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Title:
ENZYME MODULATORS AND TREATMENTS
Document Type and Number:
WIPO Patent Application WO/2006/071940
Kind Code:
A3
Abstract:
Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.

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WO/2023/0071476-SUBSTITUTED NAPHTHALENE-1,3-DISULFONIC ACID DERIVATIVES AS MODULATORS OF THE EXTRACELLULAR NICOTINAMIDE PHOSPHORIBOSYL TRANSFERASE (ENAMPT) FOR THE TREATMENT OF E.G. DIABETES
Inventors:
FLYNN DANIEL L (US)
PETILLO PETER A (US)
Application Number:
PCT/US2005/047270
Publication Date:
April 23, 2009
Filing Date:
December 23, 2005
Export Citation:
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Assignee:
DECIPHERA PHARMACEUTICALS LLC (US)
FLYNN DANIEL L (US)
PETILLO PETER A (US)
International Classes:
C07C275/28; A61K31/17
Foreign References:
US6297261B12001-10-02
EP0816329A11998-01-07
Other References:
See also references of EP 1835934A4
Attorney, Agent or Firm:
SKOCH, Gregory, J. (Suite 4002405 Grand Boulevar, Kansas City MO, US)
Download PDF:
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Claims:

We claim:

1. 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 Al 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;

Al 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- heteroaryl alkyl, 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-C6alkyl0-(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, =N0H, =N(OR6),

heteroarylC 1 -C6alkyl , heterocyclylC 1 -C6alkyl , heteroaryloxyC 1 -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, C 1-C6alkoxyC1 -C6alkyl, halogen, CF 3 , (R3) 2 N-, (IU) 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)RO, -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, heteroaryl amino, 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 heterocyclic 1 -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, RlO, 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, heterocyclic 1-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 RlO 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 RlO 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -O-(CH 2 )n-, -S-(CH 2 )I--, - 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 El ring and the E2 ring are directly linked by a covalent bond;

and wherein the carbon atoms of -(Cη2)n-, -(CH2)q-, (CH2)p, C2-C5alkenyl, and C2- C5alkynyl moieties of Xl 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 El 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-l,l,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-l,l,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 Al 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 heterocyclylC 1 -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-C6alkyl0-(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, Vl, 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 TA 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 TA 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 Al 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 Al 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 Al 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 Al 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 Al 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

I 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 Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=0)-, -0-(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(=0)-, -(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 El 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 Xl 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 El 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 R 19 is H, and C 1 -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 C 1-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, RlO, 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, heterocyclic 1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Rl 3 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-C6alkyl0-(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, heterocyclylC 1 -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, Vl, 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- Cδalkyl, 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-C6alkyl0-(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=(N0H)R6, -C=(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-Cδalkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, or moieties of the formulae

wherein t 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, -C0R8, 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-(l,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)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6- (3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-l,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)naphthaIen-2-yl)-1H-pyrazol-5- yl)-3-(2,3,5-trifluorophenyI)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-(l,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-(l,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)-l,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-l,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- 1 H- 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-l,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-(l-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t- butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t-butyl- 1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea, 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(l,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-l,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- l,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)- 1 H-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)-l H-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- tetrahydroisoquinoIin-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-methyIpiperazin-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]pyrirnidin-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]pyrirnidin-2-ylamino)phenyl)acetamide (SKI DV-M016); 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]ρyrimidin-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)pyrimidm-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-rnethyIpyrido[2,3- d]pyrimidin-7(8H)-one (PD 166326); 6-(2,6-dichlorophenyl)-8-methyl-2-(3-

(methylthio)phenylamino)pyrido[2,3-d]pyrirnidin-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).

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 readable 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(ORIo) 2 , - A3P -B(R17) 3 M2, - A3P -Si(R18) 3 , or A3P -Sn(RIo) 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

(A 3 PBO) 3 , A3P-

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 Dl-NH 2 , to yield a compound of the formula

where Dl is selected from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly-heterocyclyl.

54. The synthesis method of C1aim 53 wherein

is preferably taken from

A3P-M is taken from A3P-B(OH) 2 , A3P -B(ORIo) 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 13O°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 Dl-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-wo-propylethylamine, at temperatures ranging from 8O°C to 11O°C to yield a desired compound of the formula

55. The synthesis method of C1aim 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 Dl-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 8O°C to HO°C to yield a desired compound of the formula.

56. Compounds of the formula

I wherein A2 is selected from the group consisting of a Zl -substituted phenyl, Zl -substituted pyridyl, Zl -substituted pyrimidinyl, Zl -substituted thienyl, Zl 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 Al ring;

Al 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 Zl 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-C6alkyl0-(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(=N0H)R6, -C(=NOR3)R6, -(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC1-C6alkyl, monocyclic heteroaryl oxy, 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 w erein the site of attachment to the A2 ring is meta to the point of attachment to the Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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-C6alkyli and moieties of the formulae

wherein the symbol (#) indicates the point of attachment of the Z4' moiety to the Al ring of formula I;

in the event that ZA' 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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO 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 El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;

Xl 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 El 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 Xl 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 El 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 El 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 consisti lkyl, 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 Al 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 Al 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 Al 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 Al 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 Al 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 Al 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: (I) 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

I wherein A2 is selected from the group consisting of

3 ( Z1 ) v , and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

Al 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 El 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;

Xl 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 El 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 Xl 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 El is directly linked to the Y group of formula I;

each Zl 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-C6alkyl0-(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 where n the site of attachment to the A2 ring is meta to the point of attachment to the Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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, heterocyclyl oxyC2-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 TA 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 ZA 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 Al 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

4

and wherein the symbol (##) is the point of attachment to respective R8, RlO, Zl, 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 Ci-Cl 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 RlO 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 RlO 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-oxoethyl)phenyl)-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 (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-M016); 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- rnethylpyrido[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 (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-rnethylpyrido[2,3- d]pyrimidin-7(8H)-one; N-(3-(6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrirnidin-2-ylamino)phenyl)acetamide (SKI DV-M016); 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 cons sting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with Al 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;

Al 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 ),,, (R4) 2 NC2-C6alkyl0-(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, =0 , =N0H, =N(0R6), heteroarylC1-C β alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl,

heterocyclyloxyC 1 -C6alkyl, arylaminoC 1 -C6alkyl, heteroarylaminoC 1 -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 ZV 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-C6alkyl0-(CH 2 ) P , (R4) 2 N-CO-C 1 - 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 Zl' 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-C6alkyl0-(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)Ro, -C=(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1 -C6alkyl, arylamino, heteroaryl amino, 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, (IW) 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, RlO, 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 RlO 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 RlO 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 El 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;

Xl 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 El 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 Xl 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 El 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-l,l,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 consisti 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 Al 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 heterocyclylC 1 -C6alkyl;

each Rl 3 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, heterocyclylC 1 -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, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;

each TA 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 TA 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 Al 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 Al 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 Al 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 Al 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 Al 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

I 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 Al moiety of formula I;

Al 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 El 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;

Xl 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 El 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 Xl 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 El 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 heterocyclic 1-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, RlO, 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-Cδalkyl, 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 RlO 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 RlO 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-C6alkyl0-(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 ZV 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-C6alkyl0-(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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each Z3 is independently and individually selected from the group consisting of H, C1- C6alky], 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-C6alkyl0-(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)Ro, -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, heterocyclylC 1-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, Vl, 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-(l-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)- 1 H-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)-l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3- (2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,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)- 1 H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(l-carbamimidoyl-l, 2,3,4- tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 -(3-t-butyl- 1 -(I - (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-(l,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)- l,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)-l,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)-l,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-l,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t- butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyI)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,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-l,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)- 1 H-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-(l, 2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea, 1-(3-t- butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(l-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-(l-oxoisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4- yl)phenyl)ureido)-1H-pyrazol-1-yl)-l,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 cons sting of a Zl-substituted phenyl, Zl -substituted pyridyl, Zl-substituted pyrimidinyl, Zl-substituted thienyl, Zl 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 Al ring;

Al 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 Zl 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-C6alkyl0-(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 heteroaryl ox y, 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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (IM) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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 Zl' 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 Al 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, RlO, Zl, 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, heterocyclic 1-C6alky], 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 RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C 1 -C6alkyl, CO-N(R4) 2 , OH, C 1 -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 RlO 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 El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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 El 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 consisti lkyl, 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 TA 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 TA 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 Al 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 Al 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 Al 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 Al 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 Al 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

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 El 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;

Xl 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 El 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 Xl 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 El 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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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-C6alkyl0-(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 heterocyclylC 1 -C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1 -C6alkyl, monocyclic heterocyclyloxyC1-C6alkyl, arylamino, monocyclic heteroaryl amino, 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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1 ' -C6alkyl, C1-C6alkoxyC1-C6alkyl, (IM) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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, heterocyclic 1-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 Zl' 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 TA 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 TA 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 heterocyc 1 y 1 amino ;

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-(1H-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-yI)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, cysύ ' nylation, 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.

111. 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 Al 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;

Al 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)-

(CHj) n , (R4) 2 NC2-C6alkyl0-(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, =0, =N0H, =N(0R6), 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 Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (IU) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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 Zl' 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-C6alkyl0-(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)Ro, -C=(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroaryl amino, 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, carbon yl amino, 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, (IM) 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 t e symbol (##) is the point of attachment to respective R8, RlO, 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, heterocyclic 1-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 RlO 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 RlO 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 )ρ-, C2-C5alkenyl, C2- C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the El 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 Xl 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 El 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-l,l,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-l,l,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 Al 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 heterocyclic 1 -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-C6alkyl0-(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, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;

each ZA is & 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

w erein 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 Al 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 Al 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 Al 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 Al 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 Al 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

I 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 Al moiety of formula I;

Al 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, A- phenoxyphenyl, cyclohexyl,

wherein El 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;

Xl 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, Ql-

C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the El 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 Xl 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 El 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, RlO, 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 RlO 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 RlO 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-C6alkyI, 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-C6alkyl0-(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- C β alkyl, 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 Rl 3 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 Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-Cθalkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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 Zl' 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)RO, -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, C 1 -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 TA 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, Vl, 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-(l-

(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-dichIorophenyl)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-l,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)- 1 H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea, (3S)-6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 -(3-t-butyl- 1 -(2- oxo-l,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t- butyl-1-(2-oxo-l,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1- (3-t-butyl-1-(l-carbamimidoyl-l,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-l,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)- 1 H- 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-((I -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-pyrazoI-5-yl)-3-(2,4,5- trifluorophenyl)urea, 1-(3-t-butyl-1-((3S)-3-carbamoyl-l,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1 -(3-t-butyl- 1- (2-oxo- l,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-l,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-l,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5- yl)-3-(2,3-difluorophenyl)urea, 1-(3-t-butyl-1-(4-(nydroxymethyl)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-l,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-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-phenoxyphenyl)urea, 1-(3-t- butyl-1-(2-oxo-l,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-l -(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-(l,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-l,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-l,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-l,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-l, 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-(l,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 Zl -substituted phenyl, Zl -substituted pyridyl, Zl -substituted pyrimidinyl, Zl -substituted thienyl, Zl or Z4' -substituted monocyclic heterocyclyl rings, and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4- oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrol yl wherein the pyrrolyl nitrogen is the site of attachment to the Al ring;

Al 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, RlO, Zl, 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 RlO 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 RlO 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 El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;

Xl 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 El 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 Xl 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 El or E2 is directly linked to the Y group of formula I;

each Zl 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-C6alkyl0-(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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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 Al 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 El 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 consisti 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 TA 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 TA 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 Al 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 Al 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 Al 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 Al 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 Al 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 Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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-Cθalkyl, 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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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-C6alkyl0-(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(=N0H)R6, -C(=NOR3)R6, -(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1-C6alkyl, monocyclic heterocyclylC 1-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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 ZV 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

w erein 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)ρyrimidin-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 Al 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;

Al 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-C6alkyl0-(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- C6 ' alkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , -SO 2 R5-, -(CH 2 ) n N(R4)C(O)R8, =O, =N0H, =N(OR6), heteroarylC 1 -C6alkyl, heterocyclylC 1 -C6alkyl, heteroaryloxyC 1 -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 Zl' 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 Zl' 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-C6alkyl0-(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)RO, -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 heterocyc 1 y lamino ;

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, RlO, 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, heterocyclic 1-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 RlO 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 RlO 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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-l,l,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 consisti kyl, 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 Al 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 heterocyclylC 1 -C6alkyl ;

each Rl 3 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-C6alkyl0-(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, Vl, and V2 are each independently and respectively selected from the group consisting of O and H 2 ;

each TA 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 TA 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 TA 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 TA 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 Al 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 Al 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 Al 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 Al 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 Al 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

I 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 Al moiety of formula I;

Al 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-tetrahydronaphthalenl-yl, benzo[d][l,3]dioxol- 5-yl or benzo[d][l,3]dioxol-4-yl,

wherein El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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, RlO, R13, Z2, Z3, ZA, 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-Cθalkyl, 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 RlO 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 RlO 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,

heterocyclic 1-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 ZV 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-C6alkyl0-(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, heterocyclyl ox yC1 -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 Zl' 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 -C β alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(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)Ro, -C=(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1 -C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1 -C6alkyl, heterocyclyloxyC1 -C6alkyl, arylamino, heteroaryl amino, 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, C 1 -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 Ci-Cl 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, Vl, 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-(l-

(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)-l,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 -(3-t-butyl- 1 -( 1 - (methylcarbamoyl)-l,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, HS-t-butyl-1-Cindolin-ό-yO-1H-pyrazol-S-yO-S-Cnaphthalen-1-yOurea, 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-l,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 Zl -substituted phenyl, Zl -substituted pyridyl, Zl -substituted pyrimidinyl, Zl-substituted thienyl, Zl 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 Al ring;

Al 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 Zl 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-C6alkyl0-(CH 2 ) n , (R3) 2 N-C(=O)-, (R4) 2 N-C(=O)-, (R4) 2 N-CO-C1-C6alkyl, C1-Cδalkoxycarbonyl, carboxyC1- C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , -SO 2 R3', - SOR4, -C(=O)R6, -C(=N0H)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 heterocyclyl oxy, 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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl ' 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-C6alkyI, -Cl- 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 Al 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, RlO, Zl, 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 heteroaryl C 1-C6alkyl, heterocyclyl, heterocyclic 1-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 RlO 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 RlO 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 El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El ring and the E2 ring are directly linked by a covalent bond;

and wherein the carbon atoms of -(CH2)n-, -(Cη2)q-, (CH2)p, C2-C5alkenyl, and C2-

C5alkynyl moieties of Xl 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 El 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 El 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 consisti yl, 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 TA 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-C6alkoxycarbony!C2-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 Al 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 Al 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 Al 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 Al 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 Al 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

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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, RlO, Zl, 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, heterocyclic 1-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 RlO is independently and individually selected from the group consisting of CO 2 H, CO 2 C 1 -C6alkyl, CO-N(R4) 2 , OH, C 1 -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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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- Cθalkyl, (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, C 1-C6alkoxycarbonylC1 -C6alkyl, (R3) 2 NSO 2 , SOR3, (R4) 2 NSO 2 , -SO 2 R3\ - SOR4, -C(=0)R6, -C(=N0H)R6, -C(=NOR3)R6, -(CH 2 ) n N(R4)C(O)R8, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic heteroarylC1 -C6alkyl, monocyclic heterocyclylC 1 -C6alkyl, monocyclic heteroaryloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxyC1 -C6alkyl, monocyclic heterocyclyloxyC1 -C6alkyl, arylamino, monocyclic heteroaryl amino, 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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) P N(R4)C(O)R8, aryl, arylC1-Cδalkyl, 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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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 TA contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C 1 -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 TA 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, (IM) 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, heteroaryl amino, 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, Zl -substituted thienyl, Zl 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 Al ring;

Al 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 R 19 is H, and C 1 -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, C l-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, RlO, Zl, 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- Cδalkyl, 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 RlO 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 RlO 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 ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;

wherein ElB 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 ElA or ElB 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 Xl 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 ElA or ElB 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 ElB 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 Zl 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-C6alkyl0-(CH 2 ) n , (R3) 2 N-C(=O)-, (R4) 2 N-C(=O)-, (R4) 2 N-CO-C1-C6alkyI, 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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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-C6alkyI, 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 Al 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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , (R3) 2 N- CO, (R4) 2 N-CO, -SO 2 R3', SOR3, -SOR4, -C(=O)R6, -C(=N0H)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 Al 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 Zl 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 ElA 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-l,l,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 grou 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-l,l,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

and wherein the symbol (**) is the point of attachment to the Al 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 Al 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 Al 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 Al is selected from the group consisting of

' wh , er ein 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 Al 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 Al moiety of formula I;

Al 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-di fluorophenyl, 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 ElA 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 ElB 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-l,l,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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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-(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 ElB 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, RlO, ZA, 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, heterocyclic 1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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- C β alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(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-C6alky], arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoC1-C6alkyl, monocyclic heteroarylaminoC1-C6alkyl, monocyclic heterocyclylaminoC1-C6alkyl, or moieties of the formulae

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , (R3) 2 N- CO, (R4) 2 N-CO, -SO 2 R3', SOR3, -SOR4, -C(=0)R6, -C(=N0H)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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1 -C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl 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- 1 H-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 ther eeooff,, 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 (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).

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 (PDl 80970); 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-MO 16); 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, Zl-substituted thienyl, Zl 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 Al ring;

Al 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 heterocyclic 1-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, RlO, Zl, 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 RlO 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 RlO 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 ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;

wherein ElB 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 ElA or ElB 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 Xl 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 ElA or ElB 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 )Ii-, -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 Jq-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the ElB 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 Zl 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-C6alkyl0-(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(=N0H)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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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 Al 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-C6alkyl0-(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 Al 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 Zl 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 ElA 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-l,l,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 grou 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-l,l,3-tτionyl, 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 Al 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 Al 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 Al 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 Al 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 Al 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

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 ElA 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 ElB 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-l,l,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;

Xl 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 El 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 Xl 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 El 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 ElB 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-Cθalkyl, 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, RlO, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- Cθalkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p> (R4) 2 N-C2-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) P N(R4)C(O)R8 , aryl, arylC1-C β alkyl, 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 Zl ' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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-AlkyI, -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-C6alkyl0-(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 heteroaryloxyC 1 -

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 Al 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 Zl 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-(l-oxoisoindolin-4-yl)phenyl)urea, 1-(1-(3-(2-amino-2- oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea, 1- (1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(l-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, Zl-substituted thienyl, Zl 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 Al ring;

Al 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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO 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 ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;

wherein ElB 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;

Xl 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 ElA or ElB 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 Xl 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 ElA or ElB 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-, -0-(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 ElB 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 Zl 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(=N0H)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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyC1-C6alkyl, C l-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 Zl' 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, heterocyclic 1-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 Al 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-C6alkyl0-(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 Al 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 Zl 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 ElA 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-l,l,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 grou 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-l,l,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

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 Al 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 Al 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 Al 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 Al is selected from the group consisting of

erein 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 Al 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: (I) 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 grou consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 ElA 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 ElB 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-l,l,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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El is directly linked to the Y group of formula I;

X3 is selected from the group consisting of NR3, -C(=O)-, -0-(CH 2 )n-, -S-(CH 2 )n-, -NR3- (CH 2 )Ii-, -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 ElB 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-C7 alkyl, 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, RlO, 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 heteroarylCl -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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyCl -C6alkyl, C l-C6alkoxycarbonylCl -C6alkyl, -(CH 2 ) P N(R4)C(O)R8 , aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylCl -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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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 TA 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 TA 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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(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 heterocyclyloxyCl -C6alkyl, arylamino, monocyclic heteroarylamino, monocyclic heterocyclylamino, arylaminoCl -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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl 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- 1 H-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-l,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, Zl -substituted thienyl, Zl or Z4' -substituted monocyclic heterocyclyl rings and other monocyclic heteroaryls, excluding tetrazolyl, 1,2,4- oxadiazolonyl, 1,2,4-triazolonyl, and alkyl-substituted pyrrol yl wherein the pyrrolyl nitrogen is the site of attachment to the Al ring;

Al 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, RlO, Zl, 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, branchedCφ- 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 RlO 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 RlO 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 ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;

wherein ElB 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;

Xl 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 ElA or ElB 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 Xl 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 ElA or ElB 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 Jn-, -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 Jq-, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the either the ElB 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 Zl 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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein ZV is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (IU) 2 N-C1- C6alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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 Zl' 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-Cθalkyl, heterocyclyl, heterocyclic 1-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 Al 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 Al 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 Zl 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 ElA 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-l,l,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 grou 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, pyrrol yl, 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-l,l,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

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 Al 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 Al 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 Al 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 Al 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 Al 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: (I) 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

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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-yI, 1,2,3,4-tetrahydronaphthalenl-yl, benzo[d][l,3]dioxol- 5-yl or benzo[d][l,3]dioxol-4-yl,

wherein ElA 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 ElB 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-l,l,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;

Xl 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 El 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 Xl 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 El 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 ElB 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-Cθalkyl, 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, RlO, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Rl 3 is independently and individually selected from the group consisting of H, C1- C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyI, C1-C6alkoxyC2-C7alkyl,

(R4) 2 N-CO, (R4) 2 N-CO-C1-C6alkyl, carboxyCl -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-C6alkyl0-(CH 2 ) q , R5-C2-C6alkyl-O-(CH 2 ) q , - (CH 2 ) q N(R4)C(O)R8, aryl, arylCl -C6alkyl, heteroaryl, heteroarylCl -C6alkyl, heterocyclyl, heterocyclylCl -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 Zl' 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-C6alkyl0-(CH 2 ) p , (R4) 2 N-CO-C1- C6alkyl, carboxyCl -C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, -(CH 2 ) P N(R4)C(O)R8 , aryl, arylCl -C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyCl -C6alkyl, , heteroaryloxyCl -C6alkyl, heterocyclyloxyCl -C6alkyl, arylaminoC1- C6alkyl, heteroarylaminoCl -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 Zl' 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-C6aIkyl, 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, heteroaryl ox y, heterocyclyloxy, arylamino, heteroarylamino, and heterocyc 1 y 1 amino ;

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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , (R3) 2 N- CO, (R4) 2 N-CO, -SO 2 R3', SOR3, -SOR4, -C(=O)R6, -C(=N0H)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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl 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-(l-

(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-l,3,4-oxadiazol-2-yI)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 37or 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 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.
Description:

ENZYME MODULATORS AND TREATMENTS

Cross-Reference to Related Applications

This application claims the benefit of: (1) Provisional Application SN 60/639,087 filed

December 23, 2004; (2) Provisional Application SN 60/638,986, filed December 23, 2004; (3) Provisional Application SN 60/638,987, filed December 23, 2004; (4) Provisional Application SN 60/638,968, filed December 23, 2004; These four provisional applications are incorporated by reference herein.

Enzyme Modulators for treatment of cancers and hyperproliferative diseases

Field of the Invention

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of C-AbI, c-Kit, VEGFR, PDGFR, Raf and P38 kinases and disease polymorphs thereof.

Background of the invention

Several members of the protein kinase family have been clearly implicated in the pathogenesis of various proliferative diseases and thus represent important targets for treatment of these diseases. Some of the proliferative diseases relevant to this invention include cancer, rheumatoid arthritis, atherosclerosis, and retinopathies. Important examples of kinases which have been shown to cause or contribute to the pathogensis of these diseases include C-AbI kinase and the oncogenic fusion protein BCR-AbI kinase; PDGF receptor kinase; VEGF receptor kinases; MAP kinase p38α; and the RAF kinase family.

C-AbI kinase is an important non-receptor tyrosine kinase involved in cell signal transduction. This ubiquitously expressed kinase — upon activation by upstream signaling factors including growth factors, oxidative stress, integrin stimulation, and ionizing radiation- — localizes to the cell plasma membrane, the cell nucleus, and other cellular compartments including the actin cytoskeleton (Van Etten, Trends Cell Biol. (1999) 9: 179). There are two

normal isoforms of AbI kinase: AbI-IA and AbI-IB. The N-terminal half of c-Abl kinase is important for autoinhibition of the kinase domain catalytic activity (Pluk et al, Cell (2002) 108: 247). Details of the mechanistic aspects of this autoinhibition have recently been disclosed (Nagar et al, Cell (2003) 112: 859). The N-terminal myristolyl amino acid residue of AbI-IB has been shown to intramolecularly occupy a hydrophobic pocket formed from alpha-helices in the C-lobe of the kinase domain. Such intramolecular binding induces a novel binding area for intramolecular docking of the SH2 domain and the SH3 domain onto the kinase domain, thereby distorting and inhibiting the catalytic activity of the kinase. Thus, an intricate intramolecular negative regulation of the kinase activity is brought about by these N-terminal regions of c-Abl kinase. An aberrant dysregulated form of c-Abl is formed from a chromosomal translocation event, referred to as the Philadelphia chromosome (P. C. Nowell et al. Science (1960) 132: 1497; J.D. Rowley, Nature (1973) 243: 290). This abnormal chromosomal translocation leads aberrant gene fusion between the AbI kinase gene and the breakpoint cluster region (BCR) gene, thus encoding an aberrant protein called Bcr- AbI (G. Q. Daley et al, Science (1990) 247: 824; M. L. Gishizky et al, Proc. Natl. Acad. ScL USA (1993) 90: 3755; S. Li et al, J. Exp. Med. (1999) 189: 1399). the Bcr-Abl fusion protein does not include the regulatory myristolylation site (B. Nagar et al, Cell (2003) 112: 859) and as a result functions as an oncoprotein which causes chronic myeloid leukemia (CML). CML is a malignancy of pluripotent hematopoietic stem cells. The p210 form of Bcr-Abl is seen in 95% of patients with CML, and in 20% of patients with acute lymphocytic leukemia. A pl85 form has also been disclosed and has been linked to being causative of up to 10% of patients with acute lymphocytic leukemia .

Growth factor receptor kinases contribute to the growth and metastasis of tumors by stimulating the proliferation of endothelial cells, fibroblasts, smooth muscle cells, and matrix proteins. Conditions such as hypoxia can induce tumor cells to secrete growth factors which subsequently result in the growth of new blood vessels to support the tumor. These growth factors include platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), which subsequently stimulate secretion of other growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor, and epidermal growth factor (EGF). The formation of new blood vessels, which is known as angiogenesis, also provides the tumor with a route to metastasize to remote secondary sites. Inhibiting angiogenic factors that support stromal growth has been proposed as a useful therapy for treating cancers (R. M. Shaheen et al , Cancer Research (1999) 59: 5412; R. M. Shaheen et

α/, Cancer Research (2001) 61: 1464). Mutations of the PGDF receptor have also been identified which constituitively active in absence of growth factor. VEGF can also stimulate the formation of new lymphatic vessels through direct action on the so-called VEGF-3 receptor, providing yet another pathway for tumor metastasis. Among the three known VEGF receptors, in particular the so-called VEGFR2 (otherwise known as the kinase insert domain- containing receptor tyrosine kinase or KDR) has been demonstrated to be responsible for the role of VEGF in tumor angiogenesis.

A major signaling pathway downstream of cell surface growth factor receptor activation is the Ras-RAF-MEK-ERK-MAP kinase pathway (Peyssonnaux, C. et al, Biol. Cell (2001) 93: 53-62, Cancers arise when mutations occur in one or more of the proteins involved in this signaling cascade. Cell proliferation and differentiation become dysregulated and cell survival mechanisms are activated which allow unregulated cancer cells to override protective programmed cell death surveillance. Mutations in the p21-Ras protein have been shown to be a major cause of dysregulation of this signaling pathway, leading to the development of human cancers. P21-Ras mutations have been identified in approximately 30% of human cancers (Bolton et al, Ann. Rep. Med. Chem. (1994) 29: 165-174). Cancer- causing mutations in the P21-Ras protein lead to a constituitively active signaling cascade, causing unregulated activation of the downstream components of the RAF-MEK-ERK-MAP kinase pathway (Magnuson et al., Semin.Cancer Biol. (1994) 5: 247-253). The three RAF kinases which participate in this signaling cascade are known as ARAF, BRAF, and CRAF (Peyssonnaux, C. et al, Biol. Cell (2001) 93: 53-62; Avruch, J., Recent Prog. Horm. Res.

(2001) 56: 127-155; Kolch, W., Biochem. J. (2000) 351: 289-305). These RAF kinase isoforms are all activated by Ras, and thus are activated in cancers that result from mutated and upregulated p21-Ras protein activity. In addition to activation of this signaling cascade at the initial p21-Ras protein level, mutations have also been found in BRAF kinase which results in activation of the cascade downstream from p21-Ras (Davies, H., et al, Nature

(2002) 417: 949-954). A dominant single site mutation at position 599 in the BRAF kinase was shown to be particularly aggressive and linked to approximately 80% of the observed human malignant melanomas. This mutation substitutes the negatively charged amino acid glutamic acid for the normally occurring neutral amino acid valine. This single site mutation is sufficient to render the mutated BRAF kinase constituitively active, resulting in signaling pathway dysregulation and human cancer. Hence small molecule inhibitors of BRAF kinase

are a rational approach to the treatment of human malignancy, whether the signaling mutation is at the level of the upstream p21-Ras protein or at the level of BRAF kinase.

The MAP kinase p38α has recently been identified as an important mechanistic target for the treatment of inflammatory diseases. Inhibition of the MAP kinase p3S-alpha has been demonstrated to result in the suppression the production and release the proinflammatory mediators TNF-alpha, IL-I beta, IL-6, IL-8 and other proinflammatory cytokines (Chen, Z. et al, Chem. Rev. (2001) 101: 2449). Recently, p38-alpha kinase has been implicated in the regulation of tissue factor expression in monocytes, suggesting a role for inhibition of p38- alpha kinase in the treatment of thrombotic disorders and atherosclerosis (Chu, A.J., et al, J. Surg. Res. (2001) 101 : 85-90; Eto, M., et al, Circulation (2002) 105: 1756-1759). The p38- alpha kinase has also been shown to be involved in thrombin-induced proinflammatory conditions (V. Marin, et al, Blood, August 1, 2001, 98: 667-673). Validation of this approach has been achieved by the successful application of various protein therapeutic agents for the treatment of severe chronic inflammatory disease. Monoclonal antibodies to TNF have shown effectiveness in the treatment of rheumatoid arthritis, ulcerative colitis, and Crohn's disease (Rankin, E.C.C., et al, British J. Rheum. (1997) 35: 334-342; Stack, W.A., et al, Lancet (1997) 349: 521-524). Enbrel (etanercept), a soluble TNF receptor, has been developed by Immunex, Inc., and marketed currently by Amgen for the treatment of rheumatoid arthritis (Brower et al, Nature Biotechnology (1997) 15: 1240; Pugsley, M.K., Curr. Opin. Invest. Drugs (2001) 2: 1725). Ro 45-2081, a recombinant soluble TNF-alpha receptor chimeric protein, has also shown effectiveness in the treatment of the acute phase of lung injury and in animal models of allergic lung disease (Renzetti, et al, Inflamm Res. (1997) 46: S143). Remicade (infliximab) is a monoclonal TNF-alpha antibody that has shown effectiveness in the treatment of rheumatoid arthritis and Crohn's disease (Bondeson, J. et al, Int. J. Clin. Pracf. (2001) 55: 211).

Importantly, small molecule inhibitors of kinase activity have been shown to produce therapeutic benefit as anticipated. The most important example thus far is Gleevec (Imatinib), which is an inhibitor of BCR-AbI kinase (J. Zimmermann et al, WO 99/03854; N. von Bubnoff et al, Cancer Research (2003) 63: 6395; B. J. Druker et al, Nature Medicine (1996) 2: 561; J. Zimmermann et al, Bioorganic and Medicinal Chemistry Letters (1997) 7: 187). Gleevec has been shown to produce clinical remissions in CML patients. However,

resistance to the effects of Gleevec have often been encountered (M. E. Gorre et al, Science (2001) 293: 876). Over 17 mutations of Bcr-Abl kinase have been associated with Gleevec resistance (N. von Bubnoff et al, Lancet (2002) 359: 487; S. Branford et al, Blood (2002) 99: 3472; C. Roche-Lestienne et al, Blood (2002) 100: 1014; N P. Shah et al, Cancer Cell (2002) 2: 117; A. Hochhaus et al, Leukemia (2002) 16: 2190; H.K. Al-AIi et al, Hematology (2004) 5: 55). These mutations are primarily found in the kinase active site domain of Bcr-Abl, and frequently occur in regions proximal to the ATP binding pocket.

The majority of small molecule kinase inhibitors that have been reported have been shown to bind in one of three ways. Most of the reported inhibitors interact with the ATP binding domain of the active site and exert their effects by competing with ATP for occupancy. Other inhibitors have been shown to bind to a separate hydrophobic region of the protein known as the "DFG-in-conformation" pocket, and still others have been shown to bind to both the ATP domain and the "DFG-in-conformation" pocket. Examples specific to inhibitors of RAF kinases can be found in Lowinger et al, Current Pharmaceutical Design (2002) 8: 2269-2278; Dumas, J. et al. Current Opinion in Drug Discovery & Development (2004) 7: 600-616; Dumas, J. et al, WO 2003068223 Al (2003); Dumas, J., et al, WO 9932455 Al (1999), and Wan, P.T.C., et al, Cell (2004) 116: 855-867

Physiologically, kinases are regulated by a common activation/deactivation mechanism wherein a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket. Such binding occurs when specific amino acid residues of the activation loop are modified for example by phosphorylation, oxidation, or nitrosylation. The binding of the activation loop into the switch pocket results in a conformational change of the protein into its active form (Huse, M. and Kuriyan, J. Cell (109) 275-282.)

Summary of the Invention

The present invention describes novel potent and selective inhibitors of CAbI kinase, VEGFR2/KDR kinase, and BRAF kinase. The compounds of this invention inhibit kinase

activity in a novel way by binding into the "switch pocket" remote from the ATP-cofactor pocket with or without concomitant binding into the "DFG-in-conformation" pocket. X-ray structures determined from small molecule/BRAF co-crystals have confirmed this novel mode of binding to the kinase by the compounds of this present invention, and illustrate the novel features of this binding mode when compared to inhibitors which anchor or bind into the ATP pocket of BRAF kinase. The novel inhibitors of the present invention in some cases also exhibit a preference for inhibiting the oncogenic mutant form of a kinase (V599E- BRAF) and a sparing of normal wild-type kinase that lack the cancer-causing mutation, wherein the oncogenic mutation is a modification of a critical binding amino acid residue of the switch control pocket. An example of this profile has been identified for BRAF, wherein mutation of the valine 599 residue to a glutamic acid residue results in an oncogenic form of BRAF and for which it has been found that compounds of this invention inhibit the oncogenic mutant form of BRAF but not the wild type BRAF. This desirable feature of inhibitor selectivity enables the use of a BRAF inhibitor to treat mammalian cancer caused by mutant V559E BRAF kinase, while sparing the normal wildtype BRAF kinase present in non-cancerous cells. Enhanced safety and selectivity realized from this "wild-type kinase- sparing" provides safer inhibitors that target the cancer-causing forms of BRAF kinase.

Figures 1 and 2 further illustrates the novel binding interaction for the compounds of this invention with kinases. In Figure 1, the known interactions of kinase inhibitors reported previously are defined as directed to a combination of the ATP binding domain, an adjacent binding area known as the ATP binding domain hinge region, and in some cases a third domain known as the "DFG-in conformation" kinase pocket.

Figure 1. Illustration of the kinase binding domains of known kinase inhibitors

represents the kinase ATP binding domain

represents the kinase ATP binding domain hinge region

represents the "DFG-in conformation" kinase pocket

represents the kinase" switch" pocket

The binding modality of the compounds of this invention is illustrated in Figure 2. The unique feature is the necessary engagement of another binding domain within the kinase referred to as the switch pocket. Compounds of this invention uniquely and necessarily bind within the switch pocket, and optionally the "DFG-in conformation" domain, and optionally to the ATP binding domain hinge region. This unique binding modality confers upon compounds of this invention a novel mechanism to modulate kinase activity as well as significant advantages over previously described kinase inhibitors in achieving a therapeutically important degree of selectivity for the preferred target over inhibitors which occupy the ATP binding domain. The novel binding modality of the compounds of this invention also avoids mutations within the ATP binding domain which commonly confer resistance to inhibition by compounds which require interaction with the ATP binding domain.

Figure 2. Illustration of the binding modality for compounds of this invention to kinases

represents the kinase ATP binding domain

represents the kinase ATP binding domain hinge region

represents the "DFG-in conformation" kinase pocket

represents the kinase"switch" pocket

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

Description of the Preferred Embodiments

The following descriptions refer to various compounds and moieties thereof. Generrally, the following definitions apply to these descriptions, with the understanding that in some instances the descriptions are further limited. However, as broadly defined, the following definitions apply.

Carbocyclyl refers to monocyclic saturated carbon rings taken from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl;

Aryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring; preferred aryl rings are taken from phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;

Heteroaryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring; heteroaryl rings are taken from, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, indolinyl, benzisothiazoline-l,l,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, or benzoxazepinyl;

Heterocyclyl refers to monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms; heterocyclyl rings include, but are not limited

to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, homotropanyl;

Poly-aryl refers to two or more monocyclic or fused bicyclic ring systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring wherein the rings contained therein are optionally linked together.

