of claims 336 , 340 , 343 , 346 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
350 . The compounds of claims 336 , 340 , 343 , 346 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
351 . The compounds of claims 336 , 340 , 343 , 346 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
352 . The compounds of claims 336 , 340 , 343 , 346 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
353 . The compounds of claims 336 , 340 , 343 , 346 , wherein W and Y are each NH and X═O.
354 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-fluoro-5-cyanophenyl, 3-(R8SO 2 )-phenyl, 3-(hydroxyC1-C3alkyl)-phenyl, 3-(R3O—N═C(R6))-phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl,
wherein E1A is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group consisting of indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of alkyl, branched alkyl, fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(C1H 2 ) q —NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
In the foregoing definition of Z1, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
355 . Most preferred compounds from claim 354 are 1-(3-t-butyl-1-(3-(pyridin-3-yl)phenyl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea
356 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 336 .
357 . The method of claim 356 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
358 . The method of claim 356 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
359 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 354 .
360 . The method of claim 359 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
361 . The method of claim 359 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
362 . A pharmaceutical composition comprising a compound of claim 336 together with a pharmaceutically acceptable carrier.
363 . The composition of claim 362 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
364 . A pharmaceutical composition comprising a compound of claim 354 together with a pharmaceutically acceptable carrier.
365 . The composition of claim 364 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
366 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 336 .
367 . The method of claim 366 , said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
368 . The method of claim 366 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
369 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 354 .
370 . The method of claim 369 said condition being chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome.
371 . The method of claim 369 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
372 . An adduct comprising a compound of claim 336 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
373 . An adduct comprising a compound of claim 354 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
374 . A method of claim 356 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
375 . A method of claim 374 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
376 . A method of claim 375 , wherein the second site is an ATP cofactor site.
377 . A method of claim 374 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
378 . A method of claim 375 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
379 . A method of claim 376 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
380 . A method of claim 379 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
381 . A method of claim 359 , further comprising the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase to form a ternary adduct, such co-incident binding resulting in enhanced biological modulation of the kinase when compared to the biological modulation of the protein affected by either of said compounds alone.
382 . A method of claim 381 , wherein the second compound interacts at a substrate, cofactor, or regulatory site on the kinase, said second site being distinct from the site of interaction of the first compound.
383 . A method of claim 382 , wherein the second site is an ATP cofactor site.
384 . A method of claim 381 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
385 . A method of claim 382 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
386 . A method of claim 383 , wherein the kinase is c-Abl kinase, Bcr-Abl kinase or disease polymorphs thereof.
387 . A method of claim 386 , wherein the second compound is taken from the group consisting of N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (Gleevec); N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-(methylthio)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PD 173955); 6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173958); 6-(2,6-dichlorophenyl)-2-(4-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 173956); 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-MO16); 2-(4-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 1-10); 6-(2,6-dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV2-89); 2-(3-aminophenylamino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2-43); N-(4-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)acetamide (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV-M017); 6-(2,6-dichlorophenyl)-2-(3-ethylphenylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (SKI DV 2 87).
388 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 and Z7 moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E1A is taken from the groups consisting of carbocyclyl, mono- and poly-heterocyclyl and mono- and poly-heteroaryl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group consisting of naphthyl, a 5-membered ring heteroaryl, or a fused bicyclic heteroaryl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1A or E1B ring and the E2A or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1A or E1B or E2A or E2B are directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 ) n —, —(CH 2 )n-CO—N(R4)-, —(CH2) q —, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z I may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z7 is a substituent attached to ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
389 . The compounds of claim 388 wherein E1A is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
E2A is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl.
390 . The compounds of claim 388 wherein D comprises a moiety taken from the group consisting of carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2A or E2B is directly linked to the Y group of formula I.
391 . The compounds of claim 390 wherein the E2A ring is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is selected from the group consisting of phenyl, pyridyl and pyrimidyl.
392 . The compounds of claim 388 wherein A2 is selected from the group consisting of
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
393 . The compounds of claim 392 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
394 . The compounds of claim 393 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
395 . The compounds of claim 389 wherein said A2 group is defined as set forth in claim 392 .
396 . The compounds of claim 395 wherein said A2 group is defined as set forth in claim 393 .
397 . The compounds of claim 395 wherein said A2 group is defined as set forth in claim 394 .
398 . The compounds of claim 390 wherein said A2 group is defined as set forth in claim 392 .
399 . The compounds of claim 398 wherein said A2 group is defined as set forth in claim 393 .
400 . The compounds of claim 398 wherein said A2 group is defined as set forth in claim 394 .