Poly-heteroaryl refers to two or more monocyclic or fused bicyclic systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring wherein the rings contained therein are optionally linked together, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heteroaryl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;

Poly-heterocyclyl refers to two or more monocyclic or fused bicyclic ring systems containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms wherein the rings contained therein are optionally linked, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heterocyclyl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;

Lower alkyl refers to straight or branched chain C1-C6alkyls;

Substituted in connection with a moiety refers to the fact that a further substituent may be attached to the moiety to any acceptable location on the moiety.

The term salts embraces pharmaceutically acceptable salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutical ly-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared, from an inorganic acid or from an organic acid.

Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic , ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, (3- hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine.

The term prodrug refers to derivatives of active compounds which revert in vivo into the active form. For example, a carboxylic acid form of an active drug may be esterified to create a prodrug, and the ester is subsequently converted in vivo to revert to the carboxylic acid form. See Ettmayer et. al, J. Med. Chem, 2004, 47(10), 2393-2404 and Lorenzi et. al, J. Pharm. Exp. Therpeutics, 2005, 883-8900 for reviews.

Protein definitions

PGDF refers to platelet-derived growth factor; PGDFR refers to platelet-derived growth factor receptor; VEGF refers to vascular endothelial growth factor; VEGFR refers to vascular endothelial growth factor receptor; MAP kinase refers to mitogen-activated protein kinase; BCR refers to breakpoint cluster region; CML refers to chronic myeloid leukemia; TGF-beta refers to transforming growth factor beta; EGF refers to epidermal growth factor; KDR refers to kinase insert domain-containing receptor; TNF refers to tumor necrosis factor; ATP refers to adenosine triphosphate; DFG-in-conformation refers to the tripeptide sequence aspartylphenylalanylglycyl in the kinase protein sequence; V599E refers to the mutational

replacement of valine 599 of BRAF kinase by glutamic acid; FGFR refers to fibroblast growth factor receptor; TrkA refers to tyrosine receptor kinase type A and neurotrophic tyrosine kinase type 1 (NTRKl); TrkB refers to tyrosine receptor kinase type B and neurotrophic tyrosine kinase type 2 (NTRK2); EPHAl, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, and EPHB8 refers to members of the ephrin receptor subfamily of the receptor tyrosine kinases.

1. First aspect of the invention - C-AbI Kinase Modulator Compounds, Methods,

Preparations and Adducts

1.1 Generally - A2 Bicyclic Compounds

The invention includes compounds of the formula

wherein A2 is selected from the group cons sting of bicyclic fused aryl, bicyclic fused heteroaryl, and bicyclic fused heterocyclyl rings, each A2 moiety presenting a proximal ring bonded with Al 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;

Al 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 X,, (R4) 2 NC2-C6alkyl0-(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, =0, =N0H, =N(OR6), heteroarylC 1 -C6alkyl, heterocyclic 1 -C6alkyl, heteroaryloxyC 1 -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-C6alkyl0-(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, heteroaryl amino, 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, RlO, 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 RlO 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 RlO 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.

1.1.1 Preferred D Moieties 1.1.1a

Preferrably, the compounds of formula I above contain D moieties of the formula

wherein El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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-l,l,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.

1.1.1b

Additional preferred D moieties comprise 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.

1.1.1c

More preferred D moieties from 1.1.1b comprise the compounds of Formula III 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-l,l,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.

1.1.2 Preferred A2 Moieties

1.1.2a

Preferred A2 moieties of Formula I are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al 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 heterocyclylC 1 -C6alkyl ;

each Rl 3 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 Rl 3 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, Vl, 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.

1.1.2b

More preferred A2 moieties are selected from the group consisiting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

1.1.2c

Still more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

1.1.3 Preferred Classes of Compounds 1.1.3a

Compounds as defined in 1.1.1a wherein the A2 group is defined in 1.1.2a.

1.1.3b

Compounds as defined in 1.1.3a wherein the A2 group is defined in 1.1.2b.

1.1.3c

Compounds as defined in 1.1.3a wherein the A2 group is defined in 1.1.2c.

1.1.3d

Compounds as defined in 1.1.1b wherein the A2 group is defined in 1.1.2a.

1.1.3e

Compounds as defined in 1.1.3c wherein the A2 group is defined in 1.1.2b.

1.1.3f

Compounds as defined in 1.1.3c wherein the A2 group is defined in 1.1.2c.

1.1.4 Preferred Al Moieties 1.1.4a

Al moieties are 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;

each R7 is selected from the group consisting of halogen, C1-C3fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C1-C3alkyl, cyclopropyl, cyano, or C1-C3alkoxy.

1.1.4b

Preferred Al moieties are 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.

1.1.4c

Still more preferred Al moieties are 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.

1.1.5 Preferred W and Y Moieties

1.1.5a

(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.

1.1.5b

W and Y are each NH and X=O.

1.1.6 Further Preferred Compounds

1.1.6a

Further preferred compounds are 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 Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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(=0)-, -(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 El 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 Xl 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 El 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- Cθalkyl, 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 Ci-Cl 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, RlO, 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 RlO 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 RlO 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-C6alkyl0-(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, Vl, 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-C6alkyl0-(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)Ro, -C=(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocycIyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroaryl aminoC1-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.

1.1.6b

The following specific compounds are most preferred: l-CS-t-butyl-1-Cl-CmethanesulfonylureidoamidomethyOnaphthale n-S-yO-1H-pyrazol-S-yOS- (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-(l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichloro phenyl)urea, (3S)-6-(3-t-butyl- 5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-l,2,3,4-te trahydroisoquinoline-3- carboxylic acid, 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-y l)-l, 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)n aphthalen-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-(l,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-trifluor ophenyl)urea, 1-(3-t-butyl-1-(4- (hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,5-tr ifluorophenyl)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-trifluor ophenyl)urea, 1 -(3 -t-butyl- 1 -(4- (hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(3,5-difl uorophenyl)urea, 1-(1-(4-(2- amino-2-oxoethyl)naphthaIen-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-pyra zol-5-yl)-3-(2,5- difluorophenyl)urea, 1-(3-t-butyl-1-(4-(2-(l,3-dihydroxypropan-2-ylamino)-2- oxoethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,5-difluoroph enyl)urea, 1-(1-(4-

(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)- 3-(3-cyanophenyl)urea, 1-(3-t- butyl-1-(l,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-(p yridin-3-yloxy)phenyl)urea, 1- (3-t-butyl-1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)nap hthalen-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- 1 H-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-(l,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-pyra zol-1-yl)- l,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)-l,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-l,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-(pyridi n-3- yloxy)phenyl)urea, 1 -(3-cyclopentyl- 1 -(2-oxo- 1 ,2-dihydroquinolin-6-yl)- 1 H-pyrazol-5-yl)-3- (3-(pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H- pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)pheny l)urea, 1 -(3-t-butyl- 1-(2-oxo- l,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylca rbamoyl)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-l,2-dihydroquinolin-6-yl)-1H-pyrazol-5- yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1 -(3-t-butyl- 1-(2-(dimeth ylamino)quinolin- 6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yl oxy)phenyl)urea, 1-(3-t-butyl- 1-(2-((R)-3-(dimethylamino)pyiτolidin-1-yl)quinolin-6-yl)-1 H-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)pheny l)urea, 1 -(3-t-butyl- 1 -(2-

(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(met hylcarbamoyl)pyridin-4- yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,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-(l-oxoisoi ndolin-4-yl)phenyl)urea, 1-(3-t-

butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-(l-oxoisoind olin-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-(l -ox oisoindolin-4-yl)phenyl)ureido)-1H-pyrazol-1-yl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(l,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-l,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)- 1 H-pyrazol-5-yl)-3-(3-(8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)u rea, 1 -(3-t-butyl- 1 -(I H-indol- 5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrid o[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)u rea, 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

1.1.7 Methods

1.1.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.1 and 1.1.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

The methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI 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. The second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound. For example, the second site may be an ATP co-factor site. The second compounds may be taken from the group consisting of N-(4- memyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylarnino)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-me thylpyrido[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-methylpyr ido[2,3-d]pyrimidin-7(8H)- one (PDl 80970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrid o[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]pyrim idin-7(8H)-one (PD

166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-me thylpyrido[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-MO 16); 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-methylpyri do[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)phe nyl)acetamide (SKI DV- M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyri do[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).

1.1.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods

comprise administering to such individuals compounds of the invention, and especially those of section 1.1 and 1.1.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

1.1.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 1.1 and 1.1.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

1.1.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 1.1 and 1.1.6a.

1.2 Generally - Monocyclic A2 Compounds with Polycyclic E2 Rings The invention includes compounds of the formula

wherein A2 is selected from the group cons sting of a Zl -substituted phenyl, Zl -substituted pyridyl, Zl -substituted pyrimidinyl, Zl-substituted thienyl, Zl 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 Al ring;

Al 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 Zl 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-C6alkyl0-(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(=N0H)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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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 Al 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 heterocyclic 1-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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO 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 El is taken from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly heterocyclyl and carbocyclyl;

Xl 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 El 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 Xl may be further substituted by one or more C1-C6alkyl;

X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alky], or a direct bond wherein either El 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.

1.2.1 Preferred D Moieties

1.2.1a

Preferably, the compounds of formula I in 1.2 contain D moieties wherein El 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.

1.2.1b

Additionally preferred D moieties of formula I in 1.2 comprise a formula

wherein 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.

1.2.1c

More preferred D moieties of 1.2.1b are wherein E2 is cyclopentyl, cyclohexyl, non-fused bicyclic rings comprising pyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl, isothiazolylpyrimidinyl,

pyrazolylpyπmidinyl, tπazolylpyπmidmyl, oxadiazoylpyπmidinyl, thiadiazoylpyπmidinyl, morphohnylpyπmidinyl, dioxothiomorphohnylpyπmidinyl, thiomorphohnylpyπmidinyl, and heterocyclyls selected from the group comprising oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrohdinyl, oxazolinyl, oxazohdinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxahnyl, pipeπdinyl, morphohnyl, thiomorphohnyl, dioxothiomorphohnyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl

1.2 2 Preferred A2 Moieties 1 2 2a

and wherein the symbol (**) is the point of attachment to the Al 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.

1.2.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

1.2.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein e symbol (**) is the point of attachment to the Al ring of formula I.

1.2.3 Preferred Classes of Compounds 1.2.3a

Compounds as defined in 1.2.1a wherein the A2 group is defined in 1.2.2a.

1.2.3b

Compounds as defined in 1.2.3a wherein the A2 group is defined in 1.2.2b.

1.2.3c

Compounds as defined in 1.2.3a wherein the A2 group is defined in 1.2.2c.

1.2.3d

Compounds as defined in 1.2.1b wherein the A2 group is defined in 1.2.2a.

1.2.3e

Compounds as defined in 1.2.3c wherein the A2 group is defined in 1.2.2b.

1.2.3f

Compounds as defined in 1.2.3c wherein the A2 group is defined in 1.2.2c.

1.2.4 Preferred Al Moieties 1.2.4a

These preferred Al moieties are defined in 1.1.4a.

1.2.4b

These more preferred Al moieties are defined in 1.1.4b.

1.2.4c

These even more preferred Al moieties are defined in 1.1.4c.

1.2.5 Preferred W and Y Moieties 1.2.5a

(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.

1.2.5b

W and Y are each NH and X=O.

1.2.6 Further Preferred Compounds 1.2.6a

The invention includes compounds of the formula

wherein A2 is selected from the group cons sting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El is directly linked to the Y group of formula I;

each Zl 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-C6alkyl0-(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(=N0H)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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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 Al 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, RlO, Zl, 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 RlO 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 RlO 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.

1.2.6b

The following specific compounds are most preferred: 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-yla mino)phenyl)urea, 1-(2-(3-(2-

amino-2-oxoethyl)phenyl)-5-t-butylthiophen-3-yl)-3-(4-met hyl-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)phe nyl)urea

1.2.7 Methods

1.2.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.2 and 1.2.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

The methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI 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. The second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound. For example, the second site may be an ATP co-factor site. The second compounds may be 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)thi azole-5-carboxamide (BMS- 354825); 6-(2,6-dichlorophenyl)-2-(3-(hydroxymethyl)phenylamino)-8-me thylpyrido[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-methylpyr ido[2,3-d]pyrimidin-7(8H)- one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrid o[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]pyrim idin-7(8H)-one (PD

166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-me thylpyrido[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-MO 16); 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-methylpyri do[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)phe nyl)acetamide (SKI DV- M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyri do[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).

1.2.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1.2 and 1.2.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

1.2.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 1.2 and 1.2.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

1.2.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 1.2 and 1.2.6a.

1.3 Generally - Monocyclic A2 Compounds with Monocylic E2 Rings

wherein A2 is selected from the group cons sting of a Z7-substituted phenyl, Z7-substituted pyridyl, Z7-substituted pyrimidinyl, Zl -substituted thienyl, Zl 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 Al ring;

Al 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, RlO, Zl, 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, heterocyclic 1-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 RlO 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 RlO 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 ElA is taken from the groups consisting of carbocyclyl, mono- and poly- heterocyclyl and mono- and poly- heteroaryl;

wherein ElB 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 ElA or ElB 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 Xl 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 ElA or ElB 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 Jn-, -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 ElB 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 Zl 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-C6alkyl0-(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

an cyano wherein the site of attachment to the A2 ring is meta to the point of attachment to the Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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 Al 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-C6alkyl0-(CH 2 ) n , (R3) 2 N- CO, (R4) 2 N-CO, -SO 2 R3\ SOR3, -SOR4, -C(=O)R6, -C(=N0H)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 Al 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 Zl 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.

1.3.1 Preferred D Moieties 1.3.1a

Preferably, the compounds of formula I in 1.3 contain D moieties wherein ElA 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 E2A 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.

1.3.1b

Additionally preferred D moieties of formula I in 1.3 comprise a formula

X2 is selected from the grou 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.

1.3.1c

More preferred D moieties of 1.3.1b are 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-l,l,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl.

1.3.2 Preferred A2 Moieties

1.3.2a

Preferably, the compounds of formula I in section i.Jcontain A2 moieties as defined in section 1.2.2a.

1.3.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

1.3.2c

Even more preferred A2 moieties are selected from the grou consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

1.3.3 Preferred Classes of Compounds

1.3.3a

Compounds as defined in 1.3.1a wherein the A2 group is defined in 1.3.2a.

1.3.3b

Compounds as defined in 1.3.3a wherein the A2 group is defined in 1.3.2b.

1.3.3c

Compounds as defined in 1.3.3a wherein the A2 group is defined in 1.3.2c.

1.3.3d

Compounds as defined in 1.3.1b wherein the A2 group is defined in 1.3.2a.

1.3.3e

Compounds as defined in 1.3.3c wherein the A2 group is defined in 1.3.2b.

1.3.3f

Compounds as defined in 1.3.3c wherein the A2 group is defined in 1.3.2c.

1.3.4 Preferred Al Moieties 1.3.4a

These preferred Al moieties are defined in 1.1.4a.

1.3.4b

These more preferred Al moieties are defined in 1.1.4b.

1.3.4c

These even more preferred Al moieties are defined in 1.1.4c.

1.3.5 Preferred W and Y Moieties 1.3.5a

(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.

1.3.5b

W and Y are each NH and X=O.

1.3.6 Further Preferred Compounds 1.3.6a

The invention includes compounds of the formula

I wherein A2 is selected from the group consisting of

; wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 ElA 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 ElB 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 f 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-l,l,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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -O-(CH 2 )n-, -S-(CH 2 )n-, - NR3-(CH 2 )n-, -0-(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 El 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 Xl 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 El 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-(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 ElB 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, heteroarylC 1 - 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, RlO, 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, heterocydylC1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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-C6alkyl0-(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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl 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, heteroaryl ox yC2-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-AlkyI, -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, (IM) 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-C6alkyl0-(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 Al 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 Zl 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.

1.3.6b

The following specific compounds are most preferred: 1-(3-t-butyl-1-(3-(pyridin-3- yl)phenyl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)ure a, 1-(1-(3-(1H-pyrazol-4- yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin- 4-yl)phenyl)urea

1.3.7 Methods

1.3.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. C- AbI kinase, BCR-AbI kinase. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 1.3 and 1.3.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

The methods of the invention may also involve the step of inducing, synergizing, or promoting the binding of a second modulator compound of said kinase, especially C-AbI kinase or BCR-AbI 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. The second compound may interact at a substrate, co-factor or regulatory site on the kinase, with the second site being distinct from the site of interaction of the first compound. For example, the second site may be an ATP co-factor site. The second compounds may be 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-me thylpyrido[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-methylpyr ido[2,3-d]pyrimidin-7(8H)- one (PD180970); 6-(2,6-dichlorophenyl)-2-(4-ethoxyphenylamino)-8-methylpyrid o[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]pyrim idin-7(8H)-one (PD

166285); 2-(4-(2-aminoethoxy)phenylamino)-6-(2,6-dichlorophenyl)-8-me thylpyrido[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-methylpyri do[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)phe nyl)acetamide (SKI DV- M017); 6-(2,6-dichlorophenyl)-2-(4-hydroxyphenylamino)-8-methylpyri do[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).

1.3.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1.3 and 1.3.6a. Exemplary conditions include chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, and hypereosinophillic syndrome. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

1.3.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 1.3 and 1.3.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a

pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

1.3.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild- type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 1.3 and 1.3.6a.

2. Second aspect of the invention - VEGFR and PDGFR Kinase Modulator Compounds,

Methods, Preparations and Adducts

2.1 Generally - A2 Bicyclic Compounds

The invention includes compounds of formula I as defined in section 1.1, wherein each R2 is selected from the group consisting of monocyclic heteroaryl, 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,

wherein Zl' 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-C6alkyl0-(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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

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-C6alkyl0-(CH 2 ) m (R3) 2 N-C(=O)-, (R4) 2 N-C(=O)-, (R4) 2 N-CO-C1- C β alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1- Cδalkyl, (R3) 2 NSO 2 , (R4) 2 NSO 2 , -SO 2 R5-, -(CH 2 ) n N(R4)C(O)R8, =0 , =N0H, =N(0R6), 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-C6alkyl0-(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)Ro, -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;

2.1.1 Preferred D Moieties 2.1.1a

Preferred compounds of Formula I as defined above in section 2.1 contain D moieties as defined in section 1.1.1a.

2.1.1b

Additionally preferred compounds of Formula I as defined above in section 2.1 contain D moieties as defined in section 1.1.1b.

2.1.1c

More preferred compounds of Formula I as defined above in section 2.1.1b contain D moieties as defined in section 1.1.1c.

2.1.2 Preferred A2 moieties

2.1.2a

Compounds of Formula I as defined above in section 2.1 have preferred A2 moieties as defined in section 1.1.2a;

2.1.2b More preferred A2 moieties

Compounds of Formula I as defined above in section 2.1 have more preferred A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

2.1.2c

Still more preferred compounds of Formula I as defined above in section 2.1 have A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

2.1.3 Preferred Classes of Compounds 2.1.3a

Compounds as defined in 2.1.1a wherein the A2 group is defined in 2.1.2a.

2.1.3b

Compounds as defined in 2.1.3a wherein the A2 group is defined in 2.1.2b.

2.1.3c

Compounds as defined in 2.1.3a wherein the A2 group is defined in 2.1.2c.

2.1.3d

Compounds as defined in 2.1.1b wherein the A2 group is defined in 2.1.2a.

2.1.3e

Compounds as defined in 2.1.3c wherein the A2 group is defined in 2.1.2b.

2.Uf

Compounds as defined in 2.1.3c wherein the A2 group is defined in 2.1.2c.

2.1.4 Preferred A 1 Moieties 2.1.4a

Compounds of Formula I as defined above in section 2.1 have preferred Al moieties selected from group defined in section 1.1.4a;

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;

2.1.4b

Compounds of Formula I as defined above in section " 2.i have more preferred Al moieties selected from 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.

2.1.4c

Compounds of Formula I as defined above in section 2.1 have even more preferred Al moieties selected from 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.

2.1.5 Preferred W and Y Moieties 2.1.5a

(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.

2.1.5b

W and Y are each NH and X=O.

2.7.6 Further Preferred Compounds

2.1.6a

Further preferred compounds are 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 Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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, RlO, 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 RlO 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 RlO 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-C6alkyl0-(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 Zl' 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-C6alkyl0-(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 Zl' 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-C6alkyl0-(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)Ro, -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, C 1 -C6alkoxycarbonylC2-C6alkyl, -C2-C6alkylN(R4)C(O)R8, R8-C(=NR3)-, -SO 2 R8, -COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocycl ylC 1 -C6alkyl , heteroaryloxyC2-C6alkyl , heterocycly loxyC2-C6alkyl , arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae

wherein the symbol (#) indicates the point of attachment of the TA 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, Vl, 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.

2.1.6b

The following specific compounds of Formula I are more preferred: 1-(3-t-butyl-1-(l-methyl-1H-indol-5-yl)-1H-pyrazol-5-yl)-3-( 2,3-dichlorophenyl)urea, 1-(3-t- butyl- 1 -( 1H-indazol-5-yl)- 1 H-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-dichlo rophenyl)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)-l,2,3,4-tetrahydroisoqui nolin-6- yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,2,3,4- tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophe nyl)urea, 1 -(3-t-butyl- 1-(2-oxo- l,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichloroph enyl)urea, 1 -(3-t-butyl- 1 -(I - carbamimidoyl-l,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-(l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3 -yloxy)phenyl)urea, 1-(3-t- butyl-1-(l,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-pyra zol-1-yl)- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-l, 2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3 -yloxy)phenyl)urea, 1-(3-t- butyl-1-(3-(methylcarbamoyl)-l,2,3,4-tetrahydroisoquinolin-6 -yl)-1H-pyrazol-5-yl)-3-(3- (pyridin-3-yloxy)phenyl)urea, 1-(3-t-butyl-1-(1-(methylcarbamoyl)-l, 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-(pyridi n-3- yloxy)phenyl)urea, 1-(1-(1-((2,3-dihydroxypropyl)carbamoyl)-l,2,3,4-tetrahydroi soquinolin- 6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)pheny l)urea, 1-(3-cyclopentyl-1-(2- oxo-l,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)- 1 H-pyrazol-5-yl)-3-(4-(2-

(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,2-dihydroquinolin- 6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yl oxy)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-pyraz ol-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-(methylcarbam oyl)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)- 1 H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1 -( 1 -(2-aminoquinolin-6-yl)-3-t-butyl- 1 H- pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)pheny l)urea, 1 -(3-t-butyl- 1 -(2-

(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(met hylcarbamoyl)pyridin-4- yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,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-(l-oxoi soindolin-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-(l- oxoisoindolin-4-yl)phenyl)urea, 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-1H -pyrazol-1-yl)-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4- yl)phenyl)ureido)-1H-pyrazol-1-yl)-l,2,3,4-tetrahydroisoquin oline-3-carboxylic acid,

2.1.7 Methods

2.1.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb, FGFRl, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHAl, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHB7, EPHB8. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.1 and 2.1.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

2.1.7b Treatment Methods

The methods of the invention also include treating individuals 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. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.1 and 2.1.6a. Exemplary conditions include 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

2.1.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 2.1 and 2.1.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

2.1.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 2.1 and 2.1.6a.

2.2 Generally - Monocyclic A2 Compounds with Poly cyclic E2 Rings The invention includes compounds of the formula I as defined in section 1.2 wherein each R2 is selected from the group consisting of monocyclic heteroaryl, 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;

each Zl 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-C6alkyl0-(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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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-C6aIkyl, 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 Al 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 ZA' 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;

2.2.1 Preferred D Moieties 2.2.1a

Preferably, the compounds of formula I in 2.2 contain D moieties wherein El and E2 are as defined in section 1.2.1

2.2.1b

Additionally preferred D moieties of formula I in 2.2 are as defined in section 1.2.1b

2.2.1c

More preferred D moieties of 2.2.1b are wherein E2 is defined as in section 1.2.1c

2.2.2 Preferred A2 moieties 2.2.2a

Compounds of Formula I as defined above in section 2.2 have preferred A2 moieties as defined in section 1.2.2a;

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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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.

2.2.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

2.2.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

2.2.3 Preferred Classes of Compounds

2.2.3a

Compounds as defined in 2.2.1a wherein the A2 group is defined in 2.2.2a. 2.2.3b

Compounds as defined in 2.2.3a wherein the A2 group is defined in 2.2.2b. 2.2.3c

Compounds as defined in 2.2.3a wherein the A2 group is defined in 2.2.2c. 2.2.3d

Compounds as defined in 2.2.1b wherein the A2 group is defined in 2.2.2a. 2.2.3e

Compounds as defined in 2.2.3c wherein the A2 group is defined in 2.2.2b. 2.2.3f Compounds as defined in 2.2.3c wherein the A2 group is defined in 2.2.2c.

2.2.4 Preferred Al Moieties 2.2.4a

These preferred Al moieties are defined in 2.1.4a.

2.2.4b

These more preferred Al moieties are defined in 2.1.4b.

2.2.4c

These even more preferred Al moieties are defined in 2.1.4c.

2.2.5 Preferred W and Y Moieties 2.2.5a

(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.

2.2.5b

W and Y are each NH and X=O.

2.2.6 Further Preferred Compounds 2.2.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

. wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=0)-, -0-(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 El 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 Xl 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 El 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, RlO, Zl, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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-C6alkyl0-(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(=N0H)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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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- C β alkyl, 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.

2.2.6b

The following specific compounds of Formula I are more preferred: 1-(1-(3-(1H-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)u rea, 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

2.2.7 Methods

2.2.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,

FGFRl, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHAl, EPHA2, EPHA3, EPHA4,

EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4,

EPHB5, EPHB6, EPHB7, EPHB8. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.2 and 2.2.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid

acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

2.2.7b Treatment Methods

The methods of the invention also include treating individuals 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. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.2 and 2.2.6a. Exemplary conditions include 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

2.2.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 2.2 and 2.2.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

2.2.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 2.2 and 2.2.6a.

2.3 Generally - Monocyclic A2 Compounds with Monocyclic E2 Rings

The invention includes compounds of the formula I as defined in section 1.3 wherein 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;

wherein each Zl 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 Al 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 Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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 Al 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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) m (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 Al 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 Zl 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.

2.3.1 Preferred D Moieties 2.3.1a

Preferably, the compounds of formula I in 2.3 contain D moieties wherein El and E2 are as defined in section 1.3.1a.

2.3.1b

Additionally preferred D moieties of formula I in 2.3 are as defined in section 1.3.1b.

2.3.1c

More preferred D moieties of 2.2.1b are wherein E2 is defined as in section 1.3.1c.

2.3.2 Preferred A2 moieties 2.3.2a

Compounds of Formula I as defined above in section 2.3 have preferred A2 moieties as defined in section 2.2.2a.

2.3.2b

More pre

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

2.3.2c

Even more preferred A2 moieties are selected from the group consisting of

. and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

2.3.3 Preferred Classes of Compounds

2.3.3a

Compounds as defined in 2.3.1a wherein the A2 group is defined in 2.3.2a.

2.3.3b

Compounds as defined in 2.3.3a wherein the A2 group is defined in 2.3.2b.

2.3.3c

Compounds as defined in 2.3.3a wherein the A2 group is defined in 2.3.2c.

2.3.3d

Compounds as defined in 2.3.1b wherein the A2 group is defined in 2.3.2a.

2.3.3 e

Compounds as defined in 2.3.3c wherein the A2 group is defined in 2.3.2b.

2.3.3f

Compounds as defined in 2.3.3c wherein the A2 group is defined in 2.3.2c.

2.3.4 Preferred A 1 Moieties 2.3.4a

These preferred Al moieties are defined in 2.1.4a.

2.3.4b

These more preferred Al moieties are defined in 2.1.4b.

2.3.4c

These even more preferred Al moieties are defined in 2.1.4c.

2.3.5 Preferred W and Y Moieties 2.3.5a

(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.

2.3.5b

W and Y are each NH and X=O.

2.3.6 Further Preferred Compounds 2.3.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 ElA 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 ElB 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-l,l,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;

Xl 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 El 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 Xl 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 El 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 )Ii-, -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 ElB 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 heterocyclic 1-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, RlO, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' 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 TA 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,

(Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(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 heterocycIylaminoC1-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 Al 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 Zl 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.

2.3.6b

The following specific compounds of Formula I are more preferred: 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-y l)-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-(l-oxoisoin dolin-4-yl)phenyl)urea, 1-(1-(3- (2-amino-2-oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3 -(4-(l-oxoisoindolin-4- yl)phenyl)urea, 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)- 3-(4-(l- oxoisoindolin-4-yl)phenyl)urea

2.3.7 Methods

2.3.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. receptor tyrosine kinases including VEGFRl, VEGFR2, FLT-I, FLT-3, PDGFRa, PDGFRb,

FGFRl, FGFR2, FGFR3, FGFR4, TrkA, TrkB, EGFR, EPHAl, EPHA2, EPHA3, EPHA4,

EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHAlO, EPHBl, EPHB2, EPHB3, EPHB4,

EPHB5, EPHB6, EPHB7, EPHB8. The kinases may be wildtype kinases, oncogenic forms

thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 2.3 and 2.3.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

2.3.7b Treatment Methods

The methods of the invention also include treating individuals 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. These methods comprise administering to such individuals compounds of the invention, and especially those of section 2.3 and 2.3.6a. Exemplary conditions include 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

2.3.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 2.3 and 2.3.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

2.3.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion

proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 2.3 and 2.3.6a.

3. First aspect of the invention -Raf Kinase Modulator Compounds, Methods,

Preparations and Adducts

3.1 Generally - A2 Bicyclic Compounds

The invention includes compounds of formula I as defined in section 2.1, wherein 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.

3.1.1 Preferred D Moieties 3.1.1a

Preferred compounds of Formula I as defined above in section 3.1 contain D moieties as defined in section 1.1.1a.

3.1.1b

Additionally preferred compounds of Formula I as defined above in section 3.1 contain D moieties as defined in section 1.1.1b.

3.1.1c

More preferred compounds of Formula I as defined above in section 3.1.1b contain D moieties as defined in section 1.1.1c.

3.1.2 Preferred A2 moieties 3.1.2a

Compounds of Formula I as defined above in section 3.1 have preferred A2 moieties as defined in section 1.1.2a.

3.1.2b More preferred A2 moieties

Compounds of Formula I as defined above in section 3.1 have more preferred A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

3.1.2c

Still more preferred compounds of Formula I as defined above in section 3.1 have A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

3.1.3 Preferred Classes of Compounds 3.1.3a

Compounds as defined in 3.1.1a wherein the A2 group is defined in 3.1.2a.

3.1.3b

Compounds as defined in 3.1.3a wherein the A2 group is defined in 3.1.2b.

3.1.3c

Compounds as defined in 3.1.3a wherein the A2 group is defined in 3.1.2c.

3.1.3d

Compounds as defined in 3.1.1b wherein the A2 group is defined in 3.1.2a.

3.1.3e

Compounds as defined in 3.1.3c wherein the A2 group is defined in 3.1.2b.

3.1.3f

Compounds as defined in 3.1.3c wherein the A2 group is defined in 3.1.2c.

3.1.4 Preferred Al Moieties 3.1.4a

Compounds of Formula I as defined above in section 3.1 have preferred Al moieties selected from group defined in section 1.1.4a;

wherein 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;

3.1.4b

Compounds of Formula I as defined above in section 3.1 have more preferred Al moieties selected from 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.

3.1.4c

Compounds of Formula I as defined above in section 3.1 have even more preferred Al moieties selected from 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.

3.1.5 Preferred W and Y Moieties

3.1.5a

(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.

3.1.5b

W and Y are each NH and X=O.

3.1.6 Further Preferred Compounds

3.1.6a

Further preferred compounds are of the formula

I 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 Al moiety of formula I;

Al 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 El 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;

Xl 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 El 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 Xl 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 El 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, RlO, Rl 3, 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 RlO 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 RlO 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-C6alkyl0-(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, heterocyclylC 1-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 R 14 is independently and respectively selected from the group consisting of H and C1- C6alkyl;

wherein ZV 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-C6alkyl0-(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 Zl' 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-, (IU) 2 N-, (R4) 2 NC1 -C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , R8C0-, (R4) 2 N-CO-C1 -C6alkyl, carboxyl, carboxyC1 -C6alkyl, C1-C6alkoxycarbonyl, C 1-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)RO, -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-C6a.koxyC2-C6a.kyl, (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, C 1 -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, (IU) 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, Vl, and V2 are each independently and respectively selected from the group consisting of

0 and H 2 ;

and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.

3.1.6b

The following specific compounds are most preferred: 1 -(3-t-butyl- 1-(3-hydroxy-2,3- dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichloropheny l)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-(l-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-dichloro phenyl)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-(l-

(methylsulfonyl)indolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dic hlorophenyl)urea, 1 -(3-t-butyl- 1- (indolin-5-yl)- 1 H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 -(3-t-butyl- 1 -(I -

(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dic hlorophenyl)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)- 1 H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-

1 H-pyrazol- 1 -y l)naphthalen- 1 -y l)acetic acid, 1 -( 1 -(4-(2-amino-2-oxoethy l)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-dich lorophenyl)urea, 1-(3-t-butyl- 1 -(quinolin-6-yl)- 1 H-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-dichloro phenyl)urea, 1 -(3-t-butyl- 1 -(I - oxo-l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-( 2,3-dichlorophenyl)urea, 1-(3-t- butyl-1-(2-(methylsulfonyl)-l,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-pyrazo l-1-yl)-

l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1-(3-t-butyl-1-(3-carbamoyl-l,2,3,4- tetrahydroisoquinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea, 1 -(3-t-butyl- 1 -(2- oxo-l,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3 -dichlorophenyl)urea, 1-(3-t- butyl-1-(2-oxo-l,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3- (2,3-dichlorophenyl)urea, 1- (3-t-butyl-1-(l-carbamimidoyl-l,2,3,4-tetrahydroquinolin-6-y l)-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-d ichlorophenyl)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-pyra zol-5-yl)-3-(2,3,4- trifluorophenyl)urea, 1-(3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3,4- trifluorophenyOurea, 1-(3-t-butyl-1-(2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-1H-py razol-5- yl)-3-(2,3,4-trifluorophenyl)urea, 1 -(3-t-butyl- 1 -(2-oxo- 1 ,2-dihydroquinolin-6-yl)- 1 H- 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-trifluor ophenyl)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-((l-amino-1-oxo-methylamino)methyl)naphthale n-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-l,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea, 1-(3-t-butyl-1-(l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-triflu orophenyl)urea, 1 -(3-t-butyl- 1- (2-oxo-l, 2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,4,5-tri fluorophenyl)urea, 1- (3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-y l)-3-(2,3,5-trifluorophenyl)urea, 1 -(3-t-butyl- 1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)naphthalen-2-y l)-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-l,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-d ifluorophenyl)urea, 1-(3-t-butyl-

1-(1-(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-d ifluorophenyl)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-py razol-5-yl)-3-(2,3- difluorophenyl)urea, 1 -(3-t-butyl- 1 -(2-oxo- 1 ,2,3 ,4-tetrahydroquinolin-6-y I)- 1 H-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 r 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-fl uorophenyl)urea, 1-(3-t-butyl- 1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3 -phenoxyphenyl)urea, 1-(3-t- butyl-1-(2-oxo-l,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-chlorop yridin-3-yloxy)phenyl)urea, 1- (3-t-butyl- 1 -(2-oxo- 1 ,2-dihydroquinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(3-(pyridin-3- yloxy)phenyl)urea, 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyraz ol-5-yl)-3- (4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-t-butyl-1-(2-oxo-l,2- dihydroquinoIin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbam oyl)pyridin-4- yloxy)phenyl)urea, 1 -( 1 -(2-(2-aminoethylamino)quinolin-6-yl)-3-t-butyl- 1 H-pyrazol-5-yl)-3- (4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea, 1-(3-cyclopentyl-l -(2-oxo- 1,2- dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbam oyl)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)ph enyl)urea, 1 -(3-t-butyl- 1 -(2- (methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methyl carbamoyl)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-l,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]p yrimidin-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-l,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-l,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, HS-t-butyM-Ondolin-S-ylHH-pyrazol-S-yl^S-β-Cδ-methyl^-oxo^ S- 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-dihydropyrid o[2,3-d]pyrimidin-6- yl)ρhenyl)urea, 1-(3-t-butyl-1-(1H-indol-5-y1)-1H-pyτazol-5-yl)-3-(3-(8-met hyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(3-cyclopentyl-1-(2-oxo-l, 2,3,4- tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-o xo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)urea, 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H- pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yla mino)phenyl)urea.