401 . The compounds of claims 388 , 392 , 395 , 398 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
402 . The compounds of claims 388 , 392 , 395 , 398 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
403 . The compounds of claims 388 , 392 , 395 , 398 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
404 . The compounds of claims 388 , 392 , 395 , 398 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
405 . The compounds of claims 388 , 392 , 395 , 398 , wherein W and Y are each NH and X═O.
406 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 3-(R8SO 2 )— phenyl, 3-phenoxyphenyl, 4 phenoxyphenyl,
wherein E2A is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, and R19 substituted C3-C8carbocyclyl wherein R19 is H, or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents, or monocyclic heteroaryl;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 ) n —, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 ) n —, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
407 . Most preferred compounds from claim 406 are: 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(3-(pyridin-3-yl)phenyl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyrazin-2-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea
408 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 388 .
409 . The method of claim 408 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
410 . The method of claim 408 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
411 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 406 .
412 . The method of claim 411 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
413 . The method of claim 411 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
414 . A pharmaceutical composition comprising a compound of claim 388 together with a pharmaceutically acceptable carrier
415 . The composition of claim 414 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
416 . A pharmaceutical composition comprising a compound of claim 406 together with a pharmaceutically acceptable carrier
417 . The composition of claim 416 including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers.
418 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 388 .
419 . The method of claim 418 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
420 . The method of claim 418 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
421 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, and diseases characterized by hyper-vascularization, comprising the step of administering to such individual a compound of claim 406 .
422 . The method of claim 421 , said condition being glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, or rheumatoid arthritis characterized by the in-growth of a vascularized pannus.
423 . The method of claim 421 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
424 . An adduct comprising a compound of claim 388 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
425 . An adduct comprising a compound of claim 406 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
426 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 and Z7 moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E1A is taken from the groups consisting of carbocyclyl, mono- and poly-heterocyclyl and mono- and poly-heteroaryl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group consisting of naphthyl, a 5-membered ring heteroaryl, or a fused bicyclic heteroaryl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1A or E1B ring and the E2A or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1A or E1B or E2A or E2B are directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 ) n —, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 ) n —, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1]-C6alkyls;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
427 . The compounds of claim 426 wherein E1A is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
E2A is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl.
428 . The compounds of claim 426 wherein D comprises a moiety taken from the group consisting of carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2A or E2B is directly linked to the Y group of formula I.
429 . The compounds of claim 428 wherein the E2A ring is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is selected from the group consisting of phenyl, pyridyl and pyrimidyl.
430 . The compounds of claim 426 wherein A2 is selected from the group consisting of
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
431 . The compounds of claim 430 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
432 . The compounds of claim 431 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
433 . The compounds of claim 427 wherein said A2 group is defined as set forth in claim 430 .
434 . The compounds of claim 433 wherein said A2 group is defined as set forth in claim 431 .
435 . The compounds of claim 433 wherein said A2 group is defined as set forth in claim 432 .
436 . The compounds of claim 428 wherein said A2 group is defined as set forth in claim 430 .
437 . The compounds of claim 436 wherein said A2 group is defined as set forth in claim 431 .
438 . The compounds of claim 436 wherein said A2 group is defined as set forth in claim 432 .
439 . The compounds of claims 426 , 430 , 433 , 436 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
440 . The compounds of claims 426 , 430 , 433 , 436 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
441 . The compounds of claims 426 , 430 , 433 , 436 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
442 . The compounds of claims 426 , 430 , 433 , 436 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
443 . The compounds of claims 426 , 430 , 433 , 436 , wherein W and Y are each NH and X═O.
444 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, cyclohexyl,
wherein E1A is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH2)n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
Each R2 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C1-C6fluoroalkyl, wherein the alkyl group is partially or fully fluorinated, monocyclic heteroaryl, and R19 substituted C3-C8carbocyclyl wherein R19 is H and C1-C6alkyl;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 pyridyl, pyrimidinyl, or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
445 . Most preferred compounds from claim 444 are 1-(3-t-butyl-1-(3-(pyridin-3-yl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(1-amino-1-oxopropan-2-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(2-(2-hydroxyethylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-((4,5-dioxo-2,2-dioxo-2,1,3-thiadiaol-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-carbamimidoylphenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 (1-(3-(N-hydroxycarbamimidoyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(4-(N-hydroxycarbamimidoyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(2-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 2-(3-(3-t-butyl-5-(3-(2,3-difluorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)acetic acid, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea.
446 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 426 .