3.1.7 Methods

3.1.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of RAF kinases and other kinases in the RAS- RAF-MEK-ERK-MAP kinase pathway including, but not limited to, A- Raf, B-Raf, and C-Raf. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 3.1 and 3.1.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

3.1.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.1 and 3.1.6a. 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

3.1.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 3.1 and 3.1.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

3.1.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 3.1 and 3.1.6a.

3.2 Generally - Monocyclic A2 Compounds with Polycyclic E2 Rings The invention includes compounds of the formula I as defined in section 2.2, wherein 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;

3.2.1 Preferred D Moieties

3.2.1a

Preferably, the compounds of formula I in 3.2 contain D moieties wherein El and E2 are as defined in section 1.2.1

3.2.1b

Additionally preferred D moieties of formula I in 3.2 are as defined in section 1.2.1b

3.2.1c

More preferred D moieties of 3.2.1b are where E2 is defined as in section 1.2.1c

3.2.2 Preferred A2 moieties

3.2.2a

Compounds of Formula I as defined above in section 3.2 have preferred A2 moieties as defined in section 2.2.2a;

3.2.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

3.2.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

3.2.3 Preferred Classes of Compounds

3.2.3a

Compounds as defined in 3.2.1a wherein the A2 group is defined in 3.2.2a.

3.2.3b

Compounds as defined in 3.2.3a wherein the A2 group is defined in 3.2.2b.

3.2.3c

Compounds as defined in 3.2.3a wherein the A2 group is defined in 3.2.2c.

3.2.3d

Compounds as defined in 3.2.1b wherein the A2 group is defined in 3.2.2a.

3.2.3e

Compounds as defined in 3.2.3c wherein the A2 group is defined in 3.2.2b.

3.2.3f

Compounds as defined in 3.2.3c wherein the A2 group is defined in 3.2.2c.

3.2.4 Preferred Al Moieties 3.2.4a

These preferred Al moieties are defined in 3.1.4a.

3.2.4b

These more preferred Al moieties are defined in 3.1.4b.

3.2.4c

These even more preferred Al moieties are defined in 3.1.4c.

3.2.5 Preferred W and Y Moieties 3.2.5a

(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.

3.2.5b

W and Y are each NH and X=O.

3.2.6 Further Preferred Compounds 3.2.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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, RlO, Zl, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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 ) m (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(=N0H)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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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, heteroaryl oxy, 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.

3.2.6b

The following specific compounds of Formula I are more preferred: 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)p henyl)- 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)p henyl)-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-y l)-3-(3-(4-

(isoxazol-4-yl)pyrimidin-2-ylamino)phenyl)urea

3.2.7 Methods

3.2.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of RAF kinases and other kinases in the RAS- RAF-MEK- ERK-MAP kinase pathway including, but not limited to, A-

Raf, B-Raf, and C-Raf. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 3.2 and 3.2.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid

acylations glycosylates, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

3.2.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.2 and 3.2.6a. 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 hyperproliferatton 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

3.2.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 3.2 and 3.2.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharmaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

3.2.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 3.2 and 3.2.6a.

3.3 Generally - Monocyclic A2 Compounds with Monocyclic E2 Rings

The invention includes compounds of the formula I as defined in section 2.3 wherein 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.

3.3.1 Preferred D Moieties 3.3.1a

Preferably, the compounds of formula I in 3.3 contain D moieties wherein El and E2 are as defined in section 1.3.1a.

3.3.1b

Additionally preferred D moieties of formula I in 3.3 are as defined in section 1.3.1b.

3.3.1c

More preferred D moieties of 3.2.1b are wherein E2 is defined as in section 1.3.1c.

3.3.2 Preferred A2 moieties 3.3.2a

Compounds of Formula I as defined above in section 3.3 have preferred A2 moieties as defined in section 2.2.2a.

3.3.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

3.3.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

3.3.3 Preferred Classes of Compounds 3.3.3a

Compounds as defined in 3.3.1a wherein the A2 group is defined in 3.3.2a.

3.3.3b

Compounds as defined in 3.3.3a wherein the A2 group is defined in 3.3.2b.

3.3.3c

Compounds as defined in 3.3.3a wherein the A2 group is defined in 3.3.2c.

3.3.3d

Compounds as defined in 3.3.1b wherein the A2 group is defined in 3.3.2a.

3.3.3e

Compounds as defined in 3.3.3c wherein the A2 group is defined in 3.3.2b.

3.3.3f

Compounds as defined in 3.3.3c wherein the A2 group is defined in 3.3.2c.

3.3.4 Preferred Al Moieties 3.3.4a

These preferred Al moieties are defined in 3.1.4a.

3.3.4b

These more preferred Al moieties are defined in 3.1.4b.

3.3.4c

These even more preferred Al moieties are defined in 3.1.4c.

3.3.5 Preferred W and Y Moieties 3.3.5a

(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.

3.3.5b

W and Y are each NH and X=O.

3.3.6 Further Preferred Compounds 3.3.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

. wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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, A- phenoxyphenyl, cyclohexyl,

wherein ElA 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 ElB 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-l,l,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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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 El 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 Xl 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 El 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 )Ii-, -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 ElB 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, RlO, 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, heterocyclic 1-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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

wherein ZV 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-C6alkyl0-(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 Zl' 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, heteroarylC 1 - 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,

(Ro) 2 NC1 -C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(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 Al 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.

3.3.6b

The following specific compounds of Formula I are more preferred: 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-dichl orophenyl)urea, 1-(1-(3-(l- 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-pyr azol-5-yl)-3-(2,3- dichlorophenyl)urea, 1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phe nyl)-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-dichloro phenyl)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-l,3,4-oxadiazol-2-yl)ph enyl)-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)pheny l)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]p yrimidin-6-yl)phenyl)urea.

3.3.7 Methods

3.3.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of RAF kinases and other kinases in the RAS- RAF-MEK-ERK-MAP kinase pathway including, but not limited to, A- Raf, B-Raf, and C-Raf. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 3.3 and 3.3.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

3.3.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer and hyperproliferative diseases. These methods comprise administering to such individuals compounds of the invention, and especially those of section 3.3 and 3.3.6a. 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. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

3.3.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 3.3 and 3.3,6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

3.3.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 3.3 and 3.3.6a.

4. First aspect of the invention - P38 Kinase Modulator Compounds, Methods, Preparations and Adducts 4.1 Generally - A2 Bicyclic Compounds

The invention includes compounds of formula I as defined in section 2.1, wherein 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;

4.1.1 Preferred D Moieties 4.1.1a

Preferred compounds of Formula I as defined above in section 4.1 contain D moieties as defined in section 1.1.1a.

4.1.1b

Additionally preferred compounds of Formula I as defined above in section 4.1 contain D moieties as defined in section 1.1.1b.

4.1.1c

More preferred compounds of Formula I as defined above in section 4.1.1b contain D moieties as defined in section 1.1.1c.

4.1.2 Preferred A2 moieties 4.1.2a

Compounds of Formula I as defined above in section 4.1 have preferred A2 moieties as defined in section 1.1.2a.

4.1.2b More preferred A2 moieties

Compounds of Formula I as defined above in section 4.1 have more preferred A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

4.1.2c

Still more preferred compounds of Formula I as defined above in section 4.1 have A2 moieties selected from group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I;

wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring.

4.1.3 Preferred Classes of Compounds 4.1.3a

Compounds as defined in 4.1.1a wherein the A2 group is defined in 4.1.2a.

4.1.3b

Compounds as defined in 4.1.3a wherein the A2 group is defined in 4.1.2b.

4.1.3c

Compounds as defined in 4.1.3a wherein the A2 group is defined in 4.1.2c.

4.1.3d

Compounds as defined in 4.1.1b wherein the A2 group is defined in 4.1.2a.

4.1.3e

Compounds as defined in 4.1.3c wherein the A2 group is defined in 4.1.2b.

4.1.3f

Compounds as defined in 4.1.3c wherein the A2 group is defined in 4.1.2c.

4.1.4 Preferred Al Moieties

4.1.4a

Compounds of Formula I as defined above in section 4.1 have preferred Al moieties selected from group defined in section 4.1.4a;

wherein 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;

4.1.4b

Compounds of Formula I as defined above in section 4.1 have more preferred Al moieties selected from 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.

4.1.4c

Compounds of Formula I as defined above in section 4.1 have even more preferred Al moieties selected from 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.

4.1.5 Preferred W and Y Moieties 4.1.5a

(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.

4.1.5b

W and Y are each NH and X=O.

4.1.6 Further Preferred Compounds 4.1.6a

Further preferred compounds are of the formula

I 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 Al moiety of formula I;

Al 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-tetrahydronaphthalenl-yl, benzo[d][l,3]dioxol- 5-yl or benzo[d][l,3]dioxol-4-yl,

wherein El 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;

Xl 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 El 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 Xl 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 El 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, RlO, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each R13 is independently and individually selected from the group consisting of H, C1- C β alkyl, 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, heterocyclic 1-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 R 14 is independently and respectively selected from the group consisting of H and C1- C6alkyl;

wherein ZV 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 Zl' 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 TA is independently and individually selected from the group consisting of H, C1- C β alkyl, 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, C 1 -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, Vl, and V2 are each independently and respectively selected from the group consisting of

0 and H 2 ;

and tautomers, diastereomers, geometric isomers, enantiomers, hydrates, prodrugs, and salts of any of the foregoing.

4.1.6b

The following specific compounds are most preferred: 1 -(3-t-butyl- 1-(3-hydroxy-2,3- dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichloropheny l)urea, 1 -(3-t-butyl- 1-(3-oxo- 2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorop henyl)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-dichloro phenyl)urea, 1 -(3-t-butyl- 1-

(indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)ure a, 1-(3-t-butyl-1-(l-

(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dic hlorophenyl)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)-l,2,3,4-tetrahydroisoquin olin-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-dichloro phenyl)urea, 1-(3-t-butyl-1-(l- (methylcarbamoyl)-l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyr azol-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-d ichlorophenyl)urea, 1-(1-(3- carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazo l-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)- 1 H-pyrazol-5-yl)-3-(naphthalen- 1 -yl)urea, 1 -(I -(4-(2-amino-2- oxoethyl)naphthalen-2-yI)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(p yridin-3-yloxy)phenyl)urea, 1-

(3-t-butyl-1-(3-carbamoyl-l,2,3,4-tetrahydroisoquinolin-6 -yl)-1H-pyrazoI-5-yl)-3-(3-(8- methyI-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)u rea, 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,

4.1.7 Methods

4.1.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 4.1 and 4.1.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

4.1.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease. These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.1 and 4.1.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

4.1.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 4.1 and 4.1.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

4.1.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 4.1 and 4.1.6a.

4.2 Generally - Monocyclic A2 Compounds with Polycyclic E2 Rings The invention includes compounds of the formula I as defined in section 2.2, wherein 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;

4.2.1 Preferred D Moieties 4.2.1a

Preferably, the compounds of formula I in 4.2 contain D moieties wherein El and E2 are as defined in section 1.2.1

4.2.1b

Additionally preferred D moieties of formula I in 4.2 are as defined in section 1.2.1b

4.2.1c

More preferred D moieties of 4.2.1b are where E2 is defined as in section 1.2.1c

4.2.2 Preferred A2 moieties 4.2.2a

Compounds of Formula I as defined above in section 4.2 have preferred A2 moieties as defined in section 2.2.2a;

4.2.2b

More preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring for formula I.

4.2.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

4.2.3 Preferred Classes of Compounds

4.2.3a

Compounds as defined in 4.2.1a wherein the A2 group is defined in 4.2.2a.

4.2.3b

Compounds as defined in 4.2.3a wherein the A2 group is defined in 4.2.2b.

4.2.3c

Compounds as defined in 4.2.3a wherein the A2 group is defined in 4.2.2c.

4.2.3 d

Compounds as defined in 4.2.1b wherein the A2 group is defined in 4.2.2a.

4.2.3e

Compounds as defined in 4.2.3c wherein the A2 group is defined in 4.2.2b.

4.2.3f

Compounds as defined in 4.2.3c wherein the A2 group is defined in 4.2.2c.

4.2.4 Preferred Al Moieties 4.2.4a

These preferred Al moieties are defined in 4.1.4a.

4.2.4b

These more preferred Al moieties are defined in 4.1.4b.

4.2.4c

These even more preferred Al moieties are defined in 4.1.4c.

4.2.5 Preferred W and Y Moieties

4.2.5a

(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.

4.2.5b

W and Y are each NH and X=O.

4.2.6 Further Preferred Compounds

4.2.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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 El 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;

Xl is selected from the group consisting of O, S, NR3, -C(=O)-, -0-(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, Ql- C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the El 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 Xl may be further substituted by one or more C1-C6alkyl;

X2 is selected from the group consisting of C1-C6 alkyl, C3-C6 branched alky], or a direct bond wherein El 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-Cδalkyl;

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, RlO, Zl, 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 RlO 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 RlO may cyclize to form a C3-C7 heterocyclyl ring;

each Zl 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-C6alkyl0-(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 Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

In the foregoing definition of Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl moiety to the A2 ring;

in the event that Zl 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 Zl 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 Zl may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl' 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-C6alkyl0-(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 Zl' may cyclize to form a C3-C7 heterocyclyl ring;

each TA 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.

4.2.6b

The following specific compounds of Formula I are more preferred: 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-buty 1- 1 -(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)- 1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrirnidin-2 -ylamino)phenyl)urea

4.2.7 Methods

4.2.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 4.2 and 4.2.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

4.2.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease. These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.2 and 4.2.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

4.2.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 4.2 and 4.2.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

4.2.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 4.2 and 4.2.6a.

4.3 Generally - Monocyclic A2 Compounds with Monocyclic E2 Rings The invention includes compounds of the formula I as defined in section 2.3 wherein 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;

4.3.1 Preferred D Moieties 4.3.1a

Preferably, the compounds of formula I in 4.3 contain D moieties wherein El and E2 are as defined in section 1.3.1a.

4.3.1b

Additionally preferred D moieties of formula I in 4.3 are as defined in section 1.3.1b.

4.3.1c

More preferred D moieties of 3.2.1b are wherein E2 is defined as in section 1.3.1c.

4.3.2 Preferred A2 moieties

4.3.2a

Compounds of Formula I as defined above in section 4.3 have preferred A2 moieties as defined in section 2.2.2a.

4.3.2b

More preferred A2 moieties are selected from the group consisting of

and where n the symbol (**) is the point of attachment to the Al ring for formula I.

4.3.2c

Even more preferred A2 moieties are selected from the group consisting of

and wherein the symbol (**) is the point of attachment to the Al ring of formula I.

4.3.3 Preferred Classes of Compounds

4.3.3a

Compounds as defined in 4.3.1a wherein the A2 group is defined in 4.3.2a.

4.3.3b

Compounds as defined in 4.3.3a wherein the A2 group is defined in 4.3.2b.

4.3.3c

Compounds as defined in 4.3.3a wherein the A2 group is defined in 4.3.2c.

4.3.3d

Compounds as defined in 4.3.1b wherein the A2 group is defined in 4.3.2a.

4.3.3e

Compounds as defined in 4.3.3c wherein the A2 group is defined in 4.3.2b.

4.3.3J

Compounds as defined in 4.3.3c wherein the A2 group is defined in 4.3.2c.

4.3.4 Preferred Al Moieties 4.3.4a

These preferred Al moieties are defined in 4.1.4a.

4.3.4b

These more preferred Al moieties are defined in 4.1.4b.

4.3.4c

These even more preferred Al moieties are defined in 4.1.4c.

4.3.5 Preferred W and Y Moieties 4.3.5a

(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.

4.3.5b

W and Y are each NH and X=O.

4.3.6 Further Preferred Compounds 4.3.6a

Further preferred compounds are of the formula

I wherein A2 is selected from the group consisting of

wherein the symbol (**) denotes the attachment to the Al moiety of formula I;

Al 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-tetrahydronaphthalenl-yl, benzo[d][l,3]dioxol- 5-yl or benzo[d][l,3]dioxol-4-yl,

wherein ElA 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 ElB 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-l,l,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;

Xl 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 El 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 Xl 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 El 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 ElB 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 heterocyclic 1-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, RlO, 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, heterocyclic 1-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 RlO 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 RlO 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-C6alkyl0-(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, heterocyclic 1-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 Rl 3 may cyclize to form a C3-C7 heterocyclyl ring;

wherein Zl ' is independently and individually selected from the group consisting of H, C1- C6alkyl, C3-C7cycloalkyl, hydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, (R4) 2 N-C1- C β alkyl, (R4) 2 N-C2-C6alkylN(R4)-(CH 2 ) p , (R4) 2 N-C2-C6alkyl0-(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 Zl' 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 TA 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, (Ro) 2 NC 1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkyl0-(CH 2 ) n , (R3) 2 N- CO, (R4) 2 N-CO, -SO 2 R3\ SOR3, -SOR4, -C(=O)R6, -C(=N0H)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

Al 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 Zl, alkyl moieties may optionally be substituted by one or more C1-C6alkyl;

Wherein the asterisk (*) indicates the point of attachment of the Zl 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.

4.3.6b

The following specific compounds of Formula I are more preferred: 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-y l)-3-(3-(8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)u rea, 1-(1-(3-(2-amino-2- oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(3-(8-meth yl-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-flu orophenyl)-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-dichloropheny l)urea, 1-(1-(4-(2-amino-2- oxoethyl)phenyl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichl orophenyl)urea, 1-(2,3- dichlorophenyl)-3-(1-(4-(2-(2,3-dihydroxypropylamino)-2-oxoe thyl)phenyl)-3-(2- fluorophenyl)- 1 H-pyrazol-5-yl)urea, (R)- 1 -(3-t-butyl- 1 -(4-(2-(3-hydroxypyrrolidin- 1 -yl)-2- oxoethyl)phenyl)- 1 H-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)phen yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea, 1-(3-t-butyl-1-(3-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)ph enyl)-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-(naph thalen-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,

4.3.7 Methods

4.3.7a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of the p38 family of kinases including, but not limited to p38-alpha and other MAP kinases. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of

the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections 4.3 and 4.3.6a. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be 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.

4.3.7b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, and cardiovascular disease. These methods comprise administering to such individuals compounds of the invention, and especially those of section 4.3 and 4.3.6a, said condition being human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

4.3.8 Pharmaceutical Preparations

The compounds of the invention, especially those of 4.3 and 4.3.6a may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.

4.3.9 Kinase/Compound Adducts

The invention also provides adducts in the form of compounds of the invention bound with a species of kinase such as a wild-type kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing. The compounds are advantageously selected from the groups defined in sections 4.3 and 4.3.6a.

5. Fifth aspect of the invention - Compound Synthesis

Recently, Cu(II)-catalyzed cross coupling reactions have been described for Cu(II) catalyzed cross coupling reactions of aryl or heteroaryl metal reactants with NH-containing heterocycles. These methods have been described by P.Y.S. Lam et al, Tetrahedron Letters (1998) 39: 2941), P.Y.S. Lam et al, Journal of the American Chemical Society (2000) 122: 7600; D. M. T. Chan et al, Tetrahedron Letters (2003) 44: 3863; D. M. T. Chan et al, Tetrahedron Letters (1998) 39: 2933; D. A. Evans et al, Tetrahedron Letters (1998) 39: 2937.

5.1 Novel Syntheses

The present invention further provides novel methods for synthesizing the useful compounds.

Broadly speaking, the synthesis method comprises the steps:

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(ORIo) 2 , - A3P -B(R17) 3 M2, - A3P -Si(R18) 3 , or A3P -Sn(RIo) 3, wherein R16 is taken from lower alkyl or branched lower alkyl, R17 is halogen, Rl 8 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 Dl-NH 2 , to yield a compound of the formula

where Dl is selected from the group consisting of mono- and poly-aryl, mono- and poly- heteroaryl, mono- and poly-heterocyclyl.

Preferrably, first step of the method involves using a ring compound taken from the group consisting of

A3P-M is taken from A3P-B(OH) 2 , A3P -B(ORIo) 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 13O°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 Dl-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 8O°C to 11O°C to yield a desired compound of the formula

Still more preferably, the starting ring compound is selected from the group consisting of

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 Dl-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 8O°C to HO°C to yield a desired compound of the formula.

5.2 Other syntheses

The preparation of intermediates containing Al rings and their subsequent conversion into compounds of Formula I is illustrated in the following schemes. Throughout this specification, A2P refers to a protected form of A2, as defined above, wherein the Zl, Z2, Z3, or Z4 moieties or heteroatoms attached to A2 are suitably protected to allow their use in multi-step chemistry.

The preparation of intermediates wherein Al is taken from pyrazolyl Al-I is illustrated in Schemes 1 through 4. Scheme 1 illustrates the preparation of hydrazines 2. If the amine precursors 1 are readily available, they are converted to the hydrazines 2 by a diazotization/reduction sequence. Preferred conditions react J_ with NaNO 2 in aqueous HCl to form the diazonium salt at about OC in aqueous solvent or an aqueous/organic cosolvent. The diazonium salt is not isolated, but directly reduced by reaction with SnCl 2 .2H 2 0 under acidic conditions, preferably aqueous HCl at between about OC and room temperature. The hydrazines 2 are isolated as the HC1 addition salts. If the amine precursors! are not directly available, they can be formed from the nitro-substituted A2P precursors 3 by reduction, preferably with iron/HCl, SnCl 2 .2H 2 O, or catalytic hydrogenation, to give the requisite amines 1. Conversion to the hydrazines 2 is accomplished as described above. Alternatively, reaction of the aryl or heteroaryl bromides 4 with benzophenone hydrazone and a palladium catalyst, preferably with Pd(OAc) 2 and DPPF as ligand, can afford the protected hydrazines 5_, which are deprotected under acidic conditions, preferably p-toluenesulfonic acid or ethanolic HC1, to give rise to the desired hydrazines 2 (Hartwig, J.F., et al, Angew. Chem. Int. Ed. (1998) 37: 2090; Haddad, N., et al, Tetrahedron Letters (2002) 43: 2171-2173). Alternatively, reaction of the aryl or heteroaryl iodides 6 with t-butylcarbazate and a copper (I) catalyst, preferably CuI in DMF at about 80C with Cs 2 CO 3 base and a ligand such as 1,10- phenanthroline, can afford the BOC-protected hydrazines 7, which are converted to the desired hydrazines 2 by treatment with acid (M. Woltor et al, Organic Letters (2001) 3: 3803-3805).

Scheme 1

Preparation of pyrazoles 9 and 1 1 are illustrated in Scheme 2. Reaction of hydrazines 8 with beta-ketonitriles in an alcoholic solvent, preferably EtOH, and an acid catalyst, preferably HCl or p-toluenesulfonic acid, at about 8OC gives aminopyrazoles 9. Analogous treatment of hydrazines 8 with the ethyl 2-(methoxyimino)-4-oxobutanoates K) affords the pyrazole ethyl esters ϋ (Lam, P.Y.S., et al, Journal of Medicinal Chemistry (2003) 46: 4405-4418).

Sche

The aminopyrazoles 9 are converted into the desired pyrazole ureas \2 of Formula I (see Scheme 3) by methods described in Scheme 30 for the conversion of the aminothiophene into ureas of Formula I.

Scheme 3

Alternatively, pyrazole ureas of Formula I can be formed from the pyrazole ethyl esters JJ , by a sequence illustrated in Scheme 4. Conversion of esters 1_1 to the carboxylic acids 13 is accomplished by saponification or by treatment with aqueous acid. Curtius-type rearrangement of H, preferably by treatment with ethyl chloroformate and base, preferably triethylamine, in an organic solvent, preferably THF at about OC, and then forming the acyl azide by reaction with sodium azide, and quenching of the in situ rearranged isocyanate with D-NH 2 gives rise to the desired pyrazole ureas J4 of Formula I (El Haddad, M. et al, Journal of Heterocyclic Chemistry (2000) 37: 1247-1252).

Scheme 4

The synthesis of pyrazoles of formula I wherein Al is A 1-2 is exemplified in Scheme 5. Aryl halide 15 (bromo or iodo (preferred)) is reacted with acetylene 16 [CAS 22537-06-0] under standard palladium cross-coupling conditions to yield J/7. As described by Coispeau et. al (Bull. Chem. Soc. France, 1970, 689-696), JJ reacts monosubstituted hydrazines in the presence of catalytic mineral acid to yield pyrazole J_8, which is readily nitrated under

standard conditions at the 4-position to yield 19. Catalytic hydrogenation or reduction utilizing iron/HC1 or tin (II) chloride of J_9 yields 20, which can be coupled and deprotected as shown in Scheme 6 to yield urea 2L

The aminopyrazoles 20 are converted into the desired pyrazole ureas 21 of Formula I by methods described in Scheme 30.

Scheme 6

The synthesis of pyrazoles of formula I wherein Al is A 1-3 is exemplified in Scheme 7. Substituted pyrazole 22 is preferentially halogenated (brominated or iodinated) at the 4- position to yield 23 (see: Bull. Chem. Soc. France, 1967, 328 and J. Gen. Chem. USSR, 1963, 33, 503). Coupling of 23 with boronic acid 24 under standard conditions yields 25,

which is nitrated at the 3-position under standard conditions to yield 26. Catalytic hydrogenation or reduction of 26_utilizing iron/HCl or tin (II) chloride yields amine 27 that can be elaborated to deprotected urea 28 of Formula I using the same strategies as outlined in Scheme 30.

The synthesis of pyrroles of formula I wherein Al is Al-4 is exemplified in Scheme 8. Substituted 1,4-dicarbonyl compound 29 (see Scheme 8) is reacted with amine 30 in THF or toluene to yield intermediate pyrrole 31 , which, after nitration, reduction (see Scheme 1), urea coupling and deprotection (see Scheme 30) yields pyrazole compounds 34 of Formula I.

The synthesis of pyrroles of formula I wherein Al is Al-5 is exemplified in Scheme 9. Substituted aldehydes 35 cyclocondense with amines 36 when reacted with hot acetic acid (See: J. Chem. Soc. Perkin Trans. I, 1975, 1910). After workup, the resulting solid is immediately subjected to the action of potassium ethoxide in ethanol at room temperature to yield pyrrole 37. Elaboration of amine 37 employing the same strategy as shown in Scheme 30 affords deprotected ureas 38 of Formula I.

The synthesis of pyrroles of formula I wherein Al is Al-6 is exemplified in Scheme 10. Diethylmaleate 39 is reacted with halide 40 in the presence of NaBr, NiBr 2 and ethanol {Tetrahedron Letters, 1999, 40(33), 5993) to yield product 4L Reduction of the diacid with LAH in ether to the diol followed by oxidation under Swern or MnO 2 conditions to yield dialdehyde 42. In situ cyclization with amine 43 yields pyrrole 44. Nitration of 44 and reduction yields amine 46 which is elaborated to deprotected ureas 47 of Formula I according to the methods described in Scheme 30.

The preparation of intermediates containing ring A 1-7 is illustrated in Schemes 11 through 13. Scheme 11 illustrates the preparation of imidazole intermediate 50. Reaction of 48 with 49, affords 50 (cf. Little, T.L. et al. J. Org. Chem. 1994, 59 (24), 7299-7305).

Cross-coupling reaction of 50 is accomplished by two different methods. Scheme 12 illustrates the method of Kiyomori, A. et al. {Tetrahedron Lett. 1999, 40 (14), 2657) wherein 50 is reacted with a suitable A2P-I in the presence of Cs 2 CO 3 as base and Cu(OTf) 2 as catalyst. In another preferred mode 50 is cross-coupled with an A2P-B(OH) 3 under Cu(OAc) 2 catalysis in the presence of pyridine (Chan, D.M.T. et al. Tetrahedron Lett. 2003,

44 (19), 3863). In yet another mode, nucleophilic aromatic susbstitution between 50 and A2P-F (or Cl) in the presence of an inorganic base also provides 5JL Scheme 12

The preparation of compounds of Formula I wherein Al is Al-7 is illustrated in Scheme 13. The acetamidoimidazoles 5_i are first deprotected to the aminoimidazoles 52 and then reacted under one of the preferred modes described in Scheme 30 to give ureas 53 of Formula I.

Scheme 13

Scheme 14 illustrates the preparation of oxazole intermediates 56. Readily available acid chlorides 54 are converted to the corresponding acyl nitriles 5_5 by the action of cyanide anion, according to the method of Tanaka, M. et al. (Synthesis 1981, 12, 973-4). Employing the conditions of Lakhan, R. et al. (J. Heterocycl. Chem. 1988, 25 (5), 1413-1417) reaction of 55 with R2-CHO and NH 4 OAc gives oxazoles 56.

Scheme 14

The elaboration of 56 to compounds of Formula I wherein Al is Al-8, is illustrated in Scheme 15. Conversion of amines 56 to ureas 57 is accomplished by methods analogous to that shown previously in Scheme 30.

Preparation of compounds of Formula I wherein Al is Al-9 is illustrated in schemes 16 and 17. Scheme 16 illustrates the preparation of oxazole intermediates 6J ^ Beginning with 58, the aldehyde function is elaborated through a Strecker synthesis (Kendall, E.C. et al. Org. Synth. CV 1, 21) to provide amino-nitriles 59. Acylation with R2COC1 in the presence of a base generates intermediate 60. Alternatively, 59 can be coupled with R2COOH in the presence of a peptide-coupling or dehydrating agent and a base to also give 60. Finally, treatment of 60 with a strong organic acid (cf. EP 816347) or mineral acid (Kille, G. et al. Bull. Soc. Chim. France 1967, 11, 4619) afford the desired aminooxazoles 6L

Scheme 16

The elaboration of 61 to 62 as shown in Scheme 17, is completely analogous to that shown previously in Scheme 30.

Scheme 17

Compounds of Formula I wherein Al is Al-IO are prepared as shown in schemes 18 through 20. The preparation of thiazole intermediates of formula 67 is illustrated in Schemes 18 through 20. In one preferred mode, acylated intermediate 60, from Scheme 16 (see above), is treated with a thionating reagent such as P 4 S io or La wesson's Reagent to make 63. This, in turn, when treated with strong acid affords the desired 64, by analogy to Scheme 16.

Scheme 18

In an alternate preferred mode (Scheme 19), 59, from Scheme 16 (see above) is treated with R2-CHO in the presence of elemental sulfur and a base, according to the method of Gerwald, et al. (/ Prakt. Chem. 1973, 513, 539) to generate 66. Deprotection under aqueous acidic conditions generates 64.

Scheme 19

The elaboration of 64 to 67i as shown in Scheme 20, is completely analogous to that shown in Scheme 30.

The preparation of compounds of Formula I wherein Al is Al-I l is illustrated in Schemes 21 and 22. A2P-containing hydrazines, 68, are acylated with R2COC1 in the presence of a base to generate intermediates 69. Alternatively, 68 can be coupled with R2COOH in the presence of a peptide-coupling or dehydrating agent and a base to also give 69. Halogenation under the conditions of Joseph, B. et al. (J. Carbohydrate Chem. 1993, 12, 1127-38) or Sakamoto, T. et al. (Chem. Pharm. Bull. 1988, 36, 800-802) afford hydrazinoyl halides 70. Treatment with base generates the reactive 1,3-dipoles 71 which are trapped with cyanamide to give aminotriazoles 72, in accordance with precedent (EP 285893).

The elaboration of 72 to 73 ^ as shown in Scheme 22, is accomplished according the methods illustrated in Scheme 30.

Preparation of compounds of Formula I wherein Al is Al-12 is illustrated in scheme 23. The preparation of the furan intermediate of formula 81 follows the reported procedure of Toro, A. et al. (J. Org. Chem. 2003, 68 (18), 6847). 74 is acylated as described previously, treated with the dilithio species of 76 and finally cyclized with HBr to give 77. Introduction of the A2P moiety is accomplished by several different methods. In one preferred mode, using the method of Pridgen, L. et al. (J. Org. Chem. 1982, 47, 1590-1592), 77 is cross-coupled with an A2P -MgBr in the presence of a nickel catalyst to generate 79. In a second preferred mode, reported by Hervet, M. et al. (Helvetica Chim. Acta. 2003, 86 (10), 3461), 79 may be obtained by cross-coupling with a stannane in the presence of a palladium catalyst. In a third preferred mode reported by Burke, M. et al. (Science 2003, 302 (5645), 613-618), the cross- coupling may be accomplished under Suzuki conditions with an appropriate boronic acid. Finally, in a fourth preferred mode, 77 is converted to a boronate species, 78, which is then subjected to Suzuki coupling conditions with the requisite A2P -X. Deprotonation of 79 and quenching of the anion with CO 2 delivers acid 80. Subjecting 80 to Curtius rearrangement conditions in the presence of D-NH 2 to trap the intermediate isocyanate provides 8_1 using methods analogous to that illustrated in Scheme 4.

Preparation of compounds of Formula I wherein Al is Al-13 is illustrated in schemes 24 and 25. Scheme 24 illustrates the preparation of furan intermediates 85. The 1 ,4-dicarbonyl starting materials 82 are reacted with para-methylbenzenesulphonic acid (TsOH) in a suitable solvent such as toluene to afford furan 83. Nitration of 83 affords 84, which is reduced with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions to give the 3-aminofuran intermediates 85.

The aminofurans 85 are converted into the desired furanyl ureas 86 of Formula I by methods described in Scheme 30.

The preparation of compounds of Formula I wherein Al is Al-14 is illustrated in schemes 26 and 27. Scheme 26 illustrates the preparation of 4,5-disubstituted 2-aminothiophenes 92 according to methods reported by Knoll et al (Knoll, A. et al, Synthesis (1984) 51-53; Knoll, A. et al, J. Prakt.Chem. (1985), 327: 463-470). The compound 87 is reacted with an excess of formamide derivatives 88 in methanol to afford N-(3-aminothioacryloyl)-formamidines 89. A mixture of substituted N-(3-aminothioacryloyl)-formamidines, 89 and substituted bromides, 90 in a protic solvent, such as methanol or ethanol, is heated, preferably at a reflux temperature. The product thiophene-imines, 9_i are treated with aqueous acid to obtain the thiophene-amines 92.

The aminothiophenes 92 are converted into the desired thiophenyl ureas of Formula I by methods described in Scheme 30.

Scheme 28 illustrates the preparation of 1 ,4-dicarbonyl starting materials 96 for the preparation of compounds of Formula I, wherein Al is Al-13. One preferred method utilizes a 1,4-conjugate addition procedure, Scheme 28 (a), to transform 94 to 96 by reaction with the unsaturated ketone 9J) in the presence of a suitable base such as a lithium, sodium, or potassium amide or hydride base. Another preferred method, Scheme 28 (b), makes use of a transmetallation reaction, converting 97, wherein Xl is halogen, to an organometallic species 98 wherein the metal is magnesium, nickel, or cadmium. In situ reaction of 98 with acid chloride 99 gives rise to the 1,4-dicarbonyl species 96 after acid-catalyzed removal of the ketal protecting group. Alternative reaction of 98 wherein the metal is lithium with the Weinreb amide 100 also affords 96 after acid-catalyzed removal of the ketal protecting group. A third preferred method, illustrated in Scheme 28 (c), makes use of a palladium-catalyzed

reaction between the readily available boronic acid 101 and a suitable 2-pyridyl ester 102 as reported by Chatani et al (Organic Letters (2004) 6: 3597-3599).

Scheme 28

The 1,4-dicarbonyl starting materials 96 are reacted with Lawesson's reagent in a suitable solvent such as THF or toluene to afford thiophene 103. Nitration of 103 affords 104, which is reduced with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions to give the 3- aminothiophene intermediates 105 (Scheme 29).

Scheme 29

96

103 104 Ll = = NO 2

105 Ll = NH 2

The preparation of compounds of Formula I are illustrated in Scheme 30. The aminothiophenes 106 are reacted with carbonyl diimidazole (CDI) or phosgene CO(C1) 2 to give isocyanates 107. Alternatively, 106 can be reacted with p-nitrophenyl chloroformate to give the p-nitrophenylcarbamates 108 as synthetic equivalents to isocyanates 107. Reaction of isocyanates 107, or the corresponding p-nitrophenylcarbamates 108, with readily available amines D-NH 2 affords ureas 109. Alternatively, 106 is reacted with isocyanates 110 or the p- nitrophenylcarbamates 111 to give ureas 109. Removal of the A2P protecting groups from 109 affords the desired compounds of Formula 112.

Scheme 30

106

The preparation of compounds of Formula I wherein Al is Al-16 is illustrated in Schemes 31 and 32. Scheme 31 illustrates the preparation of 2,4-disubstituted N-protected-anilines 117. The commercially available starting materials 113 are converted to 4-substituted anilines 114 by nitration , followed by reduction with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions. The reaction of 4-substitued anilines 114 with bromine in acetic acid gives 2-brominated anilines 115. The amino groups of 115 are protected to allow their use in Suzuki coupling reactions to obtain 117.

The Suzuki coupled intermediates 117 are converted into the desired phenyl ureas 118 of Formula I by methods described in Scheme 30.

The preparation of compounds of Formula I is illustrated in Schemes 33 and 34.

Scheme 33 illustrates the preparation of 2,5-disubstituted 2-aminopyridines 125.