447 . The method of claim 446 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
448 . The method of claim 446 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
449 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 444 .
450 . The method of claim 449 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
451 . The method of claim 449 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
452 . A pharmaceutical composition comprising a compound of claim 426 together with a pharmaceutically acceptable carrier
453 . The composition of claim 452 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
454 . A pharmaceutical composition comprising a compound of claim 444 together with a pharmaceutically acceptable carrier
455 . The composition of claim 454 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
456 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, or diseases characterized angiogenesis, comprising the step of administering to such individual a compound of claim 426 .
457 . The method of claim 456 , said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
458 . The method of claim 456 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
459 . A method of treating an individual suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases, comprising the step of administering to such individual a compound of claim 444 .
460 . The method of claim 459 said condition being melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastisis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis characterized by the in-growth of a vascularized pannus, or a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway.
461 . The method of claim 459 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
462 . An adduct comprising a compound of claim 426 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
463 . An adduct comprising a compound of claim 444 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
464 . Compounds of the formula
wherein A2 is selected from the group consisting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Z1-substituted thienyl, Z1 or Z4′-substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4-oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrolyl wherein the pyrrolyl nitrogen is the site of attachment to the A1 ring;
A1 is selected from the group consisting of R2′ and R7-substituted phenyl, pyridyl, or pyrimidinyl, R2-substituted monocyclic 5-membered ring heteroaryl, and R2′-substituted monocyclic heterocyclyl moieties;
W and Y are CHR4, NR3, or O and wherein W and Y are not simultaneously O;
X is O, S, or NR3;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, or phenyl;
each R3′ is independently and individually selected from the group consisting of C2-C6alkyl, branched C3-C7alkyl, C3-C7cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z1, Z4′, Z5, Z6 and Z7 moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
D comprises a moiety taken from group consisting of
wherein the symbol (***) is the point of attachment to the Y group of formula I;
wherein E1A is taken from the groups consisting of carbocyclyl, mono- and poly-heterocyclyl and mono- and poly-heteroaryl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group consisting of naphthyl, a 5-membered ring heteroaryl, or a fused bicyclic heteroaryl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1A or E1B ring and the E2A or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1A or E1B or E2A or E2B are directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 ) n —, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 ) n —, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) q —, C2-C5 alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each Z1 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC1-C6alkyl, C2-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl, C1-C6alkoxycarbonyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , —SO 2 R3′, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4′ is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4′ moiety to the A1 ring of formula I;
in the event that Z4′ contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6, r is 0 or 1;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.
465 . The compounds of claim 464 wherein E1A is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
E2A is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl.
466 . The compounds of claim 464 wherein D comprises a moiety taken from the group consisting of carbocyclyl and a moiety of the formula
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E2A or E2B is directly linked to the Y group of formula I.
467 . The compounds of claim 466 wherein the E2A ring is selected from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is selected from the group consisting of phenyl, pyridyl and pyrimidyl.
468 . The compounds of claim 464 wherein A2 is selected from the group consisting of
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2.
469 . The compounds of claim 468 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring for formula I.
470 . The compounds of claim 4696 , wherein A2 is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I.
471 . The compounds of claim 465 wherein said A2 group is defined as set forth in claim 468 .
472 . The compounds of claim 471 wherein said A2 group is defined as set forth in claim 469 .
473 . The compounds of claim 471 wherein said A2 group is defined as set forth in claim 470 .
474 . The compounds of claim 466 wherein said A2 group is defined as set forth in claim 468 .
475 . The compounds of claim 474 wherein said A2 group is defined as set forth in claim 469 .
476 . The compounds of claim 474 wherein said A2 group is defined as set forth in claim 470 .
477 . The compounds of claims 464 , 468 , 471 , 474 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
478 . The compounds of claims 464 , 468 , 471 , 474 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I.
479 . The compounds of claims 464 , 468 , 471 , 474 , wherein A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
480 . The compounds of claims 464 , 468 , 471 , 474 , wherein: (1) W and Y are each NH, and X═O; (2) W═NH, Y═CHR4 and X═O; or (3) W═CHR4, Y═NH, and X═O.
481 . The compounds of claims 464 , 468 , 471 , 474 , wherein W and Y are each NH and X═O.