The commercially available starting material JJ9 is reacted with sodium nitrate to afford 1- methyl-3,5-dinitro-2-pyridone 120. The reaction of 120 with ketones 121 in the presence of

NH 3 gives alkyl and/or aryl-substituted 3-nitropyridine derives 122 (Tohda, Y. et al, Bull. Chem. Soc. ofJpn (1990), 63: 2820-2827). Reduction followed by selective bromination of

122 affords 123_(Canibano, V. et al, Synthesis (2001) 14: 2175-2179). The amino group of

123 is protected to give 124. 124 is reacted with a variety of Suzuki coupling reagents to obtain 125.

The aminopyridines 125 are converted into the desired pyridyl ureas 126 of Formula I by methods described in Scheme 30.

The preparation of compounds of Formula I wherein Al is Al-18 is illustrated in Schemes 35 and 35a. Scheme 35 illustrates the preparation of 2,4-disubstituted 5-aminopyridines 132. The commercially available starting materials 127 are converted to 2-substituted-4- nitropyridines 128 under standard nitration conditions. Reduction followed by a second nitration of 128 gives 4-amino-2-substituted-5-nitropyridines 129 which can purified by silica column chromatography from the other isomers. The 4-amino-2-substituted-5-nitropyridines 129 are reacted with HBr and NaN02 to afford 4-bromopyridines 130. The bromopyridine

130 is reacted with a variety of Suzuki coupling reagents to produce 131. The reduction of the nitro group of 131 with iron/HCl, tin (II) chloride, or catalytic hydrogenation conditions gives 2,4-disubstituted-5-aminopyridines 132.

The aminopyridines 132 are converted into the desired pyridyl ureas 133 of Formula I by methods described in Scheme 30.

The preparation of compounds of Formula I wherein Al is Al- 19 is illustrated in Schemes 36 and 37. Scheme 36 demonstrates the preparation of substituted pyridines 138. Amination of 134 and subsequent bromination affords 135 as previously reported (J. Am. Chem. Soc, 1990, 112, 8024 and Heterocycles, 1986, 24, 1815). Thus 3-alkyl pyridines 134 upon reaction with sodamide gives pyridines 135, which are brominated with bromine to give pyridines 136. The amine functionalities of 136 are acetylated using acetyl chloride or acetic anhydride to give 137. The brominated intermediates 137 are utilized in Suzuki cross coupling reactions to give cross-coupled intermediates 138 utilizing procedures describe above in Scheme 23.

The preparation of compounds 139 of Formula I are described in Scheme 37. The aminopyridines 138 are first deprotected and then reacted under one of the preferred routes described in Scheme 30.

Preparation of compounds of Formula I wherein Al is Al-20 is described in scheme 38 and scheme 39 according to reported procedures in Tetrahedron Lett., 2002, 43, 9287 and J. Heterocycl. Chem., 1978, 75, 665. The oximes 140 are reacted with aminoacetonitrile to afford the cyclodehydrated intermediates which are hydrogenated to give 141. Bromination of 141 affords 142. The amine functionalities of 142 are converted to the N-acetate derivatives 143, which are subjected to Suzuki cross-coupling reactions as described in scheme 23 to afford cross-coupled intermediates 144.

The preparation of compounds of Formula I is illustrated in Scheme 39. The N- Acetyl functionalities of 144 are removed and the resulting amines are converted to ureas 145 of Formula I-B as previously illustrated in scheme 30.

Synthesis of compounds of Formula I wherein Al is Al-21 is described in Scheme 40. As reported by Palanki et al (J. Med. Chem. 2000, 43, 3995-4004) diethyl ethoxymethylenemalonate and trialkylacetamidine are heated with sodium ethoxide to provide pyrimidines 146. The hydroxyl groups of 146 are converted to the bromides by reaction with PBr 3 to afford bromopyrimidines 147. Intermediates 147 are converted to 148 using Suzuki cross-coupling methods illustrated above in Scheme 23. The ester functionalities of 148 are hydrolyzed to acids 149, which are utilized in a Curtius rearrangement reaction sequence in the presence of amines D-NH 2 using methods reported above in Scheme 4, to give the desired ureas 150 of Formula I.

Preparation of compounds of Formula I wherein Al is Al-22 is described in Scheme 41. Readily available substituted acetic acids 151 are converted into the requisite acid chlorides 152 by reaction with thionyl chloride in the presence of base, preferably triethylamine or pyridine. The acid chlorides are converted to amides 153 by reaction with R2NH 2 in the presence of base, preferably triethylamine or pyridine. Reaction of 153 with dimethyloxalate in the presence of base, preferably potassium t-butoxide in DMF, affords hydroxymaleimides 154. Conversion of 154 to the chloro-substituted maleimides 155 is effected by reaction with thionyl chloride. Displacement of chloride by ammonia converts 155 into the amino- substituted maleimides 156. Reaction of 156 with isocyanates D-N=C=O affords the desired compounds 157 of Formula I.

Preparation of compounds of Formula I wherein Al is Al-23 is described in Scheme 42 according to methods disclosed by W. Buck et al, DE 2107146 (1972). Diethyl oxalate 158 is reacted with one equivalent of R2NH 2 to afford the mono amides 159. Subsequent reaction with ammonia gives the diamide 160, which is converted to the acylnitriles 161 by reaction with P 2 O 5 . Intermediates 161 are reacted with isocyanates A2P-N=C=O to give the imine- substituted hydantoins 162. Reduction of the imine functionality in 162 gives rise to compounds 163, which are reacted with isocyanates D-N=C=O to give the desired compounds 164 of Formula I.

Scheme 42

Preparation of compounds of Formula I wherein Al is Al-23 is described in Scheme 43 according to methods disclosed by A. Sasaki et al, JP 2000198771 A2. Readily available amines 165 are reacted with diethyl bromomalonate 166 to afford amino-substituted diethyl malonates 167. Reaction of 167 with an appropriate alpha-substituted ethyl acrylate 168, followed by NaCl-induced decarboxylation, gives the substituted pyrrolidineones 169. Hydrolysis of the ester functionality of 169 gives rise to 170. Acids 170 are converted to the desired compounds 171 of Formula I by two alternative methods. In the first method, 170 is subjected to a Curtius-type rearrangement in the presence of amines D-NH 2 , to give 171. In the second approach, 170 is first converted to the primary amides 172, which are then subjected to a modified Hoffman-type rearrangement utilizing bis- trifluoroacetoxyiodobenzene to afford rearranged amines that are trapped with an isocyanate D-N=C=O.

II. Synthesis of A2-containing intermediates.

The synthesis of intermediates containing A2 rings taken from A2-15 through A2-76 and A2- 87 through A2-94, required for the elaboration of compounds in the aforementioned schemes, is accomplished using readily available precursors and transformations readily understood in the art. Such A2-containing intermediates are provided which contain amino, hydrazinyl, carboxyl, or halogen functionalities useful for coupling to the aforementioned intermediates containing Al rings.

The synthesis of intermediates containing A2 rings taken from A2-1 through A2-14 and A2- 77 through A2-117 are detailed below in schemes 44 through 93.

Scheme 44 illustrates the preparation of intermediates A2P corresponding to A2-1 through A2-6. Readily available halogenated substituted benzenes, pyridines, pyrimidines, or triazines 172 through 177 are obtained commercially or are available through diazotization/H-Q2

quench (Sandmeyer reaction) of the corresponding substituted aryl- or heteroaryl-amines 178 through 183. In cases where A2 moieties need to be supplied as the substituted hydrazines, these are either derived from readily available hydrazines or are derived from the substituted aryl- or heteroaryl-amines 178 through 183 by diazotization of the amino groups followed by reduction of the diazonium salts to the corresponding hydrazines 184 through 189.

Scheme 44

Scheme 45 illustrates the preparation of intermediates A2P corresponding to A2-7. Thiourea is reacted with readily available alpha-halocarbonyl compounds 190, wherein Q2 is chloro or

bromo, to afford aminothiazoles 191. Aminothiazoles 191 are converted to thiazolylhydrazines 192 by a standard diazotization/reduction sequence. Alternatively, aminothiazoles 191 are converted to thiazolyl halides 193, wherein Q2 is chloro or bromo, by a standard Sandmeyer reaction sequence involving H-Q2 trapping of an in situ formed diazonium salt.

Scheme 46 illustrates the preparation of intermediates A2P corresponding to A2-8. Readily available aminonitriles 194 are reacted with aldehydes 195 in the presence of sulfur and base, affording intermediate aminothiazoles 196 after an acid work-up. Aminothiazoles 196 are converted to the thiazolylhydrazines 197 by a standard diazotization/reduction sequence. Alternatively, aminothiazoles 196 are converted to thiazolyl halides 198, wherein Q2 is chloro or bromo, by a standard Sandmeyer reaction sequence involving H-Q2 trapping of an in situ formed diazonium salt. Alternatively, beta-keto esters 199, wherein Q3 is a halogen leaving group, are reacted with substituted thioamides to afford thiazolyl esters 200. Esters 200 are hydrolyzed to their corresponding acids 201, which are then converted into thiazolyl

amines 202 by a Curtius-type rearrangement, or are converted into thiazolyl halides 203 by a Hunsdiecker reaction.

Scheme 47 illustrates the preparation of intermediates A2P corresponding to A2-9. Readily available thioamides 204 and beta-halo-alpha-keto esters 205 undergo a Hantzch cyclization to afford thiazolyl esters 206. Esters 206 are hydrolyzed to their corresponding acids 207,

which undergo a Curtius-type rearrangement to afford the requisite aminothiazoles 208, which then undergo a Standard diazotization/reduction sequence to give thiazolyl hydrazines 209. Alternatively, acids 207 undergo a Hunsdiecker reaction to afford the corresponding thiazolyl halides 210, wherein Q2 is chloro or bromo.

Scheme 47

Scheme 48 illustrates the preparation of intermediates A2P corresponding to A2-10. Ketal- protected amino ketones 211 are converted to the oxazolyl esters 212 by reaction with ethyl oxalyl chloride. Hydrolysis of the esters 212 affords acids 213. Acids 213 are converted to the hydrazines 215 and halides 216 by reaction sequences described above in Scheme 47.

Scheme 48

Scheme 49 illustrates the preparation of intermediates A2P corresponding to A2-11. Readily available aminonitriles 217 are reacted with substituted acid chlorides 218 in the presence of base, affording intermediate N-acyl aminonitriles 219. Cyclization of 219 affords the aminooxazoles 220. Conversion of 220 to the oxazolyl hydrazines 22J_ or the oxazolyl halides 222 is effected as described above in Scheme 45.

Scheme 49

Scheme 50 illustrates the preparation of intermediates A2P corresponding to A2-12. Acyl nitriles 223 are reacted with aldehydes 195 in the presence of ammonium acetate/acetic acid to give the aminooxazoles 224 using conditions reported above in Scheme 46. The aminooxazoles 224 are converted to the hydrazines 225 under standard diazotization/reduction conditions. Alternatively, alpha-ammo- beta-ketoesters 226 are acylated to give intermediates 227, which are cyclized to the oxazolyl esters 228 in the presence of a cyclodehydrating reagent such as thionyl chloride, triphenyl phosphine/carbon tetra-chloride, or Burgess reagent. Hydrolysis of esters 228 gives rise to acids 229, which are converted to oxazolyl hydrazines 231 and oxazolyl halides 232 by employing reaction conditions described above in Scheme 47.

Scheme 51 illustrates the preparation of intermediates A2P corresponding to A2-13. Aminoketones 232 are reacted with cyanamide to afford the aminoimidazoles 233. Conversion of 233 to the corresponding hydrazines 234 and the halides 235 is accomplished by employing reaction conditions described above in Scheme 45.

Scheme 51

Scheme 52 illustrates the preparation of intermediates A2P corresponding to A2-14. Alpha, beta-diketoesters 236 are reacted with substituted aldehydes 195 in the presence of ammonium acetate/acetic acid to give rise to imidazolyl esters 237. Imidazole NH protection (wherein P denotes suitable protection of the imidazole NH bond), followed by ester hydrolysis affords imidazole acids 238/239, which are converted to the corresponding hydrazines 242/243 and halides 244/245 by employing reaction conditions described above in Scheme 47.

A2-77 V=H 2

The synthesis of compounds of Formula I wherein A2 is A2-77 is shown in Scheme 53. Nitration of commercially available tetrahydroisoquinoline (246) by the action of H 2 SO 4 and HNO 3 affords 7-nitrotetrahydroisoquinoline 247 (see WO 03/0999284). Protection of 247 as its trifluoroacetamide yields 248, and conversion of the nitro group to the corresponding hydrazine by (a) reduction of the nitro group, (b) oxidation of the resulting amino group to the diazonium with NaNO 2 , and (c) reduction of the diazonium with SnCl 2 or FeCl 3 yields 249, which corresponds to the protected form of intermediate A2-77 containing hydrazines (V=H 2 ). In the case where the corresponding halide is required, conversion of the amine 248 to the diazonium salt, and Sandmeyer displacement with CuI and KI 3 iodine (see Harrington and Hegedus, J. Org. Chem. 1984, 49(15), 2657-2662) results in iodide 250.

A2-77 V=O

Synthesis of intermediates containing A2-77 (V= O) is shown in Scheme 54. Utilizing the procedure published by Doherty et. al (see WO 03/0999284), Wittig homologation of commercially available 2,4-dinitrobenzaldehyde (251) with ethyl

(triphenylphosphoranylidene)-acetate results in propenoate 252. Catalytic hydrogenation in the presence of glacial acetic acid and ethanol results in the target lH-quinolin-2-one 253 which, utilizing the same oxidation/reduction sequence as shown in Scheme 53 results in hydrazine 254 (R15, V=O) and iodide (255). At the conclusion of the synthesis that utilizes 254 or 255, reduction of the amide with LAη under standard conditions provides an optional synthesis of intermediates containing A2-77 (V=H 2 ).

A2-78 Vl=O. V2 = H 2

The synthesis of intermediates containing A2-78 (Vl = O, V2 = H 2 ) is shown in Scheme 55. Commercially available phenethylamine 256 is converted to the carbamate 257, and then cyclized utilizing polyphosphoric acid (PPA) to give the tetrahydroisoquinolone 258. 258 is nitrated under standard conditions to give 259, which is either converted to hydrazine 260 or iodide 261 using methodology outlined in Scheme 53.

Scheme 55

A2-78 Vl AND V2 = H 2

The synthesis of intermediates containing A2-78, wherein Vl and V2 are H 2 , is shown in Scheme 56. Reduction of 259 with LAH affords the amino-substituted tetra- hydroisoquinoline which is selectively protected at the ring nitrogen by reaction with trifluoroacetic anhydride and base, preferably triethylamine. Aniline 262 is then converted into the hydrazine 263 or the iodide 264 using methodology outlined in Scheme 54.

Scheme 56

A2-77 AND A2-98 V = H 2

The preparation of intermediates containing A2-77 and A2-98 wherein V is H 2 is illustrated in Scheme 57. In these schemes, R7 is a suitable moiety that conforms to the generic definition of TA or a protected form of such moiety. Compounds 267 and 268 are prepared by reductive alkylation of 265 or 266 with an appropriate aldehyde and sodium triacetoxyborohydride as the reducing agent. 269 and 270 are synthesized from 265 or 266 by simple amide formation using an acid chloride and base, preferably triethylamine or pyridine. 271 and 272 are synthesized by amidine or guanidine formation utilizing a thioamide or a thiourea, respectively. Intemediates 273, 274, 279, 280, 285 and 286 are prepared by palladium-catalyzed bromide substitution with benzophenone hydrazone as described by Haddad et al. {Tetrahedron Lett. 2002, 43, 2171-2173). 273, 274, 279, 280, 285 and 286 are either directly implemented by reaction with a suitable Al -containing intermediate, or, if required, first hydrolyzed to hydrazines 275, 276, 281, 282, 287 and 288, respectively, under acidic conditions. The bromide functionalities in 267 to 272 are substituted by boronic acid affording affording 277, 278, 283, 284, 289 and 290, respectively. After suitably protecting the amidine or guanidine substructure, the bromide is transformed into an organometallic species such as a grignard compound, and subsequently reacted with trimethyl borate to afford 277, 278, 283, 284, 289 and 290 after acid hydrolysis. In cases where R7 functionalities prohibit the use of organometallic reagents, the boronic acids are mildly formed from the bromides by utilizing a procedure employing bis(pinacolato)diboron and Pd(dppf).

A2-78 and A2-99. Vl AND V2 = H 2

The preparation of intermediates containing A2-78 or A2-99 wherein Vl and V2 are H 2 is illustrated in Scheme 58. 291 and 292 are converted to intermediates 293 to 316 using methods described above in Scheme 57.

A2-79. Vl AND V2 = O

The synthesis of intermediates containing A2-79 wherein Vl and V2 are O is shown in Scheme 59. The commercially available starting material 2-chloro-4-nitrobenzoic acid 317 is reacted with dimethyl malonate 318, NaOMe, and catalytic amount of Cu(I)Br to give 319 using conditions described by Quallich, G. J. et al (Quallich,G. J. et al, /. Org. Chem. (1998), 63: 4116-4119). The diester 319 is converted into diacid 320 under basic hydrolytic conditions. The diacid 320 is reacted with a primary amine containing a standard amine protecting group (such as benzyl) at about 115 °C to afford the ring closure product 321. Reduction of 321 under catalytic hydrogenation conditions gives 322. The dione 322 is converted into the hydrazine (323), bromide (324) or boronic acid (325) using standard conditions or those conditions described above in Scheme 47.

Scheme 59

A2-79, Vl AND V2 = H2

The synthesis of intermediates containing A2-79 wherein Vl and V2 are H 2 is shown in Scheme 60. Reduction of 321 (from Scheme 59) with NaBH 4 in the presence of BF 3 OEt 2 yields the tetrahydroisoquinoline 326. Subsequent reduction of the nitro functionality of 326 under catalytic hydrogenation conditions gives 327. Intermediate 327 is converted to the hydrazine 328, bromide 329 or boronic acid 330 using the methodology described in Scheme 59.

A2-79 Vl = O, V2 = H 2

The synthesis of intermediates containing A2-79 wherein Vl is O and V2 is H 2 is shown in Scheme 61. The selective reduction of 321 wherein P is a standard amine protecting group (from Scheme 59) with NaBH 4 in the presence of TFA gives the lactam 331 (Snow, R. J. et al, J. Org. Chem., (2002), 45:3394-3405). Reduction of the nitro functionality of 331 under catalytic hydrogenation conditions yields amine 332. Intermediate 332 is converted into the hydrazine 333, bromide 334 or boronic acid 335 using the methodology outlined in Scheme 59.

A2-79, Vl = H2, V2 = O

The synthesis of intermediates containing A2-79 wherein Vl is H 2 and V2 is O is shown in Scheme 62, utilizing methods reported by Tamura, Y. et al (Synthesis 1981, 534-537). The commercially available starting material 4-nitrobenzylamine 336 is protected with acetyl chloride to yield 337. Intermediate 337 is treated with D -(methyl thio)-acetyl chloride to give 338. Oxidation of 338 with 3-chloroperbenzoic acid gives the sulfoxide 339. Treatment of sulfoxide 339 with p-TsOH yields the lactam 340. Lactam 340 reacts with Raney Ni to afford the dihydroisoquinolinone 341. Reduction of the nitro functionality of 341 under catalytic hydrogenation conditions affords amine 342. Intermediate 342 is converted into the hydrazine 343, bromide 344 or boronic acid 345 using the methodology outlined in Scheme 59.

A2-79 AND A2-101, Vl AND V2 = H 2

The preparation of intermediates containing A2-79 or A2-101 wherein Vl and V2 are H 2 is illustrated in Scheme 63. 346 and 347 are converted to intermediates 348 to 371 using methods described above in Scheme 57.

A2-80 AND A2-102 V = H 2

The preparation of intermediates containing A2-80 or A2-102 wherein V is H 2 is illustrated in Scheme 64. 372 and 373 are converted to intermediates 374 to 397 using methods described above in Scheme 57.

A2-80 V=O

The synthesis of intermediates containing A2-80 (V=O) is shown in Scheme 65. Acylation of 4-nitroaniline 398, and Friedel-Crafts alkylation by the action of AlC1 3 results in 400 (see Zhang et. al Huaxue Yanjiu Yu Yingyong, 2002, 14(5), 618-619; Zhang et. al Huaxue Yanjiu Yu Yingyong, 2003, 17(5), 534-529). Elaboration of the nitro group in 400 to the hydrazine

401 (R18, V=O) and the iodide 402 (R18, V=O) proceeds under the same conditions outlined in Schemes 53 and 54. At the conclusion of the synthesis that utilizes 401 or 402, reduction of the amide with LAH under standard conditions yields intermediates A2-80 (V=H 2 ).

Alternatively, 400 can be reduced with LAH to yield 403 and subsequently protected as the trifluoroacetamide (404), which is converted to the hydrazine (405, R18, V=H2) or iodide (406, R 18, V=H2) (Scheme 66) using the same methodology outlined in Scheme 53.

A2-81 and A2-103

The preparation of intermediates containing A2-81 and A2-103 is illustrated in Scheme 67. 407 and 408 (see Scheme 54) are activated either by transformation into the corresponding

thiolactams 409 and 410 using Lawesson's reagent in dioxane or by transformation into imino ester 411 and 412 using trimethyloxonium tetrafluorborate. The displacement reaction with a primary amine (if one R4 is H) or a secondary amine affords amidines 413 and 414 when heated in a suitable solvent such as methanol or dioxane. From the thiolactam, displacement is supported by addition of mercury chloride. Structures 415 and 416 can be obtained when the bromide is reacted with benzophenone hydrazone under palladium catalysis as described by Haddad et al. {Tetrahedron Lett. 2002, 43, 2171-2173). 415 and 416 can either be directly implemented for reaction with a suitable Al intermediate or, if required, first hydrolyzed to hydrazines 417 and 418 under acidic conditions. The bromide in 413 and 414 can be substituted by a boronic acid affording 419 and 420. After suitably protecting the amidine substructure, the bromide is transformed into an organometallic species such as a grignard compound and subsequently reacted with trimethyl borate to afford 419 and 420 after acid hydrolysis. In cases where R4or R5 prohibits the use of organometallic reagents, the boronic acid can be mildly introduced with bis(pinacolato)diboron and Pd(dppf).

Scheme 67

A2-82 and A2-104

The preparation of intermediates containing A2-82 or A2-104 is illustrated in Scheme 68. 421 and 422 (Scheme 55) are converted to intermediates 423 to 434 utilizing the methods described above in Scheme 67.

A2-83 and A2-105

The preparation of intermediates containing A2-83 or A2-105 is illustrated in Scheme 69. 435 and 436 are converted into intermediates 437 to 448 using methods described above in Scheme 67.

Scheme 69

A2-84 and A2-106

The preparation of intermediates containing A2-84 or A2-106 is illustrated in Scheme 70. 449 and 450 are converted into intermediates 451 to 462 using methods described above in Scheme 67.

Scheme 70

A2-85 AND A2-86

The preparation of intermediates containing A2-85 or Ar-86 is illustrated in Scheme 71. 463 (l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) is commercially available in each enantiomeric form and as a racemic mixture. Nitration of 463 with sulfuric acid and potassium nitrate gives a mixture of 6- and 7- nitrated compounds 464 and 465. According to the literature (Bioorg. Med. Chem. Lett. 2002, 10, 3529-3544), these compounds are separated from each other by derivative crystallization. N-protection with a standard amine protecting group gives 466 and 467, respectively. Amide formation by reacting 466 or 467 with amines HN (R4) 2 or HR5 (fix scheme 71) by employing an acid-activating reagent, preferably EDCI/HOBt in the presence of base, preferably triethylamine, afford amides 468,

469, 480 and 481. Deprotection of the amine protecting group gives rise to nitro compounds

470, 471, 482 and 483. The bromides 472, 473, 484 and 485 are obtained by hydrogenation of the nitro group and subsequent Sandmeyer reaction via a diazotization/CuBr reaction sequence. 474, 475, 486 and 487 are prepared by palladium-catalyzed bromide substitution with benzophenone hydrazone as described by Haddad et al. {Tetrahedron Lett. 2002, 43, 2171-2173). 474, 475, 486 and 487 are either directly implemented by reaction with a suitable Al-containing intermediate, or, if required, first hydrolyzed to hydrazines 476, 477, 488 and 489, respectively, under acidic conditions. The bromide functionalities in 470, 471, 482 and 483 are substituted by a boronic acid affording 478, 479, 490 and 491. The bromide is transformed into an organometallic species such as a grignard compound and subsequently reacted with trimethyl borate to afford 478, 479, 490 and 491 after acid hydrolysis. In cases where R4 or R5 functionalities prohibit the use of organometallic reagents, the boronic acids are mildly formed from the bromides by utilizing a procedure employing bis(pinacolato)diboron and Pd(dppf).

A2-95

The synthesis of intermediates containing A2-95 is illustrated in Scheme 72. Commercially available substituted benzoic acid 492 is optionally subjected to a reductive amination reaction employing readily available aldehydes R30-CHO and sodium triacetoxyborohydride to give 493. Reduction of the nitro functionalities of 492 or 493 afford the amines 494 and 499. Conversion of 494 or 499 to the benzotriazoles 495 or 500, respectively, is effected by treatment with NO 3 anion as described in WO 04/041274. Conversion of 495 or 500 to substituted amines 496 or 501, hydrazines 497 or 502, or halides 498 or 503 is accomplished using conditions described in Scheme 47.

A2-96

The synthesis of intermediates containing A2-96 is illustrated in Scheme 73. Commercially available pyridine diester 504 is reacted with sodium borohydride/calcium chloride to give the selective reduction product 505 (P. Potier et al. Tetrahedron 1975, 31, 419-422).

Oxidation of the alcohol functionality of 505, preferably with MnO 2 , gives aldehyde 506. Oxime formation, followed by reduction with zinc/acetic acid, gives pyridinemethanamine 507 (M. Ohta et al. Chem. Pharm. Bull. 1996, 44 (5), 991-999). Intermediate 507 is converted to its formamide508, which is subjected to cyclodehydration with POCl 3 to give the imidazopyridine ester 509 (Q. Li et al. Bioorg. Med. Chem. Lett. (2002) 12, 465-469). Hydrolysis of the ester 509 affords acid 510. Acid 510 is converted to the amine 511, hydrazine 512, or halide 513 using conditions described in Scheme 47.

A2-97

The synthesis of intermediates containing A2-97 is illustrated in Scheme 74. Readily available 3-acylpyridines 514, wherein R32 is a substituent which conforms to the definition

of a protected or unprotected Zl moiety, are converted to the 2-chloropyridines 515 as reported in Can. J. Chem. (1988) 66: 420-428. Displacement of the chloro substituent in 515 with various hydrazines, wherein R33 conforms to the definition of a protected or unprotected TA moiety, followed by in situ cyclization, gives pyrazolylpyridines 516. Nitration of 516 under standard conditions gives 517, which are subjected to reduction to afford the amino-substituted pyrazolylpyridines 518. Conversion of 518 to hydrazines 519 or halides 520 is effected as described in Scheme 41.

A2-98, V = O

Scheme 75 illustrates the preparation of intermediates containing A2-98 wherein V is O. The commercially available starting material 7-nitro-3,4-dihydronaphthalen-l(2H)-one 521 is reacted with hydroxyl amine, followed by PC15, to give lactam 522. The nitro functionality of 522 is reduced under catalytic hydrogenation conditions to afford amine 523. The aminobenzoazepinone 523 is converted into the hydrazine 524, bromide 525 or boronic acid 526 as described in Scheme 59.

A2-98, V = H 2

The synthesis of intermediates containing A2-98 wherein V is H 2 is shown in Scheme 76. 522 (from Scheme 75) is reduced, preferably with diborane, borane.THF, or borane.Me 2 S, to yield 527, which is subsequently protected as the trifluoroacetamide (528) by reaction with trifluoroacetic anhydride in the presence of base, preferably triethylamine (TEA). Reduction of the nitro functionality of 528 under catalytic hydrogenation conditions affords amine 529, which is converted into the hydrazine 530, bromide 531 and/or boronic acid 532 using the methodology described in Scheme 59.

A2-99. Vl AND V2 = O

Scheme 77 illustrates the preparation of intermediates containing A2-99 wherein Vl and V2 are O. The commercially available starting material 2-(2-carboxyethyl)benzoic acid 533 is reacted with fuming nitric acid to give the nitrobenzoic acid 534. The nitrobenzoic acid 534 is treated with trifluoroacetamide in the presence of HOBt and EDCI to give the cyclic imide 535 (Nazar, F. et al, Tetrahedron Lett., (1999), 40: 3697-3698). The by-products and excess of reagents can be removed by using a mixed bed sulfonic acid-substituted resin and a tertiary amine-substituted resin (Flynn, D. L. et al, J. Am. Chem. Soc, (1997), 119: 4874-4881). Reduction of the nitro functionality of 535 under catalytic hydrogenation conditions affords the amine-substituted benzazepinedione 536 (Snow, R. J. et al, J. Org. Chem., (2002), 45: 3394-3405). The benzazepinedione 536 is converted into the hydrazine 537, bromide 538, or boronic acid 539 using the methodology described in Scheme 59.

An alternative synthesis of intermediates containing A2-99 wherein Vl and V2 are O is shown in Scheme 78. The commercially available starting material 2-chloro-5-nitrobenzoic acid 540 yields 541 by reaction with vinyl fπ-n-butyltin under Stille cross-coupling conditions (Littke, A. F. et al, Angew. Chem., Int. Ed. Engl, (1999), 38: 2411-2413). Intermediate 541 is reacted with thionyl chloride, followed by a primary amine containing a standard amine protecting group (such as benzylamine) to obtain the amide 542. Reaction of 542 with acrylic acid in the presence of an acid-activating reagent, such as EDCI/HOBt in the presence of base, preferably triethylamine (TEA), affords the diene 543. A Ring Closing Metathesis (RCM) reaction of 543 utilizing Grubbs' catalyst gives the benzazepinedione 544. Reduction of 544 under catalytic hydrogenation conditions produces 545 (Knobloch, K. et al, European J. ofOrg. Chem., (2001), 17: 3313-3332). Intermediate 545 is converted into the hydrazine 546, bromide 547 or boronic acid 548 as described in Scheme 77. Alternatively, intermediate 544 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 549, wherein the ring C-C bond is unsaturated. Intermediate 549 is converted into the hydrazine 550, bromide 551 or boronic acid 552 as described in Scheme 77.

A2-99, Vl AND V2 = H 2

The synthesis of intermediates containing A2-99 wherein Vl and V2 are H 2 is shown in Scheme 79. Reduction of 545 with LAH yields the benzoazepine 553. 553 is converted into the hydrazine 554, bromide 555 or boronic acid 556 using the methodology described in Scheme 59.

A2-99, Vl = O, V2 = H 2

The synthesis of intermediates containing A2-99 wherein Vl is 0 and V2 is H 2 is shown in Scheme 80. Allylation of 542, wherein P is a para-methoxybenzyl (PMB) or BOC protecting group, with allyl chloride affords the RCM precursor 557. RCM reaction of 557 with Grubbs' catalyst affords the tetrahydrobenzazepinenone 558. Reduction of 558 under catalytic hydrogenation conditions gives 559 which is reduced at the ring C-C bond and the nitro functionality (Knobloch, K. et al, European J. ofOrg. Chem., (2001), 17: 3313-3332). 559 is converted into the hydrazine 560, bromide 561, or boronic acid 562 as described in Scheme 77. Alternatively, intermediate 558 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 563, wherein the ring C-C bond is unsaturated. Intermediate 562 is converted into the hydrazine 564, bromide 565 or boronic acid 566 as described in Scheme 78.

A2-99, Vl = H 2 , V2 = O

The synthesis of intermediates containing A2-99 wherein Vl is H 2 and V2 is O is shown in Scheme 81. The readily available starting material N-PMB protected 2-bromo-5- nitrobenzylamine 567 is reacted with vinyl boronic acid under Suzuki palladium(O)-catalyzed conditions to yield 568. 568 is coupled with acrylic acid in the presence of an acid- activating reagent, preferably EDCI/HOBt, in the presence of base, preferably triethylamine (TEA), to give 569. RCM reaction of 569 with Grubbs' catalyst affords the dihydrobenzazepineone 570. Reduction of 570 under catalytic hydrogenation conditions yields the tetrahydrobenzoazepineone 571 which is reduced at the ring C-C bond and nitro group, with concomitant removal of the PMB protecting group (Knobloch, K. et al, European J. ofOrg. Chem., (2001), 17: 3313-3332). 571 is converted into the hydrazine 572, bromide 573 or boronic acid 574 as described in Scheme 78. Alternatively, intermediate 570 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 575, wherein the ring C-C bond is unsaturated. Intermediate 575 is converted into the hydrazine 576, bromide 577 or boronic acid 578 as described in Scheme 78.

A2-100, Vl AND V2 = O

Scheme 82 illustrates the preparation of intermediates containing A2-100 wherein Vl and V2 are O. The commercially available starting material 1,2-phenylendiacetic acid 579 is coupled with trifluoroacetamide under HOBt and EDCI conditions to give the cyclic imide 580 (Nazar, F. et al, Tetrahedron Lett., (1999), 40: 3697-3698). The by-products and excess of reagents can be removed by using a mixed resin containing sulfonic acid-substituted resin and a tertiary amine-substituted resin (Flynn, D. L. et al, J. Am. Chem. Soc, (1997), 119: 4874-4881). Nitration of 580 produces 58L Reduction of the nitro functionality of 581 under catalytic hydrogenation conditions affords the amine-subsgtituted benzazepinedione

582. The amine-substituted benzazepindione 582 is converted into the hydrazine 583, bromide 584, or boronic acid 585 using the methodology described in Scheme 59.

A2-100, Vl AND V2 = H2

The synthesis of intermediates containing A2-100 wherein Vl and V2 are H 2 is shown in Scheme 83. Reduction of 586 with NaBH 4 in the presence of BF 3 OEt 2 yields the nitroazepine 587. Protection of 587 with trifluoroacetic anhydride in the presence of base, preferably triethylamine (TEA), gives 588. Reduction of the nitro functionality of 588 under catalytic hydrogenation conditions yields amine 589. Amine 589 is converted into the hydrazine 590, bromide 591, or boronic acid 592 using the methodology described in Scheme 59.

A2-100, Vl = O, V2 = H?

The synthesis of intermediates containing A2-100 wherein Vl is O and V2 is H 2 is shown in Scheme 84. The commercially available starting material 4-nitrophenethylamine 593 is converted into the hydrazine 594, bromide 595, or boronic acid 596 using the methodology outlined in Scheme 62.

A2-100, Vl AND V2 = H2

The preparation of intermediates containing A2-100 wherein Vl and V2 are H 2 is illustrated in Scheme 85. 597 is converted to intermediates 598 to 609 using methods described above in Scheme 57.

A2-101, Vl AND V2 = O

Scheme 86 illustrates the preparation of intermediates containing A2-101 wherein Vl and V2 are O. The commercially available starting material 2-amino-4-nitrobenzoic acid 610 is converted into 2-iodo-4-nitrobenzoic acid 611 by a Sandmeyer reaction sequence. The iodobenzoic acid 611 is reacted with acrylonitrile under Heck conditions to give the unsaturated nitrile 612 (Bumagin, N. A. et al, J. Organometallic Chem. (1989), 371: 397- 401). Intermediate 612 is converted into the acid chloride 613 and then subjected to acid-

catalyzed cyclization, giving the ring closure product 614 (Puar, M. S. et al, Tetrahedron (1978), 34: 2887-90). Reduction of the nitro functionality of 614 under catalytic hydrogenation conditions affords the amine-substituted benzazepinedione 615 (Knobloch, K. et al, European J. of Org. Chem., (2001), 17: 3313-3332). Intermediate 6±5 is converted into the hydrazine 616, bromide 617, or boronic acid 618 using the methodology described in Scheme 59. Alternatively, intermediate 614 is selectively reduced at the nitro functionality, preferably with stannous chloride, to afford amine-substituted benzazepinedione 619, wherein the ring C-C bond is unsaturated. Intermediate 619 is converted into the hydrazine 620, bromide 621 or boronic acid 622 as described in Scheme 78.

An alternative synthesis of intermediates containing A2-101 wherein Vl and V2 are O is shown in Scheme 87. The commercially available starting material 2-chloro-4-nitrobenzoic acid 623, wherein P is an amine protecting group, preferably a para-methoxybenzyl (PMB)

group, is converted to the hydrazines 629 or 633, bromides 630 or 634, or boronic acids 631, 635 using the methodology described in Scheme 78.

A2-101, V1 AND V2 = H 2

The synthesis of intermediates containing A2-101 wherein Vl and V2 are H 2 is shown in Scheme 88. Reduction of 628 with NaBH 4 in the presence of BF 3 OEt 2 (US 6121283) yields the tetrahydroazepine 636. 636 is converted into the hydrazine 637, bromide 638 or boronic acid 639 using the methodology described in Scheme 59.

A2-101, Vl = O, V2 = H ?