482 . Compounds of the formula
wherein A2 is selected from the group consisting of
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the W moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
X is O, S, or NR3;
D comprises a member of 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2,3,4-trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-phenoxyphenyl, 4 phenoxyphenyl, 1-naphthyl-2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen 1-yl, benzo[d][1,3]dioxol-5-yl or benzo[d][1,3]dioxol-4-yl,
wherein E1A is taken from the groups consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, and pyrimidinyl;
wherein E1B is taken from the groups consisting of phenyl and naphthyl;
wherein E2A is taken from the group comprising naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl and fused bicyclic rings selected from the group comprising indolyl, isoindolyl, isoindolinyl, isoindolonyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazolonopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, furylopyrimidinyl, thienopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl;
wherein E2B is taken from the group consisting of phenyl, pyridyl, and pyrimidyl;
wherein the symbol (***) denotes the attachment to the Y moiety of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 )n-, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 ) p-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n-, —(CH2)q-, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl, or a direct bond wherein E1 is directly linked to the Y group of formula I;
X3 is selected from the group consisting of NR3, —C(═O)—, —O—(CH 2 )n-, —S—(CH 2 )n-, —NR3-(CH 2 ) n —, —O—(CH 2 )q-O—, —O—(CH 2 )q-NR3-, —N(R3)-(CH 2 )q-N(R3)-, —(CH 2 )n-N(R4)-C(═O)—, —(CH 2 )n-N(R4)-C(═O)(CH 2 )n-, —(CH 2 )n-CO—N(R4)-, —(CH 2 )q-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the E1B ring or E2B ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)q-, C2-C5alkenyl, and C2-C5alkynyl moieties of X3 may be further substituted by one or more C1-C6alkyl;
X4 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alkyl;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, a R19-substituted C3-C8carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6fluoroalkyl wherein the alkyl group is partially or fully fluorinated, and phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents or chlorine;
each R2′ is selected from the group consisting of halogen and R2;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7carbocyclyl, or phenyl;
wherein two R3 moieties independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C7alkyl are attached to the same nitrogen heteroatom, the two R3 moieties may cyclize to form a C3-C7 heterocyclyl ring;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z4, Z5, Z6 or A2 ring moieties containing a R5 moiety;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R7 is selected from the group consisting of H, halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, C1-C6 fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, branchedC4-C7alkyl, carbocyclyl, phenyl, C1-C6phenylalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , or R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R8 may cyclize to form a C3-C7 heterocyclyl ring;
each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, —N(R4) 2 ;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R10 may cyclize to form a C3-C7 heterocyclyl ring;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4) 2 N—CO, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) q , R5-C2-C6alkylN(R4)-(CH 2 ) q , (R4) 2 N—C2-C6alkylO—(CH 2 ) q , R5-C2-C6alkyl-O—(CH 2 ) q , —(CH 2 ) q N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of R13 may cyclize to form a C3-C7 heterocyclyl ring;
wherein Z1′ is independently and individually selected from the group consisting of H, C1-C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N—C1-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N—C2-C6alkylO—(CH 2 ) p , (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —(CH 2 ) p N(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, or heterocyclylaminoC1-C6alkyl;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z1′ may cyclize to form a C3-C7 heterocyclyl ring;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I,
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z4 may cyclize to form a C3-C7 heterocyclyl ring;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3) 2 , —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-N(R4) 2 , —R5, —O—(CH 2 )q-O-Alkyl, —O—(CH 2 )q-N(R4) 2 , —N(R3)-(CH 2 )q-O-Alkyl, —N(R3)-(CH 2 )q-N(R4) 2 , —O—(CH 2 )q-R5, and —N(R3)-(CH 2 )q-R5;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z5 may cyclize to form a C3-C7 heterocyclyl ring;
Each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, (R3) 2 N—, —N(R3)COR8, (R4) 2 N—, —R5, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 NHR4, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z6 may cyclize to form a C3-C7 heterocyclyl ring;
each Z7 is a substituent attached to a ring carbon and is independently and individually selected from the group consisting of hydroxyC2-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R6) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—CO, (R4) 2 N—CO, —SO 2 R3′, SOR3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, (CH 2 ) n N(R4)C(O)N(R4) 2 , (CH 2 ) n N(R4)C(O)R5, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1-C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae
cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the A1 ring and wherein A2 is phenyl, and cyano wherein the site of attachment is to a substitutable position when A2 is pyridyl, pyrimidinyl or a five-membered ring;
In the foregoing definition of Z7, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;
Wherein the asterisk (*) indicates the point of attachment of the Z1 moiety to the A2 ring;
in the event that Z7 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
wherein two R3 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen heteroatom of Z7 may cyclize to form a C3-C7 heterocyclyl ring;
and n is 0-4; p is 1-4; q is 2-6; r is 0 or 1; v is 1 or 2;
and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs and salts of any of the foregoing.