The synthesis of intermediates containing A2-101 wherein Vl is O and V2 is H 2 is shown in Scheme 89. Intermediate 625 (see Scheme 87) is converted to the hydrazines 643 or 647, bromides 644 or 648, or boronic acids 645 or 649 as shown in Scheme 89.

A2-101. Vl = H 2 ,V2 = O

The synthesis of intermediates containing A2-101 wherein Vl is H 2 and V2 is O is shown in Scheme 90. The readily available starting material 2-chloro-4-nitrobenzylamine 650 is converted to the hydrazines 651 or 654, bromides 652 or 655, or boronic acids 653 or 656 using the methodology described in Scheme 81.

A2-102, V = O

Scheme 91 illustrates the preparation of intermediates containing A2-102 wherein V is O, using methodology reported by Schultz, C. et al (J. Med. Chem. (1999), 42: 2909-2919). The commercially available starting material 2-amino-5-nitrobenzoic acid 657 is converted into the ester 658. The ester 658 is treated with ethyl 4-chloro-oxobutanoate in the presence of pyridine to yield 659. Dieckman cyclization of 659 using potassium hydride as base in mixture of toluene and DMF affords the dihydrobenzazepineone 660. Heating 660 in wet DMSO yields the tetrahydrobenzoazepinedione 661. Reduction of the nitro functionaly of 661 under catalytic hydrogenation conditions, followed by selective reduction with Et 3 SiH (Bleeker, C. et al, Pharmazie, (1999), 54: 645-650) gives the lactam 662. The lactam 662 is converted into the hydrazine 663, bromide 664 or boronic acid 665 using the methodology described in Scheme 59.

Scheme 91

An alternative synthesis of intermediates containing A2-102 wherein V is O is shown in Scheme 92. Nitration of tetralin 666 gives 5- and 6-nitrotetralin as a mixture of regioisomers, which is fractionated to yield 6-nitrotetralin 667. Oxidation of 667 with CrO 3 affords 6-nitro-1-tetralone 668. The nitrotetralone 668 can be converted into the hydrazine 663, bromide 664 or boronic acid 665 using the methodology described in Scheme 75.

A2-102, V = H 2

The synthesis of intermediates containing A2-102 wherein V is H 2 is shown in Scheme 93. Intermediate 662 (see Scheme 91) is treated with LAH to afford the tetrahydrobenzazepine 669. The tetrahydrobenzazepine 669 is converted into the hydrazine 670, bromide 671 or boronic acid 672 using the methodology described in Scheme 59.

Scheme 93

A2-107, Vl = O.V2 = O: A2-107, Vl AND V2 = H 2

The synthesis of intermediate containing A2-107 is shown in Scheme 94. Readily available isatoic anhydride 673 is reacted with amino acid esters to afford the benzdiazepinediones 674. Reduction of the ring carbonyl groups of 674 with LAH or borane-Me 2 S gives diamines 675 (P = H). Protection with standard amine protecting groups (BOC, FMOC, PMB, SEM) affords 675, wherein P is BOC, FMOC, PMB, SEM, or other standard amine protecting group.

A2-107, Vl = H 2 , V2 = O

The synthesis of intermediates containing A2-107 wherein Vl is H 2 and V2 is O is shown in Scheme 95. Iodination of ortho-amino benzyl alcohol 676 with ICl affords 677. N-acylation of 677 with protected amino acid esters gives amides 678. Oxidation of the alcohol functions of 678 to the aldehydes 679 takes place under standard oxidation conditions, preferably MnO 2 , TPAP, or periodinane oxidation. Removal of the amine protecting groups, preferably Fmoc, with base, preferably piperidine, with in situ reduction of the formed imines, preferably with sodium triacetoxyborohydride, gives benzdiazepinones 680. Amino group protection, preferably with trifluoroacetic anhydride and base, preferably triethylamine, gives the desired intermediates 681.

A2-107, Vl = O; V2 = H 2 ;

The synthesis of intermediates containing A2-107 wherein Vl is O and V2 is H 2 is shown in

Scheme 96. Nucleophilic aromatic substitution reactions between 682 and various substituted ethanediamines 683, wherein P is a standard amine protecting group, affords 684. Amine deprotection, followed by amide formation using standard acid-activating reagents, including EDCI and base, affords benzdiazepinones 685. Utilization of diamines 683 wherein R8 is H affords benzdiazepinones 685 corresponding to the structures A2-107, wherein V2 is H 2 . Utilization of diamines wherein R8 is substituted results in structures A2- 107 wherein V2 is H, R8.

A2-108 AND A2-110, Vl AND V2 = O

The preparation of the intermediates containing A2-108 and A2-110 wherein Vl and V2 = O is illustrated in schemes 97 and 98. In one preferred mode, shown in 97, following the procedure of Uskokovic, M. et al. (US 3291824), a readily available and suitably substituted anthranilic acid, 686 or 687, is acylated with an R8-containing alpha-halo acid halide, 688, to give intermediate 689 or 690. This, in turn, is cyclized by refluxing in DMF, affording 691 or 692. R' is then converted, if needed, to a group R (693 or 694) suitable for attachment to any of the Al moieties disclosed in this invention. For example, when R' is Br or I, 691 or 692 may be used directly in a metal -mediated cross-coupling, such as a Heck, Suzuki or Stille protocol (see Scheme 23). Alternatively, when R' is Br or I, it may be subjected to Pd- mediated alkoxycarbonylation using a published procedure (Stille, J.K. et al, J. Org. Chem. 1975, 40 (4), 532; Heck, R. F., et al., J. Org. Chem. 1974, 39 (23), 3318) to give an ester. This functionality is saponified or reduced to afford the carboxylic acid or aldehyde, respectively. Also, when R' is Br or I, it may be converted to a boronic ester as shown

previously in Scheme 23. When R' is NO 2 , hydrogenation provides the amine. Diazotization, followed by reduction (see Scheme 30), provides the hydrazine.

In another preferred mode, shown in Scheme 98, 686 or 687 is converted to its anhydride, 695 or 696, with phosgene or an equivalent. Reacting this with an alpha-hydroxy ester 697 in the presence of a base gives the ester, 698 or 699. Subsequently, the ring is closed using a pepti de-coupling or dehydrating reagent. Finally, R' is modified to R to give 700 or 701 as detailed above.

The preparation of the intermediates containing A2-108 and A2-110 wherein Vl is O and V2 is H 2 , or both Vl and V2 are H 2 , is illustrated in Scheme 99. 69J. or 692 is thionated with either La wesson's reagent or P 4 S 1 0 to give 702 or 703 which is dethionated with Raney nickel to provide 704 or 705. Reduction of the lactone carbonyl to give the cyclic ether 706 or 707, is effected by using LiBH 4 , NaBH 4 or LiAH 4 in the presence of BF 3 OEt 2 using the methods of Pettit, G. R. et al. (J. Org. Chem. 1960, 25, 875 and J. Org. Chem. 1961, 26, 1685). Conversion of R' to R is carried out as described previously to give 708 to 711.

The preparation of the intermediates containing A2-108 and A2-110 wherein Vl is H 2 and V2 is O is illustrated in Scheme 100. 712 or 713 is esterified and selectively reduced with LiBH 4 , using the method of H.C. Brown et al. (J. Org. Chem. 1982, 47, 4702) to give the primary alcohol. Halogenation gives 714 or 715 wherein X is Cl or Br. Depending on the identity of R", reduction or deprotection affords 716 or 717 which is acylated with 718 to provide the alpha-hydroxy amide 719 or 720. Treatment of 719 or 720 with a strong non-

nucleophilic base, such as NaH or KH affords 721 or 722. Conversion of R' to R is carried out as described previously to give 723 and 724.

The preparation of the intermediates containing A2-108 and A2-110 wherein Vl is O or H 2 and V2 is H 2 ,_is illustrated in Scheme 101. 704 or 705 (V = O) or 706 or 707 (V = H, H) can be converted to 725 or 726 (V = O) or 727 or 728 (V = H, H using the method outlined in Scheme 57. Conversion of R' to R is carried out as described previously to give 729 to 732.

A2-109, Vl AND V2 = O: A2-109. Vl AND V2 = H 2

The synthesis of intermediates containing A2-109 wherein Vl and V2 are both 0 or both H 2 is illustrated in Scheme 102. The readily available bromo-substituted isatoic anhydride 733 is reacted with amino acid esters 734 to afford amides 735. Hydrolysis of the ester functionality of 735 gives the carboxylic acids which are cyclized to afford benzdiazepinediones 736 by employment of a standard acid-activating reagent, typified by EDC and base, preferably triethylamine. Reduction of the amide carbonyl functions of 736 utilizing LAH, diborane, or BH 3 -Me 2 S gives benzdiazepines 737.

A2-109, Vl = O, V2 = H 2

The synthesis of intermediates containing A2-109 wherein Vl is O and V2 is H 2 is illustrated in Scheme 103. Isatoic anhydride 738 is reacted with acetal -protected amino ketones 739 to give amides 740. Deprotection of the acetal protection with acid, preferably p- toluenesulfonic acid or HCl, affords the aldehydes which are subjected to reductive amination conditions, preferably sodium triacetoxyborohydride, to give benzdiazepineones 741. Protection of the ring nitrogen atom with trifluoroacetic anhydride and base, preferably triethylamine, affords intermediates 742.

Alternatively, intermediates 741 can be subjected to the various reactions described in Scheme 57 to afford Z4-substituted analogs 743 (scheme 104).

A2-109. Vl = H 2 , V2 = O

The synthesis of intermediates containing A2-109 wherein Vl is H 2 and V2 is O is illustrated in Scheme 105. Readily available 744 is oxidized to the aldehyde 745 using standard oxidizing reagents, preferably MnO 2 , TPAP, or a periodinane. Reductive amination of 745 with amino acid esters 746, wherein P is an substituted alkyl protecting group or H, affords intermediates 747. Hydrolysis of the ester function of 747 and cyclization employing standard acid-activating reagents, including EDC and base, triethylamine, affords the desired benzdiazepineone intermediates 748. Concomitant reduction of the lactam carbonyl and nitro functional groups with LAH gives rise to intermediate benzdiazepines 749. Selective protection of the ring nitrogen atom with trifluoroacetic anhydride and base, preferably triethylamine, gives 750. Alternatively, 748 is converted into Z4-substituted benzdiazepineones 751 by a sequence involving amine deprotection and derivatization with Z4 moieties as described in Scheme 57. Alternatively, 749 is converted into regioisomeric Z4- substituted benzdiazepineones 752 using methods described in Scheme 57.

A2-111, Vl AND V2 = O; A2-111, Vl AND V2 = H 2

The synthesis of intermediates containing A2-111 wherein Vl and V2 are O or Vl and V2 are H 2 is illustrated in Scheme 106. Nitroaniline 753, wherein P is a substituted alkyl amine protecting, is coupled with the malonyl half esters 754 employing standard acid-activating reagents, including EDCI/HOBT or ethyl chloroformate in the presence of base, preferably triethylamine, to give amides 755. Reduction of the nitro group under standard conditions, followed by hydrolysis of the ester functionality affords acids 756. Cyclization of 756 to benzdiazepinediones 757 is effected by EDCI/HOBT in the presence of base, preferably triethylamine. Amide nitrogen deprotection, followed by reduction of the ring carbonyl functionalities by LAH or borane affords the requisite benzdiazepines 758.

A2-111. Vl = O. V2 = H 2

The synthesis of intermediates containing A2-111 wherein Vl is O and V2 is H 2 is illustrated in Scheme 107. Readily available 753, wherein P is a substituted alkyl amine protecting group, is coupled with substituted hydroxy acids 759, wherein P' is a standard alcohol protecting group, in the presence of an acid-activating reagent, including but not limited to EDCI/HOBT or ethyl chloroformate in the presence of a base, preferably triethylamine, to give amides 760. Reduction of the nitro group using standard conditions, followed by removal of the alcohol protecting group P', affords 761. Mild alcohol oxidation, preferably with MN02, TPAP, or a periodinane, gives the aldehyde which is subjected to reductive aminiation cyclization conditions, preferably sodium triacetoxyborohydride, to afford benzdiazepinones 762. Optional amide deprotection and amine protection using trifluoroacetic anhydride in the presence of base, preferably triethylamine, gives trifluoroacetyl protected benzdiazepineones 763.

A2-111, Vl = O, V2 = H 2

The synthesis of intermediates containing A2-111 wherein Vl is O and V2 is H 2 and the ring amino nitrogen is substituted with a Z4 moeity, is illustrated in Scheme 108. 762 is converted into Z4-substituted analogs 764 using conditions described in Scheme 57.

Scheme 108

A2-111, Vl = H 2 , V2 = O;

The synthesis of intermediates containing A2-111 wherein Vl is H 2 and V2 is O is illustrated in Scheme 109. Starting amine 753 is reacted with substituted malonaldehydes 754 under standard reductive amination conditions, preferably sodium triacetoxyborohydride, to afford nitro esters 765. Reduction of the nitro functionality under standard conditions and ester hydrolysis gives acids 766, which are cyclized to benzdiazepineones 767 in the presence of an acid- activating reagent, preferably EDCI/HOBt or ethyl chloroformate in the presence of a base, preferably triethylamine, to afford benzdiazepineones 767. Protection of the ring amino nitrogen is effected by reaction of 767 with t-butoxycarbonyl anhydride, (BOC) 2 O, in the presence of base, preferably triethylamine, to give the requisite protected benzdiazepineones 768.

Scheme 109

A2-112, V = O;

The synthesis of intermediates containing A2-112 wherein V is 0 is illustrated in Scheme 110. Using methods described in Scheme 69, 674 is converted to amidines 769 or 770.

A2-113 AND A2-115

The preparation of the intermediates containing A2-113 and A2-115 is illustrated in Scheme 111. By analogy to the sequence shown in Scheme 70, the lactams 771 or 772 are converted to 773 through 776 bearing an exocyclic amine function. Conversion of R' to R is carried out as described previously to give 777 to 780.

A2-114. V = O

The synthesis of intermediates containing A2-114 wherein V is O is illustrated in Scheme 112. Using methods described in Scheme 69, 738 is converted to amidines 781 or 782.

Scheme 112

A2-117, V = O

The synthesis of intermediates containing A2-117 wherein V is O is illustrated in Scheme 113. Using methods described in Scheme 69, 757 is converted to amidines 783 or 784.

Scheme 113

A2-117 , V = H2;

The synthesis of intermediates containing A2-117 wherein V is O is illustrated in Scheme 114. Using methods described in Scheme 69, 763 is converted to amidines 785 or 786.

Scheme 114

III. Synthesis of other intermediates

Synthesis of R5 intermediates

When R5 is pyrrolidine (R5-1) [CAS 123-75-1], piperidine (R5-2) [CAS 110-98-4], azepine [CAS 11-49-9], morpholine (R5-3) [CAS 110-91-8] or thiomorpholine (R5-4) [CAS 123-90- 0], these materials are purchased from a number of commercial sources. When R5 is 2- substituted pyrrolidine (R5-12), 2-substituted piperidine (R5-13), HN(CH 2 CON(R4)) 2 (R5- 14), HN(CH 2 CO 2 R4) 2 (R5-15), or 4-substituted oxazolidinone (R5-16), these are prepared from commercially available precursors using standard methods and performed by one of ordinary skill in the art.

When R5 is thiomorpholinsulphone (R5-5) [790, CAS 39093-93-1], the synthesis is shown in Scheme 114. Benzylamine 787 and divinylsulphone 788 are reacted together in refluxing methylenechloride to yield benzyl-protected thiomorpholinesulphone 789, which upon hydrogenation yields 790.

When R5 is 4-alkyl-4-piperdinol (R5-6), the synthesis proceeds as shown in Scheme 115. Commercially available N-Boc-4-piperdone is reacted with the requisite Grignard or alkyllithium reagent to yield N-Boc-4-alkyl-4-piperdinol 791, which is readily deprotected to yield species of type 792.

When R5 is 4-N-alkylpiperazine (R5-7), the synthesis proceeds as shown in Scheme 116. Commercially available N-Boc-piperazine is reacted with a suitable aldehyde under reductive amination conditions followed by deprotection to yield species of type 794. When R4=phenyl [CAS 92-54-6], the synthesis proceeds as published by Bloomer et al (see BioOrg. Med. Chem. Lett., 2001, 11(14), 1925).

Synthesis of Zl, Z2, and Z4 intermediates

The syntheses of five-membered heterocycle intermediates Zl, Z2, and Z4 corresponding to Zl-I through Zl-21, Z2-1 through Z2-21, and Z4-1 through Z4-21 are performed as described in U.S. Continuation-In-Part Application: ANTI-INFLAMMATORY MEDICAMENTS; Docket No. 34477CIP, attached by reference herein.

Synthesis of sulfoximes

The Syntheses of sulfoxime moieties

is accomplished using the method reported by Cho, G. Y., et al, Organic Letters (2004) 6: 3293-3296.

General methods

General method A: To a stirring suspension of the starting pyrazole amine (0.5mmol, 1.0 eq) in dry THF (2.0 ml) was added pyridine (5.0 mmol, 10.0 eq). The resulting slurry was stirred at RT for Ih, treated with the appropriate isocyanate (1.0 mmol, 2.0 eq) and stirred overnight at RT The reaction was diluted with EtOAc and IM HC1 (10 ml) and the layers separated. The aqueous was extracted with EtOAc (2x), and the combined organic extracts were washed with H 2 O (Ix), satd. NaHCO 3 (Ix) and brine (2x), dried (MgSO4), filtered, concentrated, and purified via column chromatography to yield the target compound.

General method B: A solution of the starting pyrazole amine (0.5 mmol, 1.0 eq), triethylamine (2.0 eq) and CDI (2.0 eq) in DMF (5.0 mL) was stirred at RT for 6h. The appropriate amine (1.0 mmol, 2 eq) was added and the solution was stirred at RT for 5h, then poured into H 2 O (50 mL). The mixture was extracted with CH 2 C1 2 (3x50 mL) and the combined organic extracts were washed with IN HC1, brine, dried (Na 2 SO 4 ), filtered, concentrated and purified by preparative TLC to afford the target compound.

General method C: To a stirred solution of the starting ester (0.23 mmol, 1.0 eq) in THF (5 mL) was added LiA1H 4 powder (18 mg, 0.5 mmol) portionwise at 0 °C under N 2 . The mixture was stirred at RT for 2h, quenched with H 2 O, and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to yield the crude product, which was purified either by preparative TLC or column chromatography to afford the target compound.

General method D: To a solution of the starting pyrazole amine (1 eq) in EtOAc were added 2,2,2-trichloroethylchloroformate (1.1 eq) and saturated NaHCO 3 (2-3 eq) at 0 °C. After stirring for 3h at RT, the layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4) and concentrated under vacuum to yield the crude TROC carbamate of the pyrazole amine. To the carbamate (1 eq) in DMSO were added diisopropylethylamine (2 eq), the appropriate amine (2 eq) and the mixture was stirred at 60 °C for 16h or until all the starting carbamate was consumed. Water was added to the mixture and the product was extracted with EtOAc (2x25 mL). The combined organic extracts were washed with brine solution, dried (Na 2 SO 4 ) and concentrated to yield crude product, which was purified by column chromatography to yield the target compound.

General method E: A mixture of the starting ester (1 eq) in an aqueous solution of LiOH (2N, 5 mL) and THF (10 mL) was stirred overnight at RT. After removal of the organic solvent, the mixture was extracted with Et 2 O. The aqueous layer was then acidified with 2N HC1 to pH 4 and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give the crude product, which was purified by reverse phase chromatography to afford the target acid.

General method F: To the starting Boc-protected amine dissolved in EtOAc (5 mL) was added 3N HCl/EtOAc (6 mL). The solution was stirred at RT for 3h. The solid was filtered and dried under vacuum to obtain the target amine as the HCl salt.

General method G: To the starting trifluoroacetamide protected amine dissolved in MeOH (2 mL) was added 2N sodium hydroxide solution (2 mL) and the resulting mixture was stirred at RT for 5 h. The solution was further basified with 2N NaOH (20 mL) and the mixture was extracted with ether (3x20 mL) and subsequently with 1-butanol (3x20 mL). The combined butanol extracts were concentrated and dried to yield the deprotected amine.

General method H: To a suspension of the amine (150 mg, 0.67 mmol) in EtOAc (2 mL) was added aqueous IN NaOH. The reaction mixture was cooled to 0 °C and treated with isopropenyl chloroformate (0.1 mL, 0.94 mmol) over 30 sec. The reaction mixture was stirred 15 min at 0 °C and Ih at RT. The reaction was poured into THF-EtOAc (1: 1; 40 mL) and washed with H 2 O (2x10 mL) and brine (2x10 mL). The organics were dried (Na 2 SO 4 ), concentrated and the residue purified via column chromatography to provide the target (prop- l-en-2-yl)carbamate.

General method I: PyBop (0.11 g, 0.22 mmol) was added to a solution of a starting acid (typically 0.2 mmol) in DMF (1 mL) and was stirred for 5 min at RT. To this mixture was added the appropriate amine (either neat or ImL of 0.5 M dioxane solution) and the resulting solution stirred for 5h and was followed by the addition of 3M HCl (2mL), water (15 mL) and the aqueous extracted with EtOAc (2x20 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to yield the amide.

General method J: To a solution of a starting acid (typically 0.21 mmol) in DMF (2 mL) was added NH 4 Cl (56 mg, 1 mmol) or the appropriate amine, 1-Pr 2 NEt (110 mg, 0.84 mmol), EDC (60 mg, 0.31 mmol) and HOBT (48 mg, 0.31 mmol). The mixture was stirred at RT for 6h, then diluted with EtOAc (30 mL). The organic extracts were washed with water (2x25 mL) and brine, dried (Na 2 SO 4 ) and concentrated to afford the target amide..

General method K: To a stirring suspension of a starting acid (typically 0.11 mmol), and the appropriate amine (1.5 eq, either neat or in a 0.5 M dioxane solution) and TBTU (1.5 eq) in DMF (1.1 ml) was added i-Pr 2 NEt (5.0 eq). The resulting solution was stirred at RT overnight and was then diluted with H 2 O (11 ml) and extracted with EtOAc (3x). The combined organics were washed with IM HC1 (Ix), satd Na 2 CO 3 (2x), dried (MgSO 4 ), filtered and evaporation to provided the target amide.

General method L: NaH (2.3 g of a 60% dispersion, 57 mmol) was activated by washing with hexanes (3x15 mL). THF (20 mL) was added and heated to 80 C. At this point a solution of the appropriate ester (19 mmol) and MeCN (0.91 g, 21 mmol) in THF (40 mL) was added slowly via syringe. After stirring about 30 min a vigorous reaction was observed and soon the color of the reaction turned to dark blue and it was stirred for 10 more min. The reaction mixture was then poured into a biphasic mixture of ice cold 5% HC1 (100 mL) and EtOAc (100 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (1x50 mL). The combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated to afford the desired 3-oxo-3-substituted-propanenitrile which was used as is in the next reaction.

General method M: To a suspension of the appropriate aniline (1.05 g, 6.95 mmol) in cone. HCl (3 mL) was added a solution of NaNO 2 (0.57 g, 8.34 mmol) in H 2 O (3 mL) at 0 ° C slowly. After stirring for Ih, to the mixture was added SnCl 2 -2H 2 O (2.98 g, 14 mmol) dissolved in cone. HCl (3 mL) at such a rate that the temperature of the mixture was not allowed to cross 5 C. After stirring for 2h, a solution of the appropriate 3-oxo-3-substituted- propanenitrile (8 mmol; general method L or commercially available) in EtOH (10 mL) was added and the mixture was heated at 60 ° C for 16h. The mixture was cooled to RT and the solvent was removed under vacuum. The residue was basified with solid NaHCO 3 and the product was extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated under vacuum to yield the desired

pyrazole amine.

To a solution of m-aminobenzoic acid (200 g, 1.46 mmol) in cone. HCl (200 mL) was added an aqueous solution (250 mL) of NaNO 2 (102 g, 1.46 mmol) at 0 °C and the reaction mixture was stirred for Ih. A solution of SnCl 2 -2H 2 O (662 g, 2.92 mmol) in cone. HCl (2 L) was then added at 0 °C. The reaction solution was stirred for an additional 2h at RT. The precipitate was filtered and washed with EtOH and ether to give 3-hydrazinobenzoic acid hydrochloride as a white solid, which was used for the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.8 (s, 3H), 8.46 (s, 1H), 7.53 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.37 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H).

A mixture of 3-hydrazinobenzoic acid hydrochloride (200 g, 1.06 mol) and 4,4- dimethyl-3-oxopentanenitrile (146 g, 1.167 mol) in EtOH (2 L) was heated at reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-1- yl)benzoic acid (93 g, 36%). 3-(5-amino-3-t-butyl-pyrazol-1-yl)benzoic acid and ethyl ester. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (s, 1H), 8.05 (brd, J = 8.0 Hz, 1H), 7.87 (brd, J = 8.0 Hz, 1H), 7.71 (t, / = 8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.28 (s, 9H).

Using general method A, Example Al (Ig, 3.09 mmol) and 1,2- dichloro-3-isocyanatobenzene (0.7 g, 3.71 mmol) were combined to afford ethyl 3-{ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-lH- pyrazol-1-yl }benzoate (0.6 g, 41% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.24 (brs, 1H), 8.70 (brs, 1H), 8.05 (t, J = 1.8 Hz, 1H), 8.00 (t, J =5.1 Hz, 1H), 7.97-7.93 (m, 1H), 7.84-7.80 (m, 1H), 7.67 (t, J =8.1 Hz, 1H), 7.39 (d, J = 4.8 Hz, 2H), 6.39 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H),

1.27 (s, 9H), 1.26 (t, J =7.2 Hz, 3H).

Using general method C, Example A2 (80 mg, 0.17 mmol) was reduced to afford l-[3-t-butyl-1-(3-hydroxymethyl- phenyl)-lH- pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (50 mg, 68% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.20 (brs, 1H), 8.75 (brs, 1H), 8.04 (dd, J= 3.6 and 6 Hz 1H) 7.49-7.44 (m 2H), 7.37-7.32 (m, 2H),

7.30-7.28 (m, 2H), 6.37 (s, 1H), 4.56 (s, 2H), 1.24 (s, 9H).

To a solution of Example A2 (100 mg, 0.21 mmol) in fresh THF (10 mL) was added dropwise a solution of MeMgBr (1.5 mL, 1.4 M in toluene/THF) at 0 °C under N 2 . After stirring for Ih, the resulting mixture was allowed to rise to RT and stirred for Ih. The reaction mixture was quenched by addition of aqueous IN HC1 (5 mL) and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford l-{ 3-t-butyl-1-[3-(2-hydroxypropan-2- yl)phenyl]-lH-pyrazol-5-yl }-3-(2,3-dichlorophenyl)urea (50 mg, 52% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.19 (brs, 1H), 8.72 (brs, 1H), 8.06 (dd, J= 3.0, and 6.6 Hz, 1H), 7.58 (m, 1H), 7.46-7.43 (m, 2H), 7.32-7.27 (m, 3H), 6.36 (s, 1H), 1.42 (s, 6H), 1.26 (s, 9H).

To a solution of Example Al (14.4 g, 50 mmol) and formamide (4.5 g, 0.1 mol) in DMF (50 mL) was added NaOMe (5.4 g 0.1 mol) at RT. The mixture was stirred at 100 °C for 2h, concentrated and the the residue dissolved in EtOAc (150 mL). The organic layer was washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered and purified by column chromatography to afford 3-(5-amino-3-t-butyl-lH-pyrazol- l-yl)benzamide (6 g, 48 % yield).

A solution of 3-(5-amino-3-t-butyl-lH-pyrazol-1-yl)benzamide (5.2 g, 20 mmol) in SOC1 2 (50 mL) was heated at reflux for 6h. After removal of the solvent, the residue was dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered, and purified by column chromatography to afford 3-(5-amino- 3-t-butyl-lH-pyrazol-1-yl)benzonitrile (3.5 g, 73% yield).

General Experimental for Examples 3-12:

A solution of Example A3 and the appropriate isocyanate (general method A) or the appropriate aniline (general method B) were converted to the target compound.

Example 9 (80 mg, 0.19 mmol) was suspended in cone. HCl (0.93 mL) and briskly stirred. More cone. HCl (1 mL) was added several times to maintain good stirring and keep the solids wetted. The reaction was stirred at RT for 5h and 24h at 40 °C. The reaction was cooled to RT, diluted with H 2 O and EtOAc and the layers separated. The aqueous was extracted with EtOAc (2x). Solids in the aqueous layer were collected by filtration, rinsed sparingly with H 2 O and dried. These solids were suspended in MeOH, then collected by filtration, rinsed with MeOH and washed with EtOAc to afford l-[3-t-butyl-1-(3-carbamoylphenyl)-lH-pyrazol-5-yl]-3-(2,3- dichlorophenyl)urea (47.3 mg, 57% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.81 (brs, 1H), 8.99 (brs, 1H), 8.25 (brs, 1H), 8.08 (s, 1H), 7.99-7.97 (m, 1H), 7.90-7.87 (m, 1H), 7.75-7.71 (m, 1H), 7.60-7.57 (m, 1H), 7.49 (brs, 1H), 7.32-7.28 (m, 2H), 6.38 (brs, 1H), 1.29 (s, 9H); MS (ESI) m/z: 446.3 (M+H + ), 448.3 (M+2H + ).

To a solution of commercially available 3-methoxyphenylhydrazine hydrochloride (1.0 g, 5.7 mmol) in toluene (5 mL) was added commercially available pivaloylacetonitrile (0.70 g, 5.5 mmol). The reaction mixture was heated at reflux for 5h, filtered and washed with hexane to obtain 3-t-butyl- 1-(3-methoxyphenyl)-lH-pyrazol-5-amine (1.22 g, 89% yield) as its hydrochloride salt as a pale yellow solid which was used without further purification. 1 H NMR (300 MHz, CDC1 3 ): δ 7.35 (t, J = 8.4 Hz, 1H), 7.04 (t, J = 2.1 Hz, 1H), 7.00 (dd, J = 1.5 and 7.5 Hz, 1H), 6.95 (dd, J = 2.1 and 8.4 Hz, 1H), 5.90 (brs, 2H), 5.83 (s, 1H), 3.81 (s,

3H), 1.89 (s, 9H); MS (EI) m/z: 246 (M+H + ).

General Experimental for Examples 14-17:

Using general method A, a solution of Example A4 (70 mg, 0.29 mmol) and the appropriate isocyanate (0.29 mmol) were converted to the target compound.

A mixture of commercially available (4-methoxyphenyl)-hydrazine (17.4 g, 0.1 mol) and commercially available pivaloylacetonitrile (13.8 g, 0.11 mol) in EtOH (500 mL) and cone. HCl (50 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to afford 3-t-butyl-1-(4- methoxyphenyl)-lH-pyrazol-5-amine (20 g, 82% yield). 1 H NMR

(300 MHz, DMSO-d 6 ): δ 7.38 (d, 7 = 9.0 Hz, 2H), 6.97 (d, 7 = 9.0 Hz, 2H), 5.32 (s, 1H), 4.99

(brs, 2H), 3.75 (s, 3H), 1.17 (s, 9H); MS (ESI) m/z: 246 (M+H + ).

Using general method A, a solution of the previous compound (123 mg, 0.29 mmol) and the l,2-dichloro-3-isocyanatobenzene (98 mg, 0.5 mmol) were combined to afford l-[3-t- butyl-1-(4-methoxyphenyl)-lH-pyrazol-5-yl]-3-(2,3-dichloroph enyl)urea (65 mg, 30% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.12 (s, 1 H), 8.75 (s, 1 H), 8.05 (m, 1 H), 7.38 (d, J = 7.2 Hz, 2 H), 7.29-7.27 (m, 2 H), 7.05 (d, J = 6.9 Hz, 2 H), 6.33 (s, 1 H), 3.79 (s, 3 H), 1.24 (s, 9 H); MS (ESI) m/z: 433 (M+H + ).

Using General method A, ethyl 4-(3-t-butyl-5-amino-lH-pyrazol- l-yl)benzoate (1 g, 3.09 mmol, prepared from ethyl 4- hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002)) and l,2-dichloro-3- isocyanato-benzene (0.7 g, 3.71 mmol) were combined to afford ethyl 4-{3-t-butyl-5-[3-(2,3-dichlorophenyl)-ureido]-lH-pyrazol- l-yl }benzoate (0.7 g, 48% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.20 (brs, 1 H), 8.77

(brs, 1 H), 8.04 (m, 1 H), 7.44 (brs, 4 H), 7.29-7.26 (m, 2 H), 6.36 (s, 1 H), 4.31 (q, / = 7.2

Hz, 2 H), 1.27 (s, 9 H), 1.26 (t, J =7.2 Hz, 3 H).

Using General method C, ethyl 4-{3-t-butyl-5-[3-(2,3-dichlorophenyl)-ureido]-lH- pyrazol-1-yl}benzoate (80 mg, 0.17 mmol) was reduced to afford 1 - { 3-t-buty 1- 1 - [4-

(hydroxymethyl)-phenyl]-lH-pyrazol-5-yl }-3-(2,3-dichlorophenyl)urea (50 mg, 68% yield).

1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.20 (brs, 1H), 8.77 (brs, 1H), 8.04 (m, 1H) 7.45 (br s,

4H), 7.30-7.25 (m, 2H), 6.36 (s, 1H), 4.55 (s, 2H), 1.27 (s, 9H).

Using the same procedure as for Example 2, Example 19 (100 mg, 0.21 mmol) in fresh THF (10 mL) was transformed to l-{3-t- butyl-1-[4-(2-hydroxypropan-2-yl)phenyl]-lH-pyrazol-5-yl}-3- (2,3-dichlorophenyl)urea (50 mg, 52% yield). 1 H NMR (300 MHz, DMSO- 6 ): δ 9.25 (brs, 1H), 8.79 (brs, 1H), 8.03 (m, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.30-7.28 (m, 2H), 6.36 (s, 1H), 1.45 (s, 6H), 1.25 (s, 9H).

A mixture of 1-(3-nitrophenyl)ethanone (82.5 g, 0.5 mol), p-TsOH (3 g) and sulfur (32 g, 1.0 mol) in morpholine (100 mL) was heated at reflux for 3h. After removal of the solvent, the residue was dissolved in dioxane (100 mL). The mixture was treated with cone. HCl (100 mL) and then heated at reflux for 5h. After removal of the solvent, the residue was extracted with EtOAc (3x150 mL). The combined organic extracts were washed with brine, dried (Na 2 SCU), filtered, and concentrated. The residue was dissolved in EtOH (250 mL) and SOCl 2 (50 mL) and heated at reflux for 2h. After removal of the solvent, the residue was extracted with EtOAc (3x150 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford ethyl (3-nitroρhenyI)acetate (40 g). 1 H NMR (300 MHz, DMSO-c? 6 ): δ 8.17 (s, 1H,), 8.11 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 4.08 (q, / = 7.2 Hz, 2H), 3.87 (s, 2H), 1.17 (t, / = 7.2 Hz, 3H).

A mixture of ethyl (3-nitrophenyl)acetate (21 g, 0.1 mol) and 10% Pd/C (2 g) in MeOH (300 mL) was stirred at RT under H 2 40 (psi) for 2h. The reaction mixture was filtered and the filtrate was concentrated to afford ethyl (3-aminophenyl)acetate (17 g). MS (ESI) m/z: 180 (M+H + ).

To a suspension of (3-aminophenyl)acetic acid (17 g, 94 mmol) in cone. HC1 (50 mL) was added dropwise a solution of NaNO 2 (6.8 g, 0.1 mol) in H 2 O at 0 °C. The mixture was stirred for Ih, after which a solution of SnCl 2 -2H 2 O (45 g, 0.2 mol) in cone. HC1 was added dropwise at such a rate that the reaction mixture never rose above 5 °C. The resulted mixture was stirred for 2h. The precipitate was collected by suction, and washed with Et 2 O to afford ethyl (3-hydrazinophenyl)acetate (15 g). MS (ESI) m/z: 195 (M+H + ).

A solution of ethyl (3-hydrazinophenyl)acetate (15 g, 65 mmol) and 4,4-dimethyl-3- oxopentanenitrile (12.5 g, 0.1 mol) in EtOH (100 mL) containing cone. HCl (25 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with Et 2 O to afford ethyl 2-(3-(5-amino-3-t-butyl-lH-pyrazol-1-yl)phenyl)acetate (18 g). MS (ESI) m/z: 302 (M+η + ).

Using general method H, Example A5 (1.08 g, 3.18 mmol) was transformed to ethyl 2-(3-(3-t-butyl-5-((prop-1-en-2-yloxy)carbonyl)- lH-pyrazol-1-yl)phenyl)acetate (1.23 g, 100 % yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.50-7.32 (m, 4H), 6.80-6.48 (brs, 1H), 4.81 (brs, 1H), 4.75 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 1.98 (brs, 3H), 1.36 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H); MS (ESI) m/z: 386.2 (M+H + ).

To a solution of N-(3-amino-4-methylphenyl)acetamide (5 g, 25 mmol, commercially available) in DMF (5 mL) was added 2- chloro-4-(pyridin-3-yl)-pyrimidine (4 g, 35 mmol, commercially available) and KI (0.5 g, 3 mmol). After stirring at 100 °C overnight, the reaction mixture was cooled to 10 °C, quenched with H 2 O, (10OmL), extracted with CH 2 C1 2 (2x100 mL) and the combined organic layers were dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in cone. HCl (10 mL), stirred at 80 °C for 2h, and then concentrated to yield 6-methyl-N'-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-l,3-diam ine hydrochloride (4.5 g, 65% yield) as the HCl salt. 1 H NMR (300 MHz, CDCl 3 ): δ 7.93-7.96 (m, 2H), 7.50-7.47 (m, 1H), 7.47-7.41 (m, 5H), 7.25-7.27 (m, 2H), 2.21(s, 3H); MS (ESI) m/e: 277 (M+H + ).

Example A6 (150 mg, 0.39 mmol) and Example A7 (108 mg, 0.39 mmol) and N-methyl pyrrolidine (8.9 mg, 0.10 mmol) in THF (0.4 mL) were heated at 55 °C for 24h. The crude reaction mixture was chromatographed on silica gel to provide ethyl 2-(3-(3- t-butyl-5-(3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamin o)phenyl)ureido)-lH-pyrazol-1- yl)phenyl)acetate (236 mg, 100% yield) as a straw-colored solid. 1 H NMR (400 MHz, DMSO-de): δ 9.29 (d, J = 1.6 Hz, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.69 (dd, J = 4.7, and 1.6 Hz, 1H), 8.51-8.46 (m, 2H), 8.42 (s, 1H), 7.82 (d, J = IA Hz, 1H), 7.54-7.40 (m, 5H), 7.31 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.06 (dd, J = 8.0, and 2.1 Hz, 1H), 6.40 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.76 (s, 2H), 2.19 (s, 3H), 1.27 (s, 9H), 1,18 (t, J = 7.0 Hz, 3H); MS (ESI) m/z: 605.3 (M+H + ).

To this material (97 mg, 0.16 mmol) was added 7N NH 3 MeOH (1.0 mL, 7.0 mmol) and the resultant solution was heated to 55 °C overnight in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue dissolved in boiling EtOAc. Upon

cooling, crystallization ensued. The solid was collected, pulverized, and suspended in THF

(10 mL). IN HCl (0.15 mmol) was added and the solution was stirred overnight and then concentrated to dryness. Acetonitrile was added and the suspension was concentrated to dryness again. To a suspension of the pumpkin-orange colored solid in MeCN (10 mL) was added just enough MeOH to affect dissolution. The resultant solution was then concentrated to about 2 mL by distillation at atmospheric pressure. The fine orange precipitate that formed was collected by filtration, washed with MeCN and dried in vacuo to provide 1-(1-(3-(2- amino-2-oxoethyl)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(4-met hyl-3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)phenyl)urea as the hydrochloride salt (30 mg, 32% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.44 (brs, 1H), 9.30 (brs, 1H), 9.11 (brs, 1H), 9.01 (m, 1H), 8.92 (m, 1H), 8.62 (m, 2H), 7.95 (m, 1H), 7.83 (s, 1H), 7.56 (m, 2H), 7.45-7.37 (m, 4H), 7.29 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.37 (s, 1H), 3.47 (s, 2H), 2.19 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 576.2(M+H + ).

Using the same method as for Example 21, ethyl 2-(3- (3-t-butyl-5-(3-(4-methyl-3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)phenyl)ureido)- lH-pyrazol- 1 - yl)phenyl)acetate (137 mg, 0.23 mmol) and 1-amino- 2,3-dihydroxypropane (49 mg, 0.54 mmol) were combined to yield 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)p henyl)-lH- pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yla mino)phenyl)urea (81 mg, 69% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.29 (dd, J = 2.2, and 0.8 Hz, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.69 (dd, J = 4.8, and 1.6 Hz, 1H), 8.51-8.47 (m, 2H), 8.38 (s, 1H), 8.10 (brt, / = 5.8 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.51 (ddd, J = 8.4, 4.7, and 0.8 Hz, 1H), 7.47-7.42 (m, 3H), 7.36 (m, 1H), 7.31 (brd, J = 7.6 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5, and 2.1 Hz, 1H), 6.41 (s, 1H), 4.76 (d, J = 4.8 Hz, 1H), 4.51 (t, / = 5.8 Hz, 1H), 3.53 (s, 2H), 3.48 (m, 1H), 3.30-3.18 (m, 3H), 2.96 (m, 1H), 2.19 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 650.3 (M+H + ).

To a solution of Example A5 (6.0 g, 20 mmol) and formamide (1.8 g, 40 mmol) in DMF (20 mL) was added NaOMe (2.1 g, 40 mmol) at RT. The mixture was heated at reflux for Ih, concentrated and the residue was purified via column chromatography to afford 2-[3-(5-amino-3-t- butyl-lH-pyrazol-1-yl)phenyl]acetamide (2.0 g, 40% yield). 1 H NMR

(300 MHz, DMSO-d 6 ): δ 7.44-7.31 (m, 4H), 7.11 (m, 1H), 6.87 (brs, 1H), 5.33 (s, 1H), 5.12

(s, 2H), 3.38 (s, 2H), 1.17 (s, 9H); MS (ESI) m/z: 273 (M+H + ).

To a solution of 3-hydroxypyridine (5.01 g, 52.7 mmol) in DMSO (60 mL) was added NaH (1.39 g, 57.9 mmol, 2.31 g of 60% suspended in oil) and stirred for 30 min at RT. To the slurry was added l-fluoro-3- nitrobenzene (9.66 g, 68.5 mmol) and mixture was heated to 80 °C for 72h. The mixture was poured into satd NH 4 Cl solution (200 mL), and extracted with EtOAc (3x125 mL). The combined organic extracts were washed with H2O (75 mL), brine, dried (Na 2 SO 4 ) and concentrated to yield a crude residue which was purified by column chromatography afford (4.43 g, 39% yield) pure 3-(3-nitrophenoxy)pyridine as a syrup. 1 H NMR (400 MHz, Acetone-cfe): δ 8.49-8.47 (m, 2H), 8.07-8.05 (m, 1H), 7.85 (t, J = 2.4 Hz, 1H), 7.74 (t, J = 8.4 Hz, 1H), 7.58-7.53 (m, 2H), 7.51-7.47 (m, 1H); MS (ESI) m/z: 217.0 (M+H + ).

To a solution of 3-(3-nitrophenoxy)pyridine (4.43 g, 20.5 mmol) in EtOAc (50 mL) was added PtO 2 (0.4g) and the mixture was stirred at RT overnight under H 2 (1 atm). The mixture was filtered through Celite ® , the Celite ® washed with EtOAc (2x20 mL) and the combined filtrates concentrated to yield (3.77 g, 99% yield) pure 3-(pyridin-3- yloxy)benzenamine as a syrup. 1 H NMR (400 MHz, OMSO-d 6 ): δ 8.34-8.32 (m, 2H), 7.40- 7.39 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 6.37-6.35 (m, 1H), 6.02-6.14 (m, 2H), 5.28 (brs, 2H); MS (ESI) m/z: 187.0 (M+H + ).

To a solution of 3-nitrophenol (0.151 g, 0.733 mmol) in DMSO (5 mL) was added NaH (35 mg of a 60% dispersion, 0.88 mmol) at 0 °C under Ar atmosphere. After stirring for 30 min, 2-iodopyrazine (0.133 mg, 0.953 mmol) was added and mixture heated to 85 °C for 4h. To the mixture was added satd. NH 4 Cl solution (25 mL) and the product extracted with EtOAc (2x25 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated to yield a crude residue which was purified by column chromatography to afford (97 mg, 61% yield) 2-(3-nitrophenoxy)pyrazine as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (brs, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.16- 8.09 (m, 3H), 7.63 (t, J = 8.0 Hz, 1H), 7.57-7.54 (m, 1H); MS (ESI) m/z: 218.0 (M+H + ).

To a solution of 2-(3-nitrophenoxy)pyrazine (97 mg, 0.45 mmol) in EtOAc (10 mL) was added PtO 2 (10 mg) and the mixture was stirred for 4h under H 2 (1 atm). The mixture was

filtered through Celite ® and the Celite ® was washed with EtOAc (2x5 mL). The combined filtrates were concentrated to yield (78 mg, 93%) 3-(pyrazi-yloxy)benzenamine as a solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.44 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.23-8.22 (m, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.43 (dd, J = 8.0 Hz, and 2.0 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 6.26 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 5.27 (brs, 2H); MS (ESI) m/z: 188.1 (M+H + ).

To a solution of 2-ethoxymethylenemalonic acid diethyl ester (59.0 g, 273 mmol) in EtOH (300 mL) was added 2-methyl-isothiourea (41.5 g, 150 mmol) in an ice-H 2 O bath. An EtOHic solution of EtONa (2M, 300 mL) was added dropwise maintaining the reaction temperature under 5 °C. The mixture was warmed to RT and stirred for 3h. After standing overnight, the solvent was removed under reduced pressure and the residue was dissolved in H 2 O (800 mL) at 0 °C. The solution was acidified to pH 3 with cone. HCl and the precipitate collected by filtration and air-dried to yield 4-hydroxy-2- methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50.8 g, 87.6% yield). 1 H NMR (400 MHz, OMSO-d 6 ): δ 8.48 (s, 1H), 4.20 (q, J = 9.6 Hz, 2H), 2.51 (s, 3H), 1.23 (t, 7 = 9.6 Hz, 3H).

A mixture of 4-hydroxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (50 g, 0.234 mmol), POC1 3 (110 mL, 1.17 mmol) and diethylamide (70 mL, 0.28 mmol) was refluxed for 5h. The solvent was removed under vacuum and the residue was dissolved in ice H 2 O and cautiously neutralized with aqueous NaHCO 3 . After extraction with EtOAc (3x400 mL), the organic extracts were combined, dried and concentrated to give 4-chloro-2- (methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (42 g, 77% yield). 1 H NMR (300 MHz, CDC1 3 ): δ 8.92 (s, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.40 (t, 7 = 7.2 Hz, 3H).

To a solution of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (42 g, 0.181 mol) in EtOH (400 mL) was added MeNH 2 (12.3 g, 0.398 mmol) in EtOH (100 mL) at 0 °C and the mixture stirred for 3h. The mixture was concentrated to remove most of the solvent and then partitioned between H 2 O (200 mL) and CH 2 Cl 2 (500 mL). The organic layer was washed with brine, dried and concentrated to give 4-(methylamino)-2- (methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a white solid (36.0 g, 88% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.59 (s, 1H), 8.18 (brs, 1H), 4.31 (q, 7 = 7.2 Hz, 2H), 3.05 (d, 7 = 4.8 Hz, 3H), 2.52 (s, 3H), 1.34 (t, 7 = 7.2 Hz, 3H).

To a solution of 4-(methylamino)-2-(methylsulfanyl)pyrirnidine-5-carboxylic acid

ethyl ester (30 g, 132 mmol) in THF (300 mL) was added LiA1H 4 powder (7.5 g, 198 mmol) at RT. After Ih, the reaction was carefully quenched with H 2 O (10 mL) and 10% NaOH (7 mL). The mixture was stirred for Ih and then filtered. The filtrate was concentrated to give crude (4-(methylamino)-2-(methylthio)pyrirnidin-5-yl)methanol (22.0 g, 90% yield), which was used in the next reaction without further purification. 1 H NMR (300 MHz, DMSO-ck): δ 7.79 (s, 1H), 6.79 (m, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.27 (d, J = 5.4 Hz, 2H), 2.83 (d, J = 4.8 Hz, 3H), 2.40 (s, 3H).

A mixture of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 119 mmol) and MnO 2 (44 g, 714 mmol) in CHCl 3 (300 mL) was stirred at RT for 3h. The reaction was filtered and the filtrate concentrated to give 4-(methylamino)-2- (methylsulfanyl)pyrimidine-5-carbaldehyde as a pale solid (20 g, 92% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.71 (s, 1H), 8.60 (brs, 1H), 8.49 (s, 1H), 2.96 (d, J = 4.8 Hz, 3H), 2.48 (s, 3H).

To a solution of 4-(methylamino)-2-(methylsulfanyl)pyrirnidine-5-carbaldehyde (10.0 g, 55 mmol) and (3-nitrophenyl)acetonitrile (10.5 g, 65 mmol) in DMF (150 mL) was added K 2 CO 3 (38 g, 275 mmol) at RT. The mixture was stirred at 100 °C for 18h. After cooling, the reaction was diluted with DMF (50 mL) and filtered. The filtrate was concentrated to give crude 8-methyl-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3- d]pyrimidin-7- ylideneamine (9.0 g, 50% yield) which was used in the next reaction without further purification.

A solution of 8-methyl-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3- d] pyrimidin-7-ylideneamine (9.0 g, crude product) in Ac 2 O (100 mL) was refluxed for 20 min. The mixture was concentrated to give a brown solid. The solid was then dissolved in cone. HCl (50 mL) and heated for 30 min. The reaction mixture was cooled and filtered to give a brown solid, which was purified by reverse phase chromatography to give 8-methy1-(2- methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin- 7-one as a white solid (1.1 g, 21% yied, two steps). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.95 (s, 1H), 8.60 (m, 1H), 8.34 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.75 (t, J = 5.4 Hz, 1H), 3.68 (t, J = 5.4 Hz, 3H), 2.62 (s, 3H).

To a solution of 8-methyI-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3- d]pyrimidin-7-one (1.0 g, 3 mmol) in EtOH (10 mL) was added Raney ® nickel (5 g) and the mixture refluxed for 3h. After cooling, the reaction was filtered and the filtrate concentrated to give 8-methyl-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.35 g, 41% yield), which was used in the next reaction without further purification.

To a solution of 8-methyl-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.35 g, 1.2 mmol) in EtOH (10 mL) was added Pd (0.2 g). The mixture was stirred under an atmosphere of H 2 (30 psi) for 1.5h. After removal of the catalyst by filtration, the solvent was evaporated under vacuum to give 6-(3-aminophenyl)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7- one (150 mg, 50% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.08 (d, J = 4.2 Hz, 1H), 8.18 (s, 1H), 7.85 (m, 1H), 7.80 (d, J = 5.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 3.85 (s, 3H).

To stirred anhydrous DMF (25 mL) was slowly added SOC1 2 (125 mL) at such a rate that the reaction temperature was maintained at 40- 50 °C. Pyridine-2-carboxylic acid (25 g, 0.2 mol) was added in portions over 30 min and the resulting mixture was heated at reflux for 16h during which time a yellow solid precipitated. After cooling to RT, the mixture was diluted with toluene (80 mL) and concentrated. This process was repeated three times. The resulting dry residue was washed with toluene and dried under reduced pressure to yield 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 79%), which was used in the next step without purification.

To a solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in anhydrous THF (100 mL) at 0 °C was added dropwise a solution of MeNH 2 in EtOH. The resulting mixture was stirred at 3 °C for 4h. The reaction mixture was concentrated under reduced pressure to yield a solid, which was suspended in EtOAc and filtered. The filtrate was washed with brine (2xl00mL), dried and concentrated to yield 4-chloro-N- methylpicolinamide as a yellow solid (16.4 g, 60% yield). 1 H NMR (300 MHz, DMSO-^ 5 ): δ 8.78 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 7.2 Hz, 1H), 7.95 (s, 1H), 7.67-7.65 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H); MS (ESI) m/z: 171 (M+H + ).

A solution of 4-aminophenol (9.6 g, 88 mmol) in anhydrous DMF (10OmL) was treated with NaH (5.28 g of a 60% dispersion, 132 mmol), and the reddish-brown mixture was stirred at RT for 2h. The contents were treated with 4-chloro-N-methylpicolinamide (15 g, 88 mmol) and K 2 CO 3 (6.5 g, 44 mmol) and heated at 8O°C for 8h. The mixture was cooled to RT and partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine (2x 50 mL), dried (Na 2 SO 4 ) and concentrated to afford 4-(4-amino-phenoxy)pyridine-2-carboxylic acid methylamide (15 g, 71% yield). 1 H NMR (300 MHz, DMSO-^ 5 ): δ 8.71 (d, J = 1.8 Hz, 1H), 8.43 (d, / = 5.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.06-7.03 (m, 1H), 6.76 (dd, J = 8.7 Hz, 4H), 5.15 (s, 2H),

2.76 (d, J = 4.8 Hz, 3H); MS (ESI) m/z: 244 (M+H + ).

A solution of 5-chloro-3-hydroxypyridine (0.45 g, 3.5 mmol) and NaH (0.15 g of 60% dispersion, 3.83 mmol) in DMSO (10 mL) was stirred at RT for 30 min and then treated with l-fluoro-3-nitrobenzene (0.69 g, 4.9 mmol). The mixture was heated at 120 °C for 24h, cooled to RT, quenched with satd. NH 4 Cl (50 mL), and extracted with EtOAc (3x 25 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated to yield a crude residue which was purified via column chromatography using to yield 3-chloro-5-(3- nitrophenoxy)pyridine (0.2 g, 23% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): D 8.46 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.41-7.39 (m, 2H); MS (ESI) m/z: 251.0 (M+H + ).

To a solution of 3-chloro-5-(3-nitrophenoxy)pyridine (0.2 g, 0.8 mmol) in EtOAc (10 mL) was added PtO 2 (0.02 g) and the mixture was stirred for 4h under H 2 (1 atm). It was then filtered through a Celite ® pad and washed with EtOAc (2x5 mL). The combined organic extracts were concentrated to afford 3-(5-chloropyridin-3-yloxy)benzenamine (0.165 g, 93% yield) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.39 (d, / = 2.0 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.54-7.53 (m, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.42-6.39 (m, 1H), 6.25-6.19 (m, 2H), 5.33 (brs, 2H); MS (ESI) m/z: 221.0 (M+H + ).

Using general method A, Example AlO (2.0 g, 6.6 mmol) and 1,2- dichloro-3-isocyanato-benzene (1.1 g, 7.5 mmol) were combined to afford ethyl 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)- lH-pyrazol-1-yl)phenyl)acetate (2.2 g, 68% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.22 (s, 1H), 8.75 (s, 1H), 8.05 (m, 1H), 7.46-

7.21 (m, 6H), 6.35 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H,), 3.72 (s, 2H), 1.24 (s, 9H), 1.16 (t, J =

7.2 Hz, 3H); MS (ESI) m/z: 489 (M+H + ).

Using general method C, Example 23 (100 mg, 0.21 mmol) was reduced to yield l-{3-t-butyl-1-[3-(2-hydroxyethyl)phenyl]-lH- pyrazol-5-yl }-3-(2,3-dichlorophenyl)urea (60 mg, 64% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.18 (s, 1H), 8.74 (s, 1H), 8.02 (m, 1H), 7.42-7.22 (m, 4H), 6.35 (s, 1H), 3.61 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H), 1.24 (s, 9H); MS (ESI) m/z: 447 (M+H + ).

General Experimental for Examples 25-29:

A solution of Example A8 and the appropriate amine were converted to the target compound using the general method indicated.

To a mixture of (3-aminophenyl)acetic acid ethyl ester (15 g, 84 mmol) in cone. HC1 (20 mL) was added sodium nitrite (6 g, 87 mmol) aqueous solution dropwise under ice-salt bath. The resulting mixture was stirred at 0 °C for 30 min and then added a solution of SnC1 2 .2H 2 O (38 g, 168 mmol) in cone. HCl dropwise also at such a rate that the reaction mixture never rose above 5 °C. After the addition was completed, the mixture was stirred for another 2 h at room temperature. The precipitate was collected by suction and washed with ethyl ether to afford (3-Hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 88%) as a brown solid. MS (ESI) m/z: 195 (M+H + ). A solution of (3- hydrazinophenyl)acetic acid ethyl ester hydrochloride (17 g, 74 mmol) and 3-cyclopentyl-3- oxopropionitrile (12.2 g, 88.8 mol) in alcohol (150 mL) containing cone. HCl (10 mL) was heated to reflux overnight. After removed of the solvent, the precipitate was collected by suction and washed with ethyl ether to afford the crude product, which was purified by column chromatography to afford [3-(5-amino-3-cyclopentylpyrazol-1-yl)phenyl]acetic acid ethyl ester hydrochloride (8.8 g, 34% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO- d 6 ): δ 7.40-7.66 (m, 4H), 5.68 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.75 (s, 2H), 3.00-3.08 (m, 1H), 1.98-2.00 (m, 2H), 1.58-1.70 (m, 6H), 1.17 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H + ).

A mixture of Example A14 (0.600 g, 1.7 mmol, 1.0) and 7N NH 3 in MeOH (9.8 ml, 69 mmol, 40 eq) was heated in a sealed screw-cap vial at 60 °C for 36h. More 7N NH 3 in MeOH (9.8 ml, 69 mmol, 40 eq) was added and the reaction heated at 60 °C 24h. The solution was concentrated to a purple residue of 2-(3-(5-amino-3-cyclopentyI-lH- pyrazol-1-yl)phenyl)acetamide. MS (ESI) m/z: 285.2 (M+η + ).

Using general method D, Example A15 (0.1000 g, 0.218 mmol, 1.00 eq) and 4-(4- aminophenyl)isoindolin-1-one (0.0488 g, 0.218 mmol, made according to literature procedures) were combined to yield 1-(1-(3-(2-amino-2- oxoethyl)phenyl)-3-cyclopentyl-lH-pyrazol-5-yl)-3-(4- (l-oxoisoindolin-4-yl)phenyl)urea (51.7 mg, 44.5% yield). 1 H NMR (400 MHz, DMSOd 6 ): δ 9.17 (s, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 7.66-7.62 (m, 2H), 7.59-7.52 (m, 6H), 7.48-7.44 (m, 2H), 7.40-7.37 (m, 1H), 7.32-7.30 (m, 1H), 6.94 (brs, 1H), 6.34 (s, 1H), 5.50 (s, 2H), 3.47 (s, 2H), 3.06-2.98 (m, 1H), 2.03-1.94 (m, 2H), 1.76- 1.59 (m, 6H); MS (ESI) m/z: 535.2 (M+H + ).

Using general method D, Example A15 (0.0805 g, 0.175 mmol, 1.00 eq) and Example All (0.0442 g, 0.175 mmol) were combined to yield 1-(1-(3-(2- amino-2-oxoethyl)phenyl)-3-cyclopentyl-lH-pyrazol- 5-yl)-3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)urea (18.3 mg, 19% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.16 (s, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.83-7.82 (m, 1H), 7.53 (brs, 1H), 7.48-7.44 (m, 3H), 7.39-7.35 (m, 2H), 7.32-7.29 (m, 2H), 6.93 (brs, 1H), 6.34 (s, 1H), 3.71 (s, 3H), 3.46 (s, 2H), 3.05-2.97 (m, 1H), 2.02-1.94 (m, 2H), 1.74-1.59 (m, 6H); MS (ESI) m/z: 563.3 (M+H + ).

To a suspension of NaH (6.0 g of a 60% dispersion, 0.15 mol) in THF (100 ml) was added dropwise trifluoroacetic acid ethyl ester (14.2 g, 0.1 mol) and anhydrous MeCN (50 g , 0.12 mol) in THF (100ml). The resulting mixture was refluxed overnight, and then cooled to RT. After removal of the volatiles in vacuo, the residue was diluted in EtOAc and aqueous 10% HCl. The organic layer was washed with H 2 O and brine, dried (MgSθ 4 ), filtered and concentrated to yield 15 g of crude 4,4,4-trifluoro-3-oxo-butyronitrile which was used for the next step reaction without further purification.

A mixture of ethyl (3-hydrazinophenyl)acetate(8.77 g, 0.028mol, available from

Example A5) and 4,4,4-trifluoro-3-oxo-butyronitrile (5.75g, 0.042mol) in EtOH (200 mL) was heated at reflux overnight. The mixture was concentrated and the residue purified by column chromatography to yield ethyl 2-(3-(5-amino-3-(trifluoromethyl)-lH-pyrazol-1- yl)phenyl)acetate (5g, 57% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d 6 ): 7.50- 7.43 (m, 3H), 7.30-7.33 (m, 1H), 5.81 (s, 1H), 5.75 (s, 2H), 4.09 (q, J = 7.2 Hz, 1H), 3.76 (s, 2H), 3.38 (s, 2H), 1.18 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H + ).

A solution of ethyl 2-(3-(5-amino-3-(trifluoromethyl)-lH-pyrazol-1-yl)phenyl)ace tate (3 g, 9.58 mmol) in cone. NH 4 OH (40 mL) was heated at reflux for 2h. After removal of the solvent, the residue was purified by column chromatography to afford 2-(3-(5-amino-3- (trifluoromethyl)-lH-pyrazol-1-yl)phenyl)acetamide (1.8 mg, 66% yield). 1 H NMR (300 MHz, DMSO-d 6 ): 7.48-7.42 (m, 4H), 7.30 (s, 1H), 6.91 (s, 1H), 5.77 (s, 1H), 5.73-5.72 (m, 2H), 4.44 (s, 2H). MS (ESI) m/z: 285 (M+H + ).

To a solution of phosgene (0.5 mL of 20% w/v solution in toluene) in MeCN (1 mL) was added over a period of 10 min a mixture of Example A9 (0.054 g, 0.29 mmol) and triethylamine (0.076 g, 0.76 mmol) in MeCN (1 mL) at 0 °C under Ar. After stirring for 30 min at RT, a solution of 2-(3-(5-amino-3-(trifluoromethyl)-7H-pyrazol-1-yl)phenyl)ace tamide (0.07 g, 0.24 mmol) and Et 3 N (0.06 g, 0.66 mmol) was added and the resulting mixture stirred at RT for 16h. The mixture was concentrated, purified via column chromatography, stirred in ηC1/EtOAc and the solid collected by filtration to yield 1-(1-(3-(2-amino-2- oxoethyl)phenyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3-(3-( pyridin-3-yloxy)phenyl)urea (0.041 g, 32% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.68 (s, 1H), 9.02 (s, 1H), 8.62 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 7.86-7.84 (m, 1H), 7.76 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.57-7.34 (m, 7H), 7.16 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.96 (s, 1H), 6.85 (s, 1H), 6.78 (dd, / = 8.4 Hz, 2.0 Hz, 1H), 3.50 (s, 2H); MS (ESI) m/z: 497.0 (M+H + ).

A solution of 2-(3-iodophenyl)acetic acid (1.05 g, 4.0 mmol, commercially available) in EtOH (12 mL) was treated with 2 drops of concentrated sulfuric acid. The resultant solution was heated at reflux for 90 min, cooled to RT and poured into hexanes (50 mL) and EtOAc (50 mL). The organics were with saturated Na 2 CO 3 (2x50 mL), H 2 O (50 mL), brine

(50 mL), dried (MgSO 4 ) and concentrated to yield ethyl 2-(3-iodophenyl)acetate (1.11 g, 95% yield). MS (ESI) m/z: 291.0 (M+H + ).

Ethyl 2-(3-iodophenyl)acetate (0.500 g, 1.72 mmol), 4-bromo-3-nitrobenzotrifluoride

(1.86 g, 6.89 mmol commercially available), tetrabutylammonium chloride (0.527g, 1.90 mmol), i-Pr 2 NEt (0.33 mL, 1.90 mmol) and Pd(OAc) 2 (0.039 g, 0.17 mmol) were combined neat in a sealed vial and heated at 130 °C for 65h. The cooled reaction mixture was applied directly to silica gel and eluted with 25% EtOAc/hexanes to provide 2'-nitro-4'- (trifluoromethyl)-[l ,l'-biphenyl]-3-acetic acid ethyl ester (0.107 g, 17% yield). MS (ESI) m/z: 354.0(M+H + ).

2'-Nitro-4'-(trifluoromethyl)-[l,l'-biphenyl]-3-acetic acid ethyl ester (107 mg, 0.30 mmol) in THF (6 mL) was treated with about 150 mg of Raney ® nickel (50 wt% in H 2 O). The reaction was shaken on a Parr apparatus under 50 psi of H 2 . After 4.5h, another 200 mg of Raney ® nickel was added and the reaction was shaken an additional 2h under 50 psi H 2 . The reaction mixture was filtered through Celite ® , concentrated in vacuo and purified via column chromatography to afford 2'-amino-4'-(trifluoromethyl)-[l,l'-biphenyl]-3-acetic acid ethyl ester (58 mg, 59% yield). MS (ESI) m/z: 324.2 (M+H + ).

2'-Amino-4'-(trifluoromethyl)-[l,l '-biphenyl]-3-acetic acid ethyl ester (45 mg, 0.14 mmol), Example A37 (44 mg, 0.14 mmol) and N-methylpyrrolidine (1 drop) were combined in THF (0.25 mL) in a screw-cap vial. The vial was sealed and the reaction mixture was heated at 55 °C for 65h. The crude reaction was purified via clumn chromatography to yield [l,r-biphenyl]-2'-(3-(4-(l-oxoisoindolin-4-yl)phenyl)-ureido )-4'-(trifluoromethyl)-3-acetic acid ethyl ester (65 mg, 81% yield). MS (ESI) m/z: 574.0 (M-I-H + ).

A solution of [l,l'-biphenyl]-2'-(3-(4-(l-oxoisoindolin-4-yl)phenyl)-ureid o)-4'- (trifluoromethyl)-3-acetic acid ethyl ester (63 mg, 0.11 mmol) in THF (2 mL) and H 2 O (2 mL) was treated with LiOH H 2 O (23 mg, 0.55 mmol). After 3h, IN HCl (0.6 mL, 0.6 mmol) was added and the reaction mixture was diluted with EtOAc (30 mL). The organic layer was washed with H 2 O (2x10 mL), brine (10 mL), dried (Na 2 SO 4 ) and concentrated to yield [1,1'- biphenyl]- 2'-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-4'-(trifluorom ethyl)-3-acetic acid (62 mg, 100% yield). MS (ESI) m/z: 546.0 (M+H + ).

[l,l'-Biphenyl]-2'-(3-(4-(l-oxoisoindolin-4-yl)phenyl)-ureid o)-4'-(trifluoromethyl)-3- acetic acid (62 mg, 0.11 mmol) was combined with HOBT (20 mg, 0.15 mmol) and 0.5M in dioxane NH 3 (1.0 mL, 0.5 mmol) in DMF (2 mL). EDC (64 mg, 0.23 mmol) was added and the reaction mixture was stirred at RT for 7h. The reaction was partitioned between H 2 O (10 mL) and EtOAc (30 mL). The organic was washed with IN HC1 (2x5 mL), saturated Na 2 CO 3 (10 mL), brine (10 mL), concentrated and purified by reverse phase chromatography to yield [l,l'-biphenyl]- 2'-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-4'-(trifluorom ethyl)-3- acetic acid amide (36 mg, 60% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d ό ): δ

9.35 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.65 (m, 2H), 7.60-7.38 (m, HH), 7.35 (dt, J = 7.5, 1.3 Hz, 1H), 6.96 (brd, J = 1.5 Hz, 1H), 4.50 (s, 2H), 3.49 (s, 2H); MS (ESI) m/z: 545.3 (M+H + ).

Using General method E, Example 23 (80 mg, 0.17 mmol) was saponified to afford 3-{ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]- lH-pyrazol-1-yl}benzoic acid (60 mg, 79% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.46 (brs, 1H), 8.82 (brs, 1H), 8.05 (brs, 1H), 7.98 (t, J = 4.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.80 (d, / = 8.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 4.5 Hz, 2H), 6.37 (s, 1H), 1.26 (s, 9H).

To a stirred solution of Example 34 (0.150 g, 0.325 mmol, 1.0 eq), (3S)-(-)-3-(dimethylamino)pyrrolidine ( 0.0446 g, 0.390 mmol, 1.2 eq) and TBTU (0.125 g, 0.390 mmol, 1.2 eq) in DMF (3 mL) was added I-PR2NET (0.173 ml, 0.975 mmol, 3.0 eq). The resulting solution was stirred at RT. Upon completion, the reaction was quenched with 3N HCl (pH 1-2) and extracted with EtOAc (Ix). This extract was set aside. The aqueous was basified (pH 9-10) with satd. Na 2 CO 3 and extracted with EtOAc (3x). The combined organics were washed with brine (2x) and dried (Na 2 SO 4 ). Filtration and evaporation provided crude product as a glass which was purified by reverse phase chromatography to afford of pure 1-(3-t-butyl-1-(3-(2-((S)-3- (dimethylamino)pyrrolidin-1-yl)-2-oxoethyl)phenyl)-lH-pyrazo l-5-yl)-3-(2,3-dichloro- phenyOurea (0.132 g, 73% yield). 1 H NMR (400 MHz, OMSO-d 6 ; rotamers): δ 9.41 and 9.39 (s, 1H), 8.88 and 8.87 (s, 1H), 8.08-8.05 (m, 1H), 7.50-7.39 (m, 4H), 7.34-7.27 (m, 4H), 6.38 (s, 1H), 3.02-3.75 (m, 4H), 3.59-3.48 (m, 2H), 2.81-2.75 (m, 6H), 2.33-2.07 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 557.3 (M+H + ), 559.2 (M+2H + ).

To a stirred solution of Example 34 (130 mg, 0.282 mmol), in DMF (3 mL) was added HOBT (48 mg, 0.310 mmol) and EDC (68 mg, 0.352 mmol). The mixture was stirred for 15 min and then treated with (S)-3-aminopropane-l,2-diol (32 mg, 0.352 mmol), stirred at RT overnight, and then diluted with H 2 O (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and

the combined organics washed with 5% citric acid (20 mL), saturated NaHCO 3 (20 mL), brine (20 mL)., dried (Na 2 SO 4 ), concentrated, and purified by column chromatography to yield 1-(3-t-butyl4-(3-(2-((S)-2,3-dihydroxypropylamino)-2-oxoethy l)phenyl)-lH-pyrazol-5- yl)-3-(2,3-dichloro-phenyl)urea (90 mg, 60% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.28 (s, 9H), 2.93-2.96 (m, 1H), 3.19-3.47 (m, 4H), 3.53 (s, 2H), 4.51 (brs, 1H), 4.76 (brs, 1H), 6.39 (s, 1H), 7.29-7.45 (m, 6H), 8.07-8.10 (m, 2H), 8.79 (s, 1H), 9.26 (s, 1H); MS (ESI) m/z: 536.0 (M+H + ).

Using the same procedure as for Example 36, Example 34 (100 mg, 0.20 mmol) and 2-aminoEtOH (2 mL) were combined to afford 1-(3-t-butyl-{ l-[3-(2-hydroxyethylamino)-2-oxo-thyl]- phenyl }-lH-pyrazol-5-yl)-3-(2,3-dichlorophenyl)-urea (70 mg, 69% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.22 (s, 1H), 8.74 (s, 1H), 8.08-8.03 (m, 2H), 7.38-7.24 (m, 6H), 6.34 (s, 1H), 3.45

(s, 2H), 3.30 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 1.22 (s, 9H); MS (ESI) m/z: 504

(M+H + ).

To a solution of N-(3-amino-4-methyl-phenyl)acetamide (5g, 25 mmol) in DMF (5 mL) was added 2-chloropyrimidine (3.8g, 33 mmol) and KI (0.5g). The reaction was stirred at 100 °C overnight, cooled to 10 °C and added to H 2 O (10OmL). The resulting mixture was extracted with CH 2 Cl 2 (2x100 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under vacuum. The residue was dissolved in cone. HCl (10 mL), stirred at 80°C for 2h and concentrated under vacuum to yield 6-methyl-N 1 -(pyrimidin-2-yl)benzene-l,3-diamine hydrochloride (3.75g, 75% yield). 1 H NMR (400 MHz, CDCl 3 ): 8.36 (dd, J = 15.2, 4.8 Hz, 2H), 7.46 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 6.67 (t, J = 4.8 Hz, 1H), 6.39 (dd, J = 8.0, 2.4, Hz, 1H), 2.20 (s, 3H); MS (ESI) m/e: 201 (M+H + ).

Using the same procedure as for Example 22, Example A6 (145 mg, 0.38 mmol) and Example A16 (80 mg, 0.40 mmol) were combined to yield 1-(3-t-butyl-1-(3-(2-(2,3- dihydroxypropylamino)-2-oxoethyl)phenyl)-lH-pyrazol-5- yl)-3-(4-methyl-3-(pyrimidin-2-ylamino)phenyl)urea (52

mg, 60% yield, 3 steps). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.93 (s, 1H), 8.70 (s, 1H), 8.36- 8.34 (m, 3H), 8.10 (t, J = 5.7 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.37-7.30 (m, 2 H), 7.16 (dd, J = 8.1, and 2.2 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.74 (t, J = 4.8 Hz, 1H), 6.37 (s, 1H), 4.76 (d, 7 = 5.0 Hz, 1H), 4.52 (t, J = 6.8 Hz, 1H), 3.54 (s, 2H), 3.49 (m, 1H), 3.31-3.18 (m, 3H), 2.96 (m, 1H), 2.13 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 573.3 (M+H + ).