483 . Most preferred compounds from claim 482: 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 2-(3-(5-(3-(2,3-dichlorophenyl)ureido)-3-(3-fluorophenyl)-1H-pyrazol-1-yl)phenyl)acetic acid, 2-(3-(5-(3-(2,3-dichlorophenyl)ureido)-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)acetic acid, 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3-(3-fluorophenyl)-1H-pyrazol-1-yl)phenyl)acetic acid, 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)acetic acid, 2-(4-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)acetic acid, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1-(3-(2-(2-hydroxyethylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)urea, 1-(2,3-dichlorophenyl)-3-(1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-t-butyl-1-(3-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(1-(4-(2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(2,3-dichlorophenyl)-3-(1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)urea, (R)-1-(3-t-butyl-1-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, (R)-1-(3-t-butyl-1-(4-(2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, (R)-1-(3-t-butyl-1-(4-(2-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea, 1-(3-cyclopentyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-cyclopentyl-1-(3-(2-(2-hydroxyethylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea. 1-(1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea, 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea, 2-(3-(3-(2-fluorophenyl)-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)acetic acid,
484 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 464 .
485 . The method of claim 484 , said kinase species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
486 . The method of claim 484 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
487 . A method of modulating a kinase activity of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claim 482 .
488 . The method of claim 487 , said species being activated or unactivated, and the species is modulated by phosphorylation, sulfation, fatty acid acylation, glycosylation, nitrosylation, cystinylation, or oxidation.
489 . The method of claim 487 , said kinase activity selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
490 . A pharmaceutical composition comprising a compound of claim 464 together with a pharmaceutically acceptable carrier.
491 . The composition of claim 490 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
492 . A pharmaceutical composition comprising a compound of claim 482 together with a pharmaceutically acceptable carrier.
493 . The composition of claim 492 including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
494 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 464 .
495 . The method of claim 494 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
496 . The method of claim 494 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
497 . A method of treating an individual suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease comprising the step of administering to such individual a compound of claim 482 .
498 . The method of claim 497 , said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.
499 . The method of claim 497 , said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.
500 . An adduct comprising a compound of claim 464 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
501 . An adduct comprising a compound of claim 482 bound with a species of a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing.
502 . The method of claims 21 , 22 , 23 , 24 , 25 , or 26 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
503 . An adduct of claims 37 or 38 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
504 . The method of claims 76 , 77 , 78 , 79 , 80 , or 81 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
505 . An adduct of claims 92 or 93 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
506 . The method of claims 356 , 357 , 358 , 359 , 360 , or 361 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
507 . An adduct of claims 372 or 373 , wherein the kinase is abl kinase, bcr-abl kinase, or disease polymorphs thereof.
508 . The method of claims 128 , 129 , 130 , 131 , 132 , or 133 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
509 . An adduct of claims 144 or 145 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
510 . The method of claims 166 , 167 , 168 , 169 , 170 , or 171 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
511 . An adduct of claims 182 or 183 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
512 . The method of claims 408 , 409 , 410 , 411 , 412 , or 413 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
513 . An adduct of claims 424 or 425 , wherein the kinase is VEGFR-2 kinase or disease polymorphs thereof.
514 . The method of claims 204 , 205 , 206 , 207 , 208 , or 209 , wherein the kinase is B-raf 5 kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
515 . An adduct of claims 220 or 221 , wherein the kinase is B-raf kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
516 . The method of claims 242 , 243 , 244 , 245 , 246 , or 247 , wherein the kinase is B-raf kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
517 . An adduct of claims 258 or 259 , wherein the kinase is B-raf kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
518 . The method of claims 446 , 447 , 448 , 449 , 450 , or 451 , wherein the kinase is B-raf kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
519 . An adduct of claims 462 or 463 , wherein the kinase is B-raf kinase, Valine599Glutamic acid mutated B-raf kinase, C-raf kinase or disease polymorphs of any of the foregoing.
520 . The method of claims 280 , 281 , 282 , 283 , 284 , or 285 , wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.
521 . An adduct of claims 296 or 297 , wherein the kinase is wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.
522 . The method of claims 318 , 319 , 320 , 321 , 322 , or 323 , wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.
523 . An adduct of claims 334 or 335 , wherein the kinase is wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.
524 . The method of claims 484 , 485 , 486 , 487 , 488 , or 489 , wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.
525 . An adduct of claims 500 or 501 , wherein the kinase is wherein the kinase is p-38 alpha kinase or disease polymorphs thereof.Join the waitlist — get patent alerts
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