To a stirring solution of 3-nitrophenylacetic acid (10.4 g, 57.3 mmol) in MeOH (250 ml) at RT was added HCl gas until saturation was achieved. The resulting solution was stirred at 70 °C for Ih. The reaction was cooled and concentrated under reduced pressure. The semisolid residue was dissolved in Et 2 O, washed with H 2 O (2x), satd. NaHCO 3 (2x), brine (Ix) and dried (MgSO 4 ). Filtration and evaporation provided methyl 2-(3-nitrophenyl)acetate as a low-melting solid (10.7 g, 96% yield), which was used without further purification. 1 H NMR (300 MHz, CDCl 3 ): δ 8.14- 8.04 (m, 2H), 7.64-7.58 (m, 1H), 7.47 (brt, J = 8.10 Hz, 1H), 3.72 (s, 2H), 3.68 (s, 3H); MS (ESI) m/z: 196.0 (M+H + ).

Methyl 2-(3-nitrophenyl)acetate (9.6 g, 49 mmol) was treated with cone. NH 4 OH (24 ml, 172 mmol). The suspension was stirred briskly at RT until complete, then chilled thoroughly in an ice bath. The solids were collected by filtration, rinsed sparingly with ice H 2 O and dried to yield pure 2-(3-nitrophenyl)acetamide as an off-white solid (7.47 g, 84% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.18-8.02 (m, 2H), 7.75-7.70 (m, 1H), 7.61-7.57 (m, 3H), 7.00 (brs, 1H), 3.58 (s, 3H); MS (ESI) m/z: 181.0 (M+H + ).

To a stirring solution of BH 3 -THF (3.5 ml, 3.5 mmol, 1.0M) was added a solution of 2-(3-nitrophenyl)acetamide (0.25 g, 1.4 mmol) in THF (7.0 mL) at RT. The resulting solution was stirred at RT until the gas evolution had subsided and then heated at 70 °C overnight. The cooled reaction was quenched carefully with 3M HCl (2 ml)and heated again at 70 °C to complete the quench. The reaction was cooled to RT and concentrated to a white solid, which was dissolved in 3M NaOH (pH 14) and extracted with CH 2 Cl 2 (4x). The organics were dried (Na 2 SO 4 ), filtered, and concentrated to provide 0.20 g (87% yield) of crude product as an oil, which was purified by precipitation from CH 2 Cl 2 and 3M HC1/EtOAc (0.26 ml, 0.78 mmol) to yield 2-(3-nitrophenyl)ethanamine as the HCl salt as an off-white solid (0.164 g). 1 H NMR (300 Mhz, DMSO-d 6 ): δ 8.18-8.15 (m, 1H), 8.13-8.04 (m, 1H), 8.02 (brs, 3H), 7.76- 7.74 (m, 1H), 7.65 (brt, J = 7.8 Hz), 3.17-3.08 (m, 2H), 3.06-3.00 (m, 2H); MS (ESI) m/z:

167.0 (M+H + ).

To a stirring suspension of 2-(3-nitrophenyl)ethanamine hydrochloride (0.164 g, 0.81 mmol) in dry CH 2 Cl 2 (8 ml) at RT was added i-Pr 2 NEt (0.42 ml, 2.43 mmol). The reaction was stirred at RT until the solids were dissolved, cooled thoroughly in an ice bath and TFAA (0.14 mL, 1.01 mmol) was added dropwise. The resulting yellow solution was stirred overnight with slow warming to RT. The reaction mixture was washed with ice H 2 O (2x) and dried (MgSO 4 ). Filtration and evaporation provided N-(3-nitrophenethyl)-2,2,2- trifluoroacetamide (0.215 g, 101% yield) as an oil that solidified on standing. 1 H NMR (300 MHz, CDCl 3 ): δ 8.17-8.14 (m, 1H), 8.11-8.10 (m, 1H), 7.58-7.52 (m, 2H), 6.4 (brs, 1H), 3.70 (q, J = 6.0 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H).

To a solution of N-(3-nitrophenethyl)-2,2,2-trifluoroacetamide (9.05 g, 34.5 mmol) in MeOH (125 ml) at RT was added 10% Pd/C (50% H 2 O wet) (3.67 g, 1.73 mmol). The resulting suspension was placed under H 2 (3 arm) at RT overnight. The reaction was filtered through Celite ® and the cake rinsed with MeOH. The filtrate was concentrated to provide N- (3-aminophenethyl)-2,2,2-trifluoroacetamide as an oil (7.83 g, 98% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.16-7.12 (m, 1H), 6.62-6.58 (m, 2H), 6.54-6.53 (m, 1H), 6.34 (brs, 1H), 3.61 (q, J = 6.40 Hz, 2H), 2.80 (t, J = 6.40 Hz, 2H), 2.68 (brs, 2H); MS (ESI) m/z: 233.3 (M+H + ).

To a stirring solution of N-(3-aminophenethyl)-2,2,2-trifluoroacetamide (7.83 g, 33.7 mmol) in EtOAc (80 ml) at RT was added 3N HCl/EtOAc (12.4 ml, 37.1 mmol). Solids precipitated almost immediately. The resulting suspension was cooled in ice 1 h. The solids were collected by filtration, rinsed with EtOAc and dried on the filter. There was obtained pure N-(3-aminophenethyI)-2,2,2-trifluoroacetamide hydrochloride free of less polar impurities as a pale tan solid (7.94 g, 88% yield). 1 H NMR 300 MHz, (DMSO-d 6 ): δ 10.3 (brs, 3H), 9.61 (t, J = 5.32 Hz, 1H), 7.43-7.39 (m, 1H), 7.25-7.23 (m, 2H), 3.42 (q, J = 6.6 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H).

N-(3-aminophenethyl)-2,2,2-trifluoroacetamide hydrochloride (0.27 g, 1.0 mmol) was suspended in 6M HC1 ( 2.0 mL) and cooled thoroughly in an ice bath. This was rapidly stirred while a solution of NaNO 2 (73 mg) in H 2 O (1.0 mL) was added slowly. The mixture was stirred at 0-5 °C for 45 min and was then treated with SnCl 2 -2H 2 O (1.3 g, 5.8 mmol) in 6N HC1 (4.0 mL). The resulting suspension was stirred at 0-5 °C for 3h and then carefully quenched with 3N NaOH (15 mL) to pH 7-8. The mixture was diluted with Et 2 O, filtered through Celite ® and the filter cake was washed with H 2 O and Et 2 O. The layers of the biphasic filtrate were separated and the aqueous extracted with Et 2 O (2x). The combined

organics extracts were washed with brine (Ix), dried (Na 2 SO 4 ), filtered and evaporated to provided N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide as a pale yellow oil (0.18 g, 72% yield), which was used without further purification. MS (ESI) m/z: 248.0 (M+H + ).

To a stirring solution of N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide (0.18 g, 0.73 mmol) in absolute EtOH (5 ml) at RT was added pivaloylacetonitrile (0.11 g, 0.87 mmol) and saturated HC1/EtOH (3 drops from a pipet). The resulting solution was stirred at 75-80 °C overnight, then cooled to RT and concentrated. The residue was dissolved in Et 2 O and washed with saturated. NaHCO 3 . The aqueous was extracted with Et 2 O (Ix). The combined organics were washed with brine (Ix), dried (MgSO 4 ), filtered, concentrated and purified via flash chromatography to provide N-[3-(5-amino-3-t-butyl-1H-pyrazol-1- yl)phenethyl]-2,2,2-trifluoroacetamide as an orange glass (0.18 g, 70% yield). 1 H NMR (300 MHz, CDC1 3 ): δ 7.47-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.14-7.12 (m, 1H), 5.51 (s, 1H), 3.67 (q, J = 6.6 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 355.2 (M+H + ).

Using general method A, Example A17 (0.180 g, 0.51 mmol) and 2,3-dichlorophenyl isocyanate (82 mg, 0.53 mmol) were combined to yield 1-(3-t-butyl-1-(3-(2-(2,2,2-trifluoro- acetamido)ethyl)phenyl)-lH-pyrazol-5-yl)-3-(2,3-dichloro- phenyl)urea as an orange foam (0.134 g, 52% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (brs, 1H), 7.39-7.20 (m, 8H), 7.03 (brs, 1H), 6.57 (s, 1H), 3.77 (m, 2H), 2.88 (m, 2H), 1.35 (s, 9H); MS (ESI) m/z: 508.3 (M+H + ).

To a stirring solution of 1-(3-t-butyl-1-(3-(2-(2,2,2-trifluoro-acetamido)ethyl)phenyl )- lH-pyrazol-5-yl)-3-(2,3-dichloro-phenyl)urea (0.134 g, 0.264 mmol) in MeOH (10 mL) and H 2 O (0.6 mL) at RT was added K 2 CO 3 (0.182 g, 1.32 mmol). The resulting suspension was stirred at 60-65 °C for 2h, then cooled to RT and the volatiles evaporated. The residue was carefully dissolved in IN HCl to pH 1-2 and extracted with Et 2 O (2x). The aqueous was then basified (pH 13-14) with 3M NaOH and extracted with CH 2 C1 2 (4x). The combined CH 2 Cl 2 extracts were washed with brine (Ix), dried (Na 2 SO 4 ), filtered, and concentrated to provided l-{ l-[3-(2-aminoethyl)phenyl]-3-t-butyl-lH-pyrazol-5-yl }-3-(2,3-dichlorophenyl)urea as a foam (25.6 mg, 97% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.17 (dd, J = 1.2, and 8.0 Hz, 1H), 7.31-7.28 (m, 4H), 7.14-7.06 (m, 4H), 6.45 (s, 1H), 3.48 (brt, / = 4.4 Hz, 2H), 3.46-3.39 (m, 2H), 2.86 (t, J = 7.0 Hz, 2H), 1.3 (s, 9H); MS (ESI) m/z: 446.3 (M+H + ).

To a stirring solution of Example 39 (54.2 mg, 0.121 mmol) in MeOH (1.2 rtiL) at RT was added aq. formaldehyde (37 wt%, 0.036 mL, 0.49 mmol) and cone, formic acid (0.037 mL, 0.97 mmol). The reaction was stirred at 60-65 °C overnight, then cooled to RT, diluted with IN HCl and filtered. The filtrate was made basic (pH 13) with 3N NaOH and extracted with CH 2 Cl 2

(2x). The combined organics were washed with brine (Ix), dried (Na 2 SO 4 ), filtered, concentrated and purified by column chromatography, to yield 1-(3-t-butyl-1-{3-[2- (dimethylarnino)ethyl]phenyl }-lH-pyrazol-5-yl)-3-(2,3-di- chlorophenyl)urea (17.4 mg, 30% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.37-8.34 (m, 1H), 7.51-7.45 (m, 3H), 7.21-7.10 (m, 5H), 6.57 (s, 1H), 3.30-3.27 (m, 2H), 3.23-3.19 (m, 2H), 2.71 (s, 6H), 1.39 (s, 9H); MS (EI) 474.2 (M+H + ).

Using general method C, Example 5 (0.17 g, 0.39 mmol) was reduced to yield 1-(l-[3-(aminomethyl)phenyl]-3-t-butyl-lH- pyrazol-5-yl)-3-(3-bromophenyl)urea as the HCl salt (0.131 g, 70% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.93 (s, 1H), 8.83 (s, 1H), 8.36 (brs, 3H), 7.82-7.81 (m, 1H), 7.71 (brs, 1H), 7.57-

7.55 (m, 2H), 7.48-7.46 (m, 1H), 7.31-7.29 (m, 1H), 7.24-7.20 (m, 1H), 7.15-7.13 (m, 1H), 6.42 (s, 1H), 4.16-4.12 (m, 2H), 1.29 (s, 9H); MS (ESI) m/z: 442.3 (M+H + ), 444.2 (M+2H + ).

Using general method C, Example 9 (50 mg, 0.12 mmol) was reduced to afford l-{ l-[3-(aminomethyl)phenyl]-3-t-butyl-7H- pyrazol-5-yl }-3-(2,3-dichloro- phenyl)urea as a white solid (20.6 mg, 41% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.55 (s, 1H), 8.47 (br s, 3H), 7.97-7.96 (m, 1H), 7.70-7.32 (m, 4H), 7.15-7.11

(m, 3H), 6.81 (s, 1H), 4.10 (br s, 2H), 1.38 (s, 9H); MS (ESI) m/z: 432.2 (M+H + ), 434.2

(M+2+H + ).

To a stirring solution of Example 9 (80 mg, 0.19 mmol) and hydroxylamine hydrochloride (26 mg, 0.37 mmol,) in absolute EtOH (2.0 mL) was added triethylamine (0.052 mL, 0.37 mmol). The resulting mixture was stirred at 80 °C for 5h. The reaction was cooled to RT and the volatiles evaporated. The residue was partitioned between EtOAc and H 2 O and the aqueous was extracted with EtOAc (3x). The combined organic extracts were washed with saturated NaHCO 3 (2x), brine (Ix), dried (Na 2 SO 4 ), filtered and concentrated to provide l-{ l-[3-(N-hydroxycarbamimidoyl)phenyl]-3- t-butyl-7H-pyrazol-5-yl }-3-(2,3-dichlorophenyl)-urea (92 mg), which was used without further purification. MS (ESI) m/z: 461.2 (M+η + ), 463.3 (M+2H + ).

To a stirring suspension of Example 43 ( 92 mg, 0.20 mmol) and 10% Pd/C (50% H 2 O wet, 21 mg, 0.0100 mmol) in absolute EtOH (2 mL) was added Ac 2 O (0.019 ml, 0.20 mmol) and 99% formic acid (0.038 mL, 1.00 mmol). The resulting mixture was stirred at 40-45 °C for 18h. The reaction was cooled to RT, filtered through Celite^, concentrated to dryness and the residue dissolved in EtOAc and H 2 O. The layers were separated and the aqueous extracted with EtOAc (2x). The combined organic extracts were washed with saturated NaHCO 3 (Ix), brine (Ix), then dried (Na 2 SO 4 ), filtered, concentrated and purified via reverse phase chromatography to provide of l-[3-t- butyl-1-(3-carbamimidoylphenyl)-lH-pyrazol- 5-yl]-3-(2,3-dichlorophenyl)urea as the TFA salt (27.2 mg, 24% yield). 1 H NMR (400 MHz, DMSO-^ 6 ): 59.40 (s, 2H), 9.32 (s, 1H), 9.04 (s, 2H), 8.74 (s, 1H), 8.03-8.00 (m, 2H), 7.94-7.92 (m, 1H), 7.81-7.78 (m, 2H), 7.32-7.31 (m, 2H), 6.45 (br s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 445.2 (M+H + ), 447.3 (M+2H + ).

Using general method M, (4-aminophenyl)acetic acid (20 g, 0.13 mol) was converted to ethyl 2-(4-(3-t-butyl-5-amino-lH-pyrazol-1-yl)phenyl)acetate (22.5 g, 57.5% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 7.55-7.45 (m, 4H), 5.61 (s, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.77 (s, 2H), 1.27 (s, 9H), 1.19 (t, / = 6.9 Hz, 3H); MS (ESI) m/z: 302 (M+lT).

Using general method A, Example A18 (5 g, 14.8 mmol) and 1,2- dichIoro-3-isocyanatobenzene (2.8 g, 15.0 mmol) were combined to afford 2-(4-{3-t-butyl-5-[3-(2,3- dichlorophenyOureidoJ-lH-pyrazol-1-ylJphenyOacetic acid (2.1 g, 29% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.24 (s, 1H), 8.77 (s, 1H), 8.05 (m, 1H), 7.47-7.38 (m, 4H), 7.30-7.28 (m, 2H), 6.36 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.72 (s, 2H), 1.25 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 489 (M+H + ).

Using general method C, 2-(4-{3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-lH- pyrazol-1-yl}phenyl)acetic acid (100 mg, 0.21 mmol) was reduced to afford l-{3-t-butyl-1- [4-(2-hydroxyethyl)-phenyl]-lH-pyrazol-5-yl }-3-(2,3-dichlorophenyl)urea (60 mg, 64% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.21 (s, 1H), 8.77 (s, 1H), 8.06 (m, 1H), 7.41-7.34 (m, 4H), 7.30-7.28 (m, 2H), 6.36 (s, 1H), 4.66 (t, / = 5.1 Hz, 1H), 3.63 (q, J = 7.2 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 447 (M+H + ).

To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH 2 Cl 2 (200 mL) was added dropwise (triphenyl-phosphanylidene)acetic acid ethyl ester (34.8 g, 0.1 mol) in CH 2 C1 2 (100 mL) at 0 °C. After the addition was complete, the resulting mixture was stirred for Ih. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3- (3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 % yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 8.23 (dd, J = 0.8, and 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 16.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 6.56 (d, / = 16.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.36 (t, / = 6.8 Hz, 3H).

A mixture of 3-(3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in MeOH (200 mL) was stirred under 40 psi of H 2 at RT for 2h, then filtered through Celite ® . After removal the solvent, 14 g of 3-(3-aminophenyl)propionic acid ethyl ester was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 7.11 (t, J = 5.6 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13 (q, J =7.2 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H); MS (ESI): m/z: 194 (M+H + ).

To a solution of 3-(3-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in cone. HCl (200 mL) was added aqueous (10 mL) NaNO 2 (5 g, 72.5 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl 2 -2H 2 O (33 g, 145 mmol) in cone. HCl (150 mL) was then added at 0 °C. The reaction solution was stirred for an additional 2h

at RT. The precipitate was filtered and washed with EtOH and ether to yield 3-(3- hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H + ).

A mixture of 3-(3-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in EtOH (150 mL) was heated at reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(3-(3-t-butyl-5-amino-lH-pyrazol-1- yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1 H NMR (300 MHz, DMSO-^ 6 ); δ 7.50-7.42 (m, 4H), 5.63 (s, 1H), 5.14 (s, 2H), 4.04 (q, J = 6.9 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.66 (t, / = 7.5 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J = 7.5 Hz, 3H); MS (ESI) m/z: 316 (M+H + ).

Using general method A, the previous compound (300 mg, 1.0 mmol) and 1,2- dichloro-3-isocyanato-benzene (187 mg, 1.0 mmol) were combined to afford 3-(3-{3-t-butyl- 5-[3-(2,3-dichlorophenyl)ureido]-lH-pyrazol-1-yl}phenyl)prop ionic acid ethyl ester (210 mg, 42 % yield), which was used without further purification. 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.20 (s, 1H), 8.76 (s, 1H), 8.05 (m, 1H), 7.47-7.26 (m, 6H), 6.38 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 1.28 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 503 (M+H + ).

Using general method E, the previous compound (100 mg, 0.199 mmol) was saponified to afford 3-(3-{3-t-Butyl-5-[3-(2,3-dichloπ> phenyl)ureido]-lH-pyrazol-1-yl}- phenyl)propionic acid (60 mg, 63% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.03 (m, 1H), 7.44-7.21 (m, 6H), 6.36 (s, 1H), 2.88 (t, / = 7.5 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 475 (M+H + ).

To a solution of 4-nitrobenzaldehyde (15.1 g, 0.1 mol) in CH 2 Cl 2 (200 mL) was added dropwise (triphenylphosphanylidene)acetic acid ethyl ester (34.8 g, 0.1 mol) in CH 2 Cl 2 (100 mL) at 0 °C. After the addition was completed, the resulting mixture was stirred for 2h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(4-nitrophenyl)acrylic acid ethyl ester (16.5

74.6% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.25 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 16.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 16.0 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.34 (t, / =7.2 Hz, 3H).

A mixture of 3-(4-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C

(1.65 g) in MeOH (200 mL) was stirred under 40 psi of H 2 at RT for 2h. After filtration over Celite ® and removal of the solvent, 14 g of 3-(4-aminophenyl)propionic acid ethyl ester was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 6.98 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.12 (q, J =7.2 Hz, 2H), 2.84 (t, J = 8.0 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI): m/z: 194 (M+H + ).

To a solution of 3-(4-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in cone. HCl (200 mL) was added aqueous (10 mL) NaNO 2 (5 g, 72.5 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl 2 2H 2 O (33 g, 145 mmol) in cone. HCl (150 mL) was then added at 0 °C. The reaction solution was stirred for an additional 2h at RT The precipitate was filtered and washed with EtOH and Et 2 O to yield 3-(4- hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H + ).

A mixture of 3-(4-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in EtOH (150 mL) was heated at reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(4-(3-t-butyl-5-amino-lH-pyrazol-1- yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ); δ 7.44 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 5.34 (s, 1H), 5.11 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 316 (M+H + ).

Using general method A, Example A19 (300 mg, 1.0 mmol) and l,2-dichloro-3-isocyanato-benzene (187 mg, 1.0 mmol) were combined to afford 3-(4-{3-t-butyl-5-[3-(2,3-dichloro- phenyl)ureido]-lH-pyrazol-1-yl }phenyl)propionic acid ethyl ester (250 mg, 50% yield), which was used without further purification. MS (ESI) m/z: 503 (M+η*).

Using general method E, Example 47 (100 mg, 0.199 mmol) was saponified to afford of 3-(3-{ 3-t-butyl-5-[3-(2,3-dichloro- phenyl)ureido]pyrazol-1-yl }-phenyl)-propionic acid (60 mg, 64% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.29 (s, 1H), 8.80 (s, 1H), 8.04 (m, 1H), 7.44-7.33 (m, 4H), 7.29-7.27 (m, 2H), 6.36 (s, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 1.25 (s,

9H); MS (ESI) m/z: 475 (M+H + ).

POCl 3 (26 g, 0.18 mol) was added over 1 h to anhydrous DMF (66 g) while keeping the temperature at 15-20 °C. After the solution had stirred at RT for Ih, 3-nitrophenyl acetic acid (10 g, 0.06 mol) was added. The solution was heated to 85 °C and stirred for 18h. The solution was cooled to RT and poured onto 160 g of ice with vigorous stirring. A solution of sodium perchlorate (H g, 0.09 mol) in H 2 O was added, and a crystalline precipitate formed over 10 min. The precipitate was filtered, washed with H 2 O, and dried in vacuo at 50 °C to yield a tan power (E)-N-[3-(dimethylamino)-2-(3-nitrophenyl)-2-propenylidene]- N-methylmethanaminium monoperchlorate (12 g, 58% yield). 1 H NMR (300 MHz, DMSO-d 6 ): 8.23 (d, / = 7.5 Hz, 1H), 8.12 (s, 1H), 7.75-7.64 (m, 4H), 3.22 (s, 3H), 2.39 (s, 6H); MS (ESI) m/z: 349 (M+H + ).

A solution of the material from the previous reaction (12 g, 32 mmol) dissolved in DMF (600 mL) were added t-butyl cyanoacetate (5 mL, 35 mmol) and Et 3 N (4.9 mL, 35 mmol). The solution was stirred at RT for 18h and then partitioned between H 2 O and. The aqueous layer was extracted with CH2CI2 (3x500 mL), the combined organic layers were dried (MgSO 4 ), concentrated and the yellow residue was purified by column to yield 2- cyano-5-dimethylamino-4-(3-nitrophenyl)penta-2,4-dienoic acid t-butyl ester (9 g, 82% yield). 1 H NMR (300 MHz, DMSO-d 6 ): 8.9-8.23 (m, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.50- 7.55 (m, 2H), 7.05 (s, 1H), 2.81 (brs, 6H), 1.44 (s, 9H); MS (ESI) m/z: 344 (M+H + ).

To a solution of the material from the previous reaction (9 g, 26 mmol) in acetic acid (150 mL) was added gaseous HC1 at a moderate rate for 15 min at RT. The solution was stirred at RT for 18h and then partitioned between H 2 O and CH 2 C1 2 . The aqueous layer was extracted with CH 2 Cl 2 (3x250 mL), the combined organic layers were dried (MgSO 4 ), concentrated and the yellow residue was purified by column to yield 2-chloro-5-(3- nitrophenyl)pyridine (3.5 g, 55% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.65 (s, 1H), 8.42 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.92-7.86 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H).

To a solution of the material from the previous reaction (5 g, 21 mmol) in MeOH (50 mL) was added Raney-Ni and the mixture stirred at RT under a atmosphere of H 2 for 5h. After the Raney-Ni was filtered, the filtrate was concentrated to yield 3-(6-chloro-pyridin-3- yl)phenylamine (3.8 g, 89% yield). 1 H NMR (300 MHz, DMSO-d 6 ): □ 8.55 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.4 Hz, and 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.10 (t, / = 7.8 Hz, 1H),

6.82-6.76 (m, 2H), 6.60 (d, J = 7.8 Hz, 1H), 6.22 (d, 2H); MS (ESI) m/z: 205 (M+H + ).

To a solution of the material from the previous reaction (3.5 g, 17 mmol) in cone. HCl (6 mL) was added an aqueous solution (2 mL) of NaNO 2 (1.21 g, 17 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl 2 .2H 2 O (8.0 g, 36 mmol) in cone. HCl (7.5 mL) was then added at 0 °C. The reaction solution was stirred for an additional 2h at RT. The precipitate was filtered and washed with EtOH and ether to give [3-(6-chloropyridin-3- yl)phenyl]hydrazine hydrochloride as a white solid, which was used for the next reaction without further purification. MS (ESI) m/z: 220 (M+H + ).

A mixture of the material from the previous reaction and 4,4-dimethyl-3-oxo- pentanenitrile (2.18 g, 35 mol) in EtOH (25 mL) was heated at reflux overnight. The reaction solution was concentrated and the residue purified by column chromatography to give 5-t- butyl-2-[3-(6-chloropyridin-3-yl)-phenyl]-2H-pyrrazol-3-ylam ine (3.7 g, 60% yield, two steps). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.71 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 6.3 Hz, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.78 (t, J = 6.3 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 6.3 Hz, 1H), 5.80 (s, 1H), 1.39 (s, 9H); MS (ESI) m/z: 327 (M+H + ).

To a solution of 3-bromoaniline (17 g, 0.1 mol) in cone. HCl (200 mL) was added an aqueous solution (20 mL) of NaNO 2 (7 g, 0.1 mol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnC1 2 - 2H 2 O (45 g, 0.2 mmol) in cone. HCl (500 mL) was then added at 0 °C. The reaction solution was stirred for 2h at RT. The precipitate was filtered and washed with EtOH and ether to yield (3- bromophenyl)hydrazine hydrochloride as a white solid, which was used for the next reaction without further purification

A mixture of (3-bromophenyl)hydrazine hydrochloride (22.2 g, 0.1 mol) and 4,4- dimethyl-3-oxo-pentanenitrile (18.7 g, 0.15 mol) in EtOH (250 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified via column chromatography to yield 2-(3-bromophenyl)-5-t-butyl-2H-pyrazol-3-ylamine as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.85 (s, 1H), 7.68 (d, J =7.6 Hz, 1H), 7.62 (d, J =7.2 Hz, 1H), 7.50 (t, J =8.0 Hz, 1H), 5.62 (s, 1H), 1.27 (s, 9H).

Using general method D, the material from the previous reaction (0.833 g, 2.51 mmol) and 2,3-dichloroaniline (0.377 g, 2.33 mmol) were combined to yield 1-(1-(3- bromophenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichloropheny l)urea (0.389 g, 42% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.26 (s, 1 H), 8.77 (s, 1 H), 8.01 (m, 1 H), 7.74 (t, J = 2.0

Hz, 1 H), 7.62-7.56 (m, 2 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.30 (m, 2 H), 6.41 (s, 1 H), 1.28 (s, 9 H); MS (ESI) m/z: 483.0 (M+H + ).

Example 49 (156 mg, 0.32 mmol), t-butyl 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaboran-2-yl)- 1 -pyrazole-carboxylate (146 mg, 0.50 mmol) and Cs 2 CO 3 (316 mg, 0.97 mmol) were combined in DMF (8.0 mL) and H 2 O (2.5 mL). The reaction mixture was purged of air under vacuum and the head-space was back-filled with N 2 . Palladium tetrakis(triphenylphosphine) (40 mg, 0.035 mmol) was added and the reaction mixture was heated to 80 °C under N 2 . After 5.5 h, the reaction mixture was cooled to RT and partitioned between H 2 O and EtOAc. The organic layer was washed with H 2 O and brine, dried (Na 2 SO 4 ), concentrated in vacuo and purified via column chromatography to yield 1-(1-(3-(1H-pyrazol-4-yl)phenyl)-3-t-butyl-1H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (39 mg, 26% yield) as a film. Further purification by reverse phase chromatography provided a white powder. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.26 (s, 1H), 8.80 (s, 1H), 8.29 (brs, 1H), 8.06 (m, 1H), 7.99 (brs, 1H), 7.73 (t, J = 1.7 Hz, 1H), dt (J = 8.4, 1.7 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.33-7.28 (m, 3H), 6.42 (s, 1H), 1.29 (s, 9 H); MS (ESI) m/z: 469.0 (M+H + ).

A solution of 1-(3-bromophenyl)-3-t-butyl-1H-pyrazol- 5-amine hydrochloride (0.253 g, 0.77 mmol, available from Example 54), t-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole-1-carboxylate (0.28 g, 0.95 mmol, commercially available) and Cs 2 CO 3 (1.0 g, 3.1 mmol) in DMF (5 mL) and H 2 O (2 mL) was placed under Ar for 15 min. Palladium tetrakis(triphenylphosphine) was added and the reaction mixture was heated at 80 °C overnight. The reaction mixture was poured into H 2 O (20 mL) and extracted with EtOAc (2x30 mL). The extracts were washed with H 2 O (10 mL) and brine (10 mL), dried (Na 2 SO 4 ) concentrated and purified via column chromatography to yield 1-(3-(lH-pyrazol-4- yl)phenyl)-3-t-butyl-lH-pyrazol-5-amine (163 mg, 76% yield). MS (ESI) m/z: 282.3 (M+η + ). 1-(3-(lH-pyrazol-4-yl)phenyl)-3-t-butyl-lH-pyrazol-5-amine (160 mg, 0.57 mmol) in EtOAc (3 mL) was cooled to 0 °C and treated with IM NaOH (0.85 mL, 0.85 mmol) and

isopropenyl chloroformate (0.080 mL, 0.74 mmol). The reaction was allowed to warm to RT overnight. The organic layer was washed with saturated NaHCO 3 , brine, dried (Na 2 SO 4 ) and was concentrated to a film, which was dissolved in Et 2 O (5 mL) and the solution was lowed to stand overnight. The resultant crystals were collected, washed with Et 2 O and dried in vacuo to provide prop-1-en-2-yl 4-(3-(3-t-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol- l-yl)phenyl)-1H-pyrazole-1-carboxylate (193 mg, 75% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.73 (brs, 1H), 8.96 (d, J = 0.7 Hz, 1H), 8.46 (d, J = 0.7 Hz, 1H), 7.87 (t, J = 1.7 Hz, 1H), 7.81 (dt, J = 8.2, 1.3 Hz, 1H), 7.54 (t, / = 7.9 Hz, 1H), 7.41 (brd, / = 7.9 Hz, 1H), 6.34 (s, 1H), 5.02 (s, 2H), 4.66 (brs, 1H), 4.57 (brs, 1H), 2.06 (s, 3H), 1.76 (brs, 3H), 1.30 (s, 9H). MS (ESI) m/z: 450.2 (M+H + ).

Using the procedure for Example 151, prop-1-en-2-yl 4-(3-(3-t-butyl-5-((prop-1-en-2- yloxy)carbonyl)-lH-pyrazol-1-yl)phenyl)-lH-pyrazole-1-carbox ylate (63 mg, 0.14 mmol) and 4-(4-aminophenyl)isoindolin-1-one (31 mg, 0.14 mmol) were combined to yield prop-1- en-2-yl 4-(3-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido) -lH-pyrazol-1- yl)phenyl)-lH-pyrazole-1-carboxylate (75 mg, 87% yield). MS (ESI) m/z: 616.2 (M+η + ).

Using general method E, prop-1-en-2-yl 4-(3-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4- yl)phenyl)ureido)-lH-pyrazol-1-yl)phenyl)-lH-pyrazole-1-carb oxylate (75 mg, 0.12 mmol) was saponified to yield 1-(1-(3-(lH-pyrazol-4-yl)phenyl)-3-t-butyl-lH-pyrazol-5-yl)- 3-(4-(l- oxoisoindolin-4-yl)phenyl)urea as a white powder (9.5 mg, 15% yield). 1 H NMR (400 MHz, DMSO-Uf 6 ): δ 9.24 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.30 (brs, 1H), 8.00 (brs, 1H), 7.74 (brs, 1H), 7.69-7.62 (m, 3H), 7.59-7.48 (m, 7H), 7.33 (brd, J = 7.9 Hz, 1H), 6.43 (s, 1H), 4.50 (s, 2H), 1.30 (s, 9H). MS (ESI) m/z: 532.3 (M+H + ).

To a solution of quinolin-6-ylamine (5 g, 35 mmol) in cone. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO 2 (2.42 g, 35 mmol) at 0 °C. The resulting mixture was stirred for Ih and then treated dropwise with a solution of SnCl 2 2H 2 O (15.8 g, 70 mmol) in cone. HCl (15 mL) at 0 °C. The reaction mixture was stirred for 2h at RT. The precipitate was collected and washed with EtOH and Et 2 O to yield 1-

(quinolin-6-yl)hydrazine hydrochloride as a yellow powder (4.3 g, 77% yield), which was used for the next reaction without further purification.

A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4- dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and cone. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column

chromatography to yield 3-t-butyl-1-(quinolin-6-yl)-lH-pyrazol-5-amine (2.8 g, 51% yield). 1 H NMR (300 MHz, DMSCM 5 ): δ 8.84 (d, / = 4.2 Hz, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52(m, 1H), 5.46 (s, 1H), 5.40 (brs, 2H), 1.29 (s, 9H).

General Experimental for Examples 52-55:

A solution of Example A21 and the appropriate isocyanate or aniline was converted to the target compound using the general method indicated.

To a solution of quinolin-3-ylamine (5 g, 35 mmol) in cone. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO 2 (2.42 g, 35 mmol) at 0 °C. The resulting mixture was stirred for Ih, and then treated with a solution of SnCl 2 -2H 2 O (15.8 g, 70 mmol) in cone. HCl (15 mL). The reaction solution was stirred for an additional 2h at RT. The precipitate was filtered and washed with EtOH and ether to yield 1- (quinolin-3-yl)hydrazine hydrochloride (4.5 g, 81% yield), which was used in the next reaction without further purification.

A mixture of 1-(quinolin-3-yl)hydrazine hydrochloride (4 g, 20.5 mmol) and 4,4- dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and cone. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-3-yl)-1H-pyrazol-5-amine (3.0 g, 55% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.16 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.72 (t, / = 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 5.72 (s, 1H), 5.45 (s, 3H), 1.23 (s, 9H).

Using general method A, Example A22 (134 mg, 0.5 mmoL) and l-chloro-4-isocyanatobenzene (90 mg, 0.6 mmoL) were combined to afford 1-(3-t-butyl-1-(quinolin-3-yl)-lH-pyrazol-5- yl)-3-(4-chlorophenyl)urea (100 mg, 48% yield). 1 H NMR (300 MHz, DMSO-J 5 ): δ 9.10 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.67 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.81

(t, J = 8.4 Hz, 1H), 7.68 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 6.45 (s, 1H), 1.30 (s, 9H).

Using general method A, Example A22 (133 mg, 0.5 mmoL) and 2,3-dichlorophenyl isocyanate (0.6 mmol) were combined to afford l-[3-t-butyl-1-(quinolin-3-yl)-lH-pyrazol-5-yl]-3-(2,3- dichlorophenyl)urea.

To a solution of 1,8-naphthalic anhydride (25 g, 0.13 mol) in cone. H 2 SO 4 (100 ITiL) was added dropwise a solution of cone. HNO 3 (7.85 g, 0.13 mol) in cone. H 2 SO 4 (25 mL) at 0 °C. After the addition was complete, the resulting mixture was allowed to warm to RT, stirred for 90 min and then poured into ice-H.0. The solid was filtered by suction, washed with H 2 O, and re-crystallized from glacial AcOH to yield 3-nitro- 1,8-naphthalic anhydride (24.5 g). 1 H NMR (300 MHz, CDCl 3 ): δ 9.11 (s, 1H), 9.06 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H).

To a solution of 3-nitro-l,8-naphthalic anhydride (21.8 g, 89.7 mmol) in H 2 O (550 mL) containing 14.4 g of NaOH was added a solution of yellow HgO (25.1 g) in a mixture of H 2 O (75 mL) and glacial AcOH (25 mL). After reflux for 4 days, the reaction mixture was cooled and filtered to afford the mercurated product, which was then refluxed in 700 mL of 5N HCl for 3h. The cream-colored precipitate was filtered, washed with cold H 2 O, dried, and recrystallized from hot glacial AcOH to yield 3-nitronaphthalene-1-carboxylic acid (12 g). 1 H NMR (300 MHz, DMSO-^): δ 13.7 (brs, 1H), 9.18 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.70 (s, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.76 (t, J = 6.9 Hz, 1H).

To a solution of 3-nitronaphthalene-1-carboxylic acid (4.34 g, 20 mmol) in EtOH (50 mL) was added SOCl 2 (3.70 mL, 30 mmol) at 0 °C. The mixture was heated at reflux for 2h and then concentrated. The residue was recrystallized from EtOH to yield ethyl 3- nitronaphthalene-1-carboxylate (4.2 g). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.16 (s, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.62 (s, 1H), 8.34 (d, 7 = 8.1 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 4.43 (q, / = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

A mixture of 3-nitronaphthalene-1-carboxylic acid ethyl ester (2.45 g, 10 mmol) and Pd/C (0.3 g) in EtOH (20 mL) was stirred overnight at RT under 35 psi of H 2 . After filtration, the filtrate was concentrated to yield ethyl 3-aminonaphthalene-1-carboxylate (2.04 g). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.63 (m, 1H), 7.93-7.97 (m, 2H), 7.84 (s, 1H), 7.54-7.57 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

To a solution of 3-aminonaphthalene-1-carboxylic acid ethyl ester (2 g, 9.3 mmol) in cone. HCl (2 mL) was added dropwise an aqueous solution of NaNO 2 (0.63 g, 9.3 mmol) at 0 °C. The resulted mixture was stirred for Ih and then treated dropwise with a solution of SnCl 2 -2H 2 O (4.2 g, 18.6 mmol) in cone. HCl (10 mL) at 0 °C. The reaction mixture was stirred for 2h at RT. precipitate was collected and washed with EtOH and Et 2 O to yield ethyl 3-hydrazinonaphthalene-1-carboxylate hydrochloride as a white solid (1.5 g), which was used for the next reaction without further purification.

A mixture of 3-hydrazinonaphthalene-1-carboxylic acid ethyl ester hydrochloride (1.5 g, 5.6 mmol) and 4,4-dimethyl-3-oxopentanenitrile (875 mg, 7.0 mmol) in EtOH (50 mL) and cone. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield ethyl 3-(5-amino-3-t-butyl-/H-pyrazol-1- yl)-1-naphthoate (1.8 g, 95% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.74 (d, J = 6.3 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.15 (d, / = 6.0 Hz, 1H), 7.76 (t, J = 5.7 Hz, 1H), 7.71 (t, J = 5.7 Hz, 1H), 5.68 (s, 1H), 4.44 (q, J = 5.4 Hz, 2H), 1.37 (t, J = 5.4 Hz, 3H), 1.30 (s, 9H).

In EtOAc (25 mL) at RT was stirred Example A23 (1.20 g, 3.21mmol), to this was added saturated NaHCO 3 (20 mL). The mixture was stirred for 20 min and then treated dropwise with Troc- Cl (0.66 mL). The mixture was stirred vigorously overnight at RT, then diluted with EtOAc (50 mL) and H 2 O (50 mL). The organic phase was separated, washed with 5% citric acid (50 mL), brine (50 mL), dried (Na 2 SO 4 ) and concentrated yield an oil. This oil was dissolved in hexane (15 mL), warmed to reflux and then cooled to precipitate. The solids were collected by filtration and dried at 65 °C under reduced pressure to yield 885 mg of ethyl 3-(3-t-butyl-5-((2,2,2- trichloroethoxy)carbonylarnino)-lH-pyrazol-1-yl)-1-naphthoat e. This material was used without further purification.

Using general method A, Example A23 (500 mg, 1.3 mmol) and l,2-dichloro-3-isocyanatobenzene (243 mg, 1.3 mmol) were combined afford 3-{3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]- pyrazol-1-yl } naphthalene- 1-carboxylic acid ethyl ester (265 mg, 39 %). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.32 (s, 1H), 8.72 (d, J = 6.3 Hz, 2H), 8.33 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.98 (t, 7 = 5.1 Hz, 1H), 7.71-7.62 (m, 2H), 7.26 (d, J = 4.8 Hz, 2H), 6.42 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 525 (M+H + ).

Using general method D, Example A24 (180 mg, 0.351 mmol), and 3,5-difluoroaniline (59 mg, 0.456 mmol) were combined to yield ethyl 3-(3-t-butyl-5-(3-(3,5-difluorophenyl)ureido)-/H- pyrazol-1-yl)-1-naphthoate (100 mg, 57% yield). MS (ESI) m/z: 493.0 (M+η + ).

Using general method C, this ester (100 mg, 0.203 mmol) was reduced to yield 1-(3-t-butyl-1-(4-

(hydroxymethyl)naphthalen-2-yl)-/H-pyrazol-5-yl)-3-(3,5-difl uorophenyl)urea (71 mg, 78% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 1.31 (s, 9H), 5.03 (s, 2H), 5.305.60 (brs, 1H), 6.44 (s, 1H), 6.76-6.81 (m, 1H), 7.11-7.12 (d, 2H), 7.59-7.61 (m, 2H), 7.72 (s, 1H), 7.95-8.10 (m, 3H), 8.65 (s, 1H), 9.38 (s, 1H). MS (ESI) m/z: 451.0 (M+H + ).

Using general method C, Example 58 (150 mg 0.29 mmol) in anhydrous THF (10 mL) was reduced to afford l-[5-t-butyl-2-(4- hydroxymethylnaphthalen-2-yl)-2H-pyrazol-3-yl]-3-(2,3-dichlo ro- phenyl)urea (98 mg, 70% yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.33 (s, 1H), 8.81 (s, 1H), 8.08 (d, J = 8.4 Hz, 3H), 7.98 (s, 1H), 7.75 (s, 1H), 7.65-7.60 (m, 2H), 7.32 (t, J = 9.9 Hz, 2H), 6.47 (s, 1H) 5.52 (t, J = 6.3 Hz, 1H), 5.05 (d, / = 6.3 Hz, 2H), 1.32 (s, 9H). MS (ESI) m/z: 483

(M+H + ).

Using general method A, Example A23 (169 mg, 0.5 mmol) and l-chloro-4-isocyanato-benzene (92 mg) were combined to afford ethyl 3-{3-t-butyl-5-[3-(4-chlorophenyl)ureido]-lH-pyrazol-1- yl}naphthoate (180 mg, 73% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.18 (s, 1H), 8.72 (d, J = 8.1 Hz, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.62-7.71 (m, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.24-7.27 (d, J = 8.7 Hz, 2H), 6.40 (s, 1H), 4.37 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H), 1.28 (s, 9H).

Using general method C, ethyl 3-{3-t-butyl-5-[3-(4-chlorophenyl)ureidoJ-lH-pyrazol- l-yl }naphthoate (lOOmg, 0.20 mmol ) was reduced to afford l-[3-t-butyl-2-(4- (hydroxymethyl)naphthalen-2-yl)-7H-pyrazol-5-yl]-3-(4-chloro phenyl)urea (50 mg, 56% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.20 (brs, 1H), 8.58 (brs, 1H), 8.06 (m, 1H), 7.97 (ms, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.57 (m, 2H), 7.38 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0

Hz, 2H), 6.39 (s, 1H), 5.45 (t, / = 5.1 Hz, 1H), 5.00 (d, J = 5.1 Hz, 2H), 1.28 (s, 9H).

Using general method D, Example A24 (120 mg, 0.234 mmol), and 2,3,4-trifluoroaniline (35 mg, 0.234 mmol) were combined to yield ethyl 3-(3-t-butyl-5-(3-(2,3,4-trifluoro phenyl)ureido)-7H- pyrazol-1-yl)-1-naphthoate as an oil.

Using general method C, ethyl 3-(3-t-butyl-5-(3-(2,3,4- trifluoro phenyl)ureido)-7H-pyrazol-1-yl)-1-naphthoate (120 mg,

0.240 mmol) was reduced to yield 1-(3-t-butyl-1-(4-(hydroxylmethyl)naphthalen-2-yl)-7H- pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea (14 mg, 13% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.30 (s, 9H), 5.02-5.05 (m, 2H), 5.49 (m, 1H), 6.45 (s, 1H), 7.20-7.30 (m, 1H), 7.60-8.10 (m, 8H), 8.92 (s, 1H), 9.06 (s, 1H). MS (ESI) m/z: 469.2 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 2,4-difIuoroaniline (30 mg, 0.234 mmol) were combined to yield ethyl 3-(3-t-butyl-5-(3-(2,4-difluorophenyl)ureido)-1H- pyrazol-1-yl)-1-naphthoate (89 mg, 21% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.25-1.31 (m, 3H), 1.29 (s, 9H), 4.39-4.47 (m, 2H), 6.45 (s, 1H), 7.02-7.03 (m, 1H), 7.28-7.29 (m, 1H),

7.68-7.73 (m, 2H), 7.99-8.01 (m, 1H), 8.13-8.15 (m, 1H), 8.24 (brs, 1H), 8.36 (s, 1H), 8.76- 8.78 (m, 1H), 8.84 (s, 1H), 8.91 (s, 1H); MS (ESI) m/z: 493.2 (M+H + ).

Using general method C, ethyl 3-(3-t-butyl-5-(3-(2,4-difluorophenyl)ureido)-7H- pyrazol-1-yl)-1-naphthoat (68 mg, 0.14 mmol) was reduced to yield 1-(3-t-butyl-1-(4- (hydroxylmethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,4-dif luorophenyl)urea (13 mg, 22% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.30 (s, 9H), 5.04-5.05 (m, 2H), 5.45 (m, 1H), 6.44 (s, 1H), 7.03-7.10 (m, 1H), 7.25-7.30 (m, 1H), 7.59-7.62 (m, 2H), 7.71 (brs, 1H), 7.95 (s, 1H), 8.02-8.10 (m, 3H), 8.88 (s, 2H); MS (ESI) m/z: 451.2 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 2,4,5-trifluoroaniline (35 mg, 0.234 mmol) were combined to yield 3-(3-t-butyl-5-(3-(2,4,5-trifluorophenyl)ureido)-lH- pyrazol-1-yl)-1-naphthoate (120 mg, 19% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.25-1.31 (m, 3H), 1.29 (s, 9H), 4.39-4.47 (m, 2H), 6.45 (s, 1H), 7.02-7.03 (m, 1H), 7.28-7.29 (m, 1H),

7.68-7.73 (m, 2H), 7.99-8.01 (m, 1H), 8.13-8.15 (m, 1H), 8.24 (brs, 1H), 8.36 (s, 1H), 8.76- 8.78 (m, 1H), 8.84 (s, 1H), 8.91 (s, 1H); MS (ESI) m/z: 493.2 (M+H + ).

Using general method C, 3-(3-t-butyl-5-(3-(2,4,5-trifluorophenyl)ureido)-lH-pyrazol- l-yl)-1-naphthoate (126 mg, 0.250 mmol) was reduced to yield 1-(3-t-butyl-1-(4- (hydroxymethyl)naphthalen-2-yl)-7H-pyrazoI-5-yl)-3-(2,4,5-tr ifluorophenyl)urea (22 mg). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.30 (s, 9H), 5.04-5.05 (m, 2H), 5.48-5.50 (m, 1H), 6.46 (s, 1H), 7.58-7.71 (m, 4H), 7.95-8.19 (m, 4H), 8.97 (s, 1H), 9.11 (s, 1H). MS (ESI) m/z: 469.2 (M+H + ).

Using general method D, Example A24 (180 mg, 0.351 mmol) and 2,3,5-trifluoroaniline (68 mg, 0.456 mmol) were combined to yield 3-(3-t-butyl-5-(3-(2,3,5-trifluorophenyl)ureido)-7H-pyrazol- l-yl)-1-naphthoate (120 mg, 32% yield).

Using general method C, 3-(3-t-butyl-5-(3-(2,3,5- trifluorophenyl)ureido)-/H-pyrazol-1-yl)-1-naphthoate (52 mg, 0.20 mmol) was reduced to yield 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-1H- pyrazol-5-yI)-3-(2,3,5-trifluorophenyl)urea (24 mg, 50%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.31 (s, 9H), 5.04-5.05 (d, 2H), 5.49 (t, 1H), 6.48 (s, 1H), 7.10-7.12 (m, 1H), 7.59-7.71 (m, 3H), 7.86-7.90 (m, 1H), 7.96 (s, 1H), 8.03-8.11 (m, 2H), 9.07 (s, 1H), 9.35 (s, 1H); MS (ESI) m/z: 469.0 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 3,4,5-trifluoroaniline (35 mg, 0.234 mmol) were combined to yield 3-(3-t-butyl-5-(3-(3,4,5-trifluorophenyl)ureido)-1H- pyrazol-1-yl)-1-naphthoate (147 mg, 123% yield). This material was used directly in the next reaction without purification. Using general method C, 3-(3-t-butyl-5-(3-(3,4,5- trifluorophenyl)ureido)-1H-pyrazol-1-yl)-1-naphthoate (52 mg, 0.203 mmol) was reduced to yield 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-7H-pyrazol -5-yl)-3-(3,4,5- trifluorophenyl)urea (46 mg, 35% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.31 (s, 9H), 5.02-5.04 (m, 2H), 5.48 (t, J= 5.5 Hz, 1H), 6.43 (s, 1H), 7.29-7.33 (m, 2H), 7.58-7.62 (m, 2H), 7.72 (s, 1H), 7.94 (s, 1H), 7.99-8.02 (m, 1H), 8.07-8.09 (m, 1H), 8.67 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z: 469.2 (M+H + ).

Using general method D, Example A24 (130 mg, 0.24 mmol) and Example A9 (35 mg, 0.234 mmol) were combined to yield 3-(3-t-butyl-5-(3-(3-(pyridin-3- yloxy)phenyl)ureido)- 1 H-pyrazol- 1 -yl)- 1 -naphthoate ( 122 mg, 91% yield). Using general method C, 3-(3-t-butyl-5-(3-(3- (pyridin-3-yloxy)phenyl)ureido)-lH-pyrazol-1-yl)-l -naphthoate (52 mg, 0.203 mmol) was reduced to yield 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-7H-pyrazol -5-yl)-3-(3- (pyridin-3-yloxy)phenyl)urea (24 mg, 21% yield). 1 H-NMR (400 MHz, DMSO-^ 5 ): δ 1.30 (s, 9H), 5.03 (s, 2H), 6.41 (s, 1H), 6.67 (d, 1H), 7.07 (d, 1H), 7.24-7.30 (m, 2H), 7.43-7.45 (m, 2H), 7.59-7.61 (m, 2H), 7.71 (s, 1H), 7.95 (s, 1H), 8.00-8.10 (m, 2H), 8.36-8.39 (m, 2H), 8.49 (s, 1H), 9.15 (s, 1H); MS (ESI) m/z: 508.3 (M+H + ).

Using general method C, Example A24 (2.0 g, 6.0 mmol) was reduced to yield [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]methanol (1.6 g, 92% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 8.05 (m, 1H), 7.88-7.96 (m, 2H), 7.91 (s, 1H), 7.48-7.52 (m, 2H), 5.40 (s, 1H), 5.38 (t, J = 5.4 Hz, 1H), 5.28 (brs, 2H), 4.97 (d, J = 5.4 Hz, 2H), 1.24 (s, 9H); MS (ESI) m/z: 296 (M+H + ).

To [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]methanol (1.6 g, 5.4 mmol) in THF (20 mL) was added SOCl 2 (3.0 g, 25 mmol). The mixture was heated at reflux for 3h and then concentrated under pressure to yield crude 3-t-butyl-1-[4-(chloromethyl)naphthalen- 2-yl]-1H-pyrazol-5-amine (1.5 g), which was used for the next reaction without further purification. MS (ESI) m/z: 314 (M+η + ).

To a solution of 3-t-butyl-1-[4-(chloromethyl)naphthalen-2-yl]-7H-pyrazol-5-a mine (1.5 g, 4.8 mmol) in DMF (8 mL) was added NaN 3 (325 mg, 5.0 mmol). The mixture was stirred at RT overnight, then poured into JCe-H 2 O and extracted with EtOAc (3x100 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford l-[4- (azidomethyl)naphthalen-2-yl]-3-t-butyl-7H-pyrazol-5-amine (1.35 g, 88% yield). 1 H NMR (300 MHz, DMSO-dβ): δ 8.06 (m, 2H), 8.04 (m, 1H), 7.85 (s, 1H), 7.54-7.57 (m, 2H), 5.41 (s, 1H), 5.35 (brs, 2H), 4.96 (s, 2H), 1.21 (s, 9H); MS (ESI) m/z: 321 (M+H + ).

Using general method A, Example A25 (400 mg, 1.25 mmol) and l-ichloro-4-isocyanatobenzene (230 mg, 1.5 mmol) were combined to afford l-[1-(4-(azidomethyl)naphthalen-2-yl)-3-t- butyl-/H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (360 mg, 61% yield). MS (ESI) m/z: 474 (M+η + ). A mixture of l-[1-(4-(azidomethyl)naphthalen-2-yl)-3-t- butyl-7H-pyrazol-5-yl]-3-(4-chlorophenyI)urea (350 mg, 0.74 mmol) and 10% Pd/C (60 mg) in MeOH (20 mL) was stirred at RT under 20 psi of H 2 for 3h and then filtered. The filtrate was concentrated to yield the crude product, which was purified by reverse phase chromatography to afford the product as the TFA salt. A solution of the TEA salt in MeCN/H 2 0 (50 mL) was basified to pH 10 with IN Na 2 CO 3 . After lyophylization, the residue was dissolved in THF and filtered. The filtrate was adjusted to pH 6 with IN HC1/MeOH (2.0 mL) and then concentrated to afford l-[1-(4-(aminomethyl)naphthalen-2-yl)- 3-t-butyl-;H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (190 mg, 57% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.80 (s, 1H), 8.88 (s, 1H), 8.49 (brs, 3H), 8.17-8.18 (m, 2H), 8.08 (d, 7 = 7.2 Hz, 1H), 7.85 (s, 1H), 7.64-7.65 (m, 2H), 7.41 (d, J = 6.6 Hz, 2H), 7.21 (d, J = 6.6 Hz, 2H), 6.44 (s, 1H), 4.61 (d, J = 5.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 448 (M+H + ).

Using the same procedure as for Example 68, Example A25 (400 mg, 1.25 mmol) and l,2-dichloro-3-isocyanatobenzene (280 mg, 1.5 mmol) were combined to afford l-[1-(4- (azidomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl]-3-( 2,3- dichlorophenyl)urea (330 mg, 52% yield). MS (ESI) m/z: 508 (M+η + ). This material (320 mg, 0.63 mmol) was reduced to afford l-[1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-lH-pyrazol-5 -yl]-3-(2,3- dichlorophenyl)urea (185 mg, 61% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.71 (s, 1H), 9.04 (s, 1H), 8.53 (brs, 3H), 8.18 (s, 2H), 8.08 (d, J = 4.8 Hz, 1H), 7.94 (t, J = 6.3 Hz, 1H), 7.89 (s, 1H), 7.62-7.68 (m, 2H), 7.25 (d, J = 4.2 Hz, 1H), 6.44 (s, 1H), 4.61 (s, 2H), 1.30 (s, 9H); MS (ESI) m/z: 482 (M+H + ).

Using general method C, Example A25 (2.0 g, 6.0 mmol) was reduced to yield 1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-7H- pyrazol-5-amine, which was immediately protected as the Boc- amine under standard conditions to yield crude t-butyl (3-(5-amino- 3-t-butyl-7H-pyrazol-1-yl)naphthalen-1-yl)methylcarbamate (3.1 g) which was used without further purification. Using general method D, this crude material (3.1 g, 7.9 mmol) was transformed to yield the desired product as a tan- colored foam (5.1 g, 114% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.11 (brd, J = 7.6 Hz, 1H), 7.92 (dd, J = 2.0, and 7.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.93 (m, 3H), 6.89 (bs, 1H), 6.50 (brs, 1H), 4.94 (brs, 1H), 4.86 (d, J = 4.0Hz, 2H), 4.84 (s, 2H), 1.49 (s, 9H), 1.40 (s, 9H); MS (EI) m/z: 569.0 (M + H + ).

Using general method D, Example A26 (l.Og, 1.75 mmol), and 2,3,5-trifluoroaniline (0.31 g, 2.11 mmol) were combined to yield t-butyl (3-(3-t-butyl-5-(3-(2,3,5-trifluorophenyl)ureido)-7H- pyrazol-1-yl)naphthalen-1-yl)methylcarbamate. LC-MS (EI) m/z: 568.2 (M+η + ). To this material, dissolved in EtOAc (5 mL) was added 3N HCl/EtOAc (5.85 mL). The solution was stirred at room temperature for 3h. The solid was filtered and dried under vacuum to obtain 1-(1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5 -yl)-3-(2,3,5- trifluorophenyl)urea HCl salt as a white solid (0.31 g, 38% yield). 1 H-NMR (400 MHz, DMSOd 6 ): δ 9.49 (brs, 1H), 9.29 (brs, 1H), 8.42 (brs, 2H), 8.22 (d, J = 7.2 Hz, 1H), 8.18 (brs, 1H), 8.12 (dd, J = 2.4, and 6.8 Hz, 1H), 7.83 (m, 2H), 7.69 (m, 2H), 7.12 (m, 1H), 6.50 (s, 1H), 4.64 (q, J = 6.0 Hz, 2H), 1.32 (s, 9H); LC-MS (EI) m/z: 468.2 (M+H + ).

Using the same procedure as for Example 70, Example A26 and 2,4,5-trifluoroaniline were combined to afford 1-(1-(4- (aminomethyl)naphthalen-2-yl)-3-t-butyl-7H-pyrazol-5-yl)-3- (2,4,5-trifluorophenyl)urea as a white solid (0.45 g, 56% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.24 (brs, 1H), 9.19 (brs, 1H), 8.42 (brs, 2H), 8.21 (d, J = 7.2 Hz, 1H), 8.18 (brs, 1H), 8.12 (m,

2H), 7.85 (brs, 1H), 7.5 -7.7 (m, 3H), 6.49 (s, 1H), 4.64 (q, J = 6.0 Hz, 2H), 1.32 (s, 9H); LC- MS (EI) m/z: 468.2 (M+H + ).

Using the same procedure as for Example 70, Example A26 and Example A9 were combined to yield 1-(1-(4- (aminomethyl)naphthalen-2-yl)-3-t-butyl- 1 H-pyrazol-5-yl)- 3-(3-(pyridin-3-yloxy)phenyl)urea (87 mg, 86% yield). 1 H- NMR (400 MHz, DMSO-^ 6 ): δ 8.45 (m, 4H), 8.19 (m, 2H), 8.11 (m, 1H), 7.88 (m, 1H), 7.68 (m, 1H), 7.0-7.6 (m,5H),

6.68 (m, 1H), 6.44 (s, 1H), 4.64 (q, J = 6.0 Hz, 2H), 1.33 (s, 9H); LC-MS (EI) m/z: 507.2 (M

+ H + ).

Using the same procedure as for Example 70, Example A26 was combined with 3-aminobenzonitrile to afford 1-(1-(4- (aminomethyl)naphthalen-2-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-( 3- cyanophenyl)urea as a white solid. (67 mg, 66 % yield). 1 H- NMR (DMSOd 6 ): δ 8.45 (m, 4H), 8.19 (m, 2H), 8.11 (m, 1H), 7.88 (m, 1H), 7.68 (m, 1H), 7.0-7.6 (m,5H), 6.68 (m, 1H), 6.44 (s, 1H), 4.64 (q, / = 6.0 Hz, 2H), 1.33 (s, 9H); LC-MS (EI) m/z: 507.2 (M+H + ).

Using the same procedure as Example 122, Example 68 (140 mg, 0.31 mmol) was transformed to yield 1 - { 3 -t-buty 1- 1 -[ 1 - (methanesulfonylureidoamidornethyl)naphthalen-3-yl]-1H- pyrazol-5-yl }-3-(4-chlorophenyl-1-yl)urea (45 mg, 26% yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.27 (brs, 1H), 8.55 (brs, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.92 (s, 1H), 7.55-7.58 (m, 3H), 7.38

(d, J = 8.4 Hz, 2H), 7.19 (t, J = 9.0 Hz, 2H), 6.39 (s, 1H), 4.69 (s, 2H), 2.95 (s, 3H), 1.28 (s,

9H); MS (ESI) m/z: 569 (M+H + ).

Using the same procedure as Example 122, Example 69 (135 mg, 0.28 mmol) was transformed to yield l-{3-t-butyl-1-[l- (methanesulfonylureidoamidomethyl)naphthalen-3-yl]-lH- pyrazol-5-yl}-3-(2,3-dichlorophenyl-1-yl)urea (50 mg, 30% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.29 (brs, 1H), 8.81 (s, 1H), 8.15 (m, 1H), 7.99-8.00 (m, 2H), 7.92 (s, 1H), 7.55-7.58 (m, 3H), 7.26 (d, J = 4.5 Hz, 2H), 6.42 (s, 1H), 4.71 (s, 2H), 2.88 (s, 3H), 1.28 (s, 9H); MS (ESI)

m/z: 603 (M+H + ).

A solution of 3-nitronaphthalene-1-carboxylic acid (10 g, 46 mmol, available from Example A23) in SOCl 2 (50 mL) was heated at reflux for 3h. After removal of the solvent, the resultant 3-nitro-napthalene-1- carbonyl chloride was used without further purification (8.4 g, 78% yield). A 2-necked round-bottomed flask, equipped with a dropping funnel and distillation apparatus was cooled in acetone-dry ice bath. A mixture of KOH (12 g, 0.2 mmol) in 20 mL of H 2 O and 60 mL of Carbitol ® (2(2-ethoxyethoxy)ethanol) was heated at 70 °C and a solution of N-methyl-N-nitroso-p-toluenesulfonamide (42.5 g, 0.2 mmol) in 300 mL of Et 2 θ was added dropwise. The ethereal diazomethane solution (250 mL, 83%) was collected at -20 °C and then used directly in the next reaction.

To a solution of 3-nitro-napthalene-1-carbonyl chloride (8.4 g, 35.7 mmol) in anhydrous THF (70 mL) was added an ethereal solution of diazomethane (250 mL) dropwise at 0 °C. The reaction mixture was stirred for 5h, and then warmed to RT overnight. Excess diazomethane was decomposed by the dropwise addition of AcOH (50 mL). The mixture was extracted with Et 2 O (3x150 ml), washed with brine and saturated NaHCO 3 aqueous solution, dried and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography to yield 2-diazo-1-(3-nitronaphthalen-1-yl)ethanone (7.0 g, 81% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.14 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.35 (d, J = 7.2 Hz , 1H), 8.35 (s, 1H), 7.84 (t, J = 7.2 Hz, 2H), 7.76 (t, / = 7.8 Hz, 2H), 6.84 (s, 1H); MS (ESI) m/z: 242 (M+H + ).

To a mixture of 2-diazo-1-(3-nitronaphthalen-1-yl)ethanone (3 g, 12.4 mmol) in EtOH (40 mL) was heated at 70 °C added AgOAc (300 mg, 1.8 mmol). The resulting mixture was stirred for 2h. After filtration, the residue was washed with THF (3x30 mL). The combined organic layers were concentrated to the crude product, which was recrystallized from EtOH to give (3-nitronaphthalen-1-yl)acetic acid ethyl ester (2.1 g, 66% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 8.92 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 4.30 (s, 2H), 4.06 (d, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 260 (M+H + ).

A mixture of (3-nitronaphthalen-1-yl)-acetic acid ethyl ester (3 g, 11.58 mmol) and 10% Pd/C (300 mg) in EtOH (100 mL) was stirred under H 2 atmosphere (45 psi) at RT overnight. The mixture was filtered over Celite ® and washed with EtOH. The filtrate was

concentrated to afford (3-aminonaphthalen-1-yl)-acetic acid ethyl ester, which was put to the next reaction without further purification. 1 H NMR (300 MHz, DMSO-d 6 ), δ 7.65 (d, J = 8.1 Hz, 1H), 7.48 (d, / = 8.1 Hz, 1H), 7.27 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 5.35 (s, 2H), 4.06 (d, J = 7.2 Hz, 2H), 3.94 (s, 2H), 1.14 (t, / = 7.2 Hz, 3H); MS (ESI) m/z: 260 (M+H + ).

To a mixture of (3-aminonaphthalen-1-yl)acetic acid ethyl ester (2.7 g, 11.8 mmol) in cone. HCl (20 mL) was added an aqueous solution of NaNCh (0.9 g, 13 mmol) dropwise at 0-5 °C. The resulting mixture was stirred at 0 °C for 30 min and then treated with a solution of SnCl 2 ^H 2 O (5.9 g, 26.2 mmol) in cone. HCl at such a rate that the reaction temperature never rose above 5 °C. After the addition was completed, the mixture was stirred for another 2h at RT. The precipitate was collected by filtration and washed with ethyl ether to afford (3- hydrazinonaphthalen-1-yl)-acetic acid ethyl ester hydrochloride as a brown solid (2.3 g, 80% yield).

A solution of [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]acetic acid ethyl ester hydrochloride (3 g, 12.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (2.3 g, 18.4 mol) in alcohol (30 mL) containing concentrated hydrochloric acid (10 mL) was heated at reflux overnight. After removed of the solvent, the precipitate was collected by suction and washed with ethyl ether to afford [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]acetic acid ethyl ester hydrochloride as a yellow solid (3.5 g, 80% yield). 1 H NMR (300 MHz, DMSO- d 6 ): δ 8.11 (s, 1H), 8.05 (m, 1H), 8.01 (m, 1H), 7.72 (s, 1H), 7.64 (m, 1H), 5.58 (s, 1H), 4.27 (s, 2H), 4.13 (d, J = 7.2 Hz, 2H), 1.31 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 352 (M+H + ).

Using general method A, Example A27 (400 mg, 1.1 mmol) and l,2-dichloro-3-isocyanatobenzene (800 mg, 4.2 mmol) were combined to yield 3-{3-t-butyl-5-[3-(2,3-dichloro- phenyl)ureido]pyrazol-1-yl }naphthalen-1-yl)-acetic acid ethyl ester as a white solid (184 mg, 12.3% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.28 (s, 1H), 8.75 (s, 1H), 8.04-7.92 (m, 4H),

7.61-7.54 (m, 3H), 7.28-7.24 (m, 2H), 6.40 (s, 1H), 4.20 (s, 1H), 4.03 (q, J = 7.2 Hz, 2H),

1.25 (s, 9H), 1.11 (t, / = 7.2 Hz, 3H); MS (ESI) m/z: 539 (M+H + ).

Using general method E, Example 76 (130 mg, 0.24 mmol) was saponified to afford 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)- ureido)-1H-pyrazol-1-yl)naphthalen-1-yl)acetic acid as a white solid (106 mg, 87 % yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.39 (s, 1H), 8.83 (s, 1H), 8.03-7.97 (m, 4H), 7.63-7.54 (m, 3H), 7.30-7.23 (m, 2H), 6.42 (s, 1H), 4.11 (s, 2H), 1.27 (s, 9H); MS

(ESI) m/z: 511 (M-I-H + ).

Example 77 (500 mg, 0.98 mmol) was dissolved in a mixed solvent of SOCl 2 (5 mL) and DMF (1 mL). The mixture was refluxed for 2h, after which dry toluene was added and the solvent was removed under vacuum. The process was repeated twice and the crude product of acid chloride was obtained, which was dissolved in dry THF immediately and cooled to -20 °C. NH 3 was bubbled through the solution for 15 min. The solution was allowed to warm to RT, and the solvent was removed under reduced pressure to yield a residue, which was purified by preparative HPLC to provide 2-(3-{3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]pyrazol-1- yl}naphthalen-1-yl)acetamide (47 mg, 10% yield). 1 H NMR (300 MHz, DMSOd 6 ): 9.41 (s, 1H), 8.81 (s, 1H), 8.09 (m, 1H), 7.99-7.93 (m, 3H), 7.60-7.56 (t, 4H), 7.27-7.24 (m, 2H), 7.00 (s, 1H), 6.40 (s, 1H), 3.84 (s, 2H), 1.26 (s, 1H); MS (ESI) m/z: 510 (M+H + ).

Using general method D, Example A27 (1.50 g, 4.40mmol) was transformed to ethyl 2-(3-(3-t-butyl-5-((2,2,2- trichloroethoxy)carbonyIamino)-1H-pyrazol- 1 -yl)naphthalen- 1 - yl)acetate (1.46 g, 63% yield). 1 H NMR (400 Mhz, DMSO-d 6 ): δ 1.31 (s, 9H), 3.62 (s, 3H), 4.23 (s, 2H), 4.84 (s, 2H), 6.35 (s, 1H), 7.57-7.63 (m, 3H), 7.93-7.98 (m, 3H), 10.09 (s, 1H); MS (ESI) m/z:

514.0 (M+H + ).

In DMSO (2 mL) was placed Example A28 (120 mg, 0.266 mmol), 4-aminobenzonitrile (31 mg, 0.266 mmol) and i-Pr 2 NEt base (34 mg, 0.266 mmol). The mixture was stirred overnight at 65 °C, cooled to RT and diluted with H 2 O (20 mL). The micxture was diluted with EtOAc (20 mL) and the organic phase separated, washed with 5% citric acid (20 mL), brine (20 mL), dried (Na 2 SO 4 ) and concentrated to yield methyl 2-(3-(3-t-butyl-5-(3-(4-cyanophenyl)- ureido)-lH-pyrazol-1-yl)naphthalen-1-yl)acetate as an oil (115 mg, 102% yield). This material was used directly in the next reaction without purification.

Using general method E, the above ester (115 mg, 0.239 mmol) was saponified to yield 2-(3-(3-t-butyl-5-(3-(4-cyanophenyl)ureido)-lH-pyrazol-1-yl) naphthalen-1-yl)-acetic acid as a foam (81mg, 73% yield). This material was used directly in the next reaction without purification.

In DMF (1 mL) was placed the above acid (81 mg, 0.20 mmol), ηOBT (31 mg, 0.2 mmol) and EDC (50 mg, 0.2 mmol). The mixture was stirred for 15 min and treated with a solution of 0.5M NH 3 in dioxane (1 mL, 0.5 mmol) and stirred overnight at RT. Additional EDC (30 mg) and 0.5M NH 3 in dioxane (1 mL, 0.5 mmol) were added and the reaction stirred until all starting material was consumed.. The reaction mixture was diluted with EtOAc (15 mL) and IN HCl (10 mL). The organic phase was separated, washed with 5% citric acid (10 mL), satd. NaHCO 3 (10 mL), brine (10 mL), dried (Na 2 SO 4 ), concentrated, and purified to yield 1-(1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-t-butyl-1H-py razol-5-yl)-3-(4- cyanophenyl)urea (17 mg, 21% yield). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.31 (s, 9H), 3.95 (s, 2H), 6.46 (s, 1H), 7.05 (s, 1H), 7.53-7.71 (m, 8H), 7.95-8.02 (m, 2H), 8.13-8.16 (m, 1H), 8.70 (s, 1H), 9.50 (s, 1H); MS (ESI) m/z: 467.3 (M+H + ).

General Experimental for Examples 80-99:

The following compounds were prepared using the appropriate aniline and the same procedures as for Example 79. For Examples 94-98, l-amino-2,3-dihydroxypropane was used in place of ammonia. For Example 99, serinol was used in place of ammonia.

To a solution of Example 58 (240 mg, 0.457 mmol) in THF (10 mL), at 0 °C was added dropwise MeMgCl (0.92 mL, 205 mg, 2.74 mmol). The mixture stirred at 0 °C for Ih and then warmed to RT for 3h. The reaction mixture was stirred at RT and treated with two additional batches of MeMgCl (2x0.6 mL, 1.8 mmol), subsequently quenched with H2O (25 mL) and diluted with EtOAc (25 mL) and 5% citric acid (10 mL). The organic phase was separated, washed with brine, dried (Na 2 SO 4 ), concentrated and purified to yield 1-(1-(4-acetylnaphthalen-2-yl)-3-t- butyl-7H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (42 mg, 18% yield) . 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.33 (s, 9H), 2.75 (s, 3H), 6.49 (s, 1H), 7.29-7.33 (m, 2H), 7.64-7.71 (m,

2H), 8.03-8.06 (m, 1H), 8.12-8.14 (m, 1H), 8.26 (s, 1H), 8.31 (s, 1H), 8.58-8.61 (m, 1H), 8.77 (s, 1H), 9.36 (s, 1H); MS (ESI) m/z: 497.0 (M+H + ).

Example 60 (310 mg, 0.641 mmol) and MnO 2 (1.12g, 12.8 mmol) were refluxed in CH 2 Cl 2 (20 mL) for 23h. The mixture was filtered hot through Celite ® and washed with CH 2 Cl 2 (2 x 20 mL). The combined organic solutions were evaporated at reduced pressure to yield 1-(3-t-butyl-1-(4-formylnaphthalen-2-yl)-7H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea a pale pink foam which was used without further purification.

To this aldehyde (150 mg, 0.312 mmol) in TηF (5 mL) at 0 °C was added dropwise MeMgCl (0.37 mL, 82 mg, 1.09 mmol). The mixture was stirred at 0 °C for Ih and then warmed to RT and stirred for 7h. The mixture was treated with an additional batch of MeMgCl (0.2 mL, 0.6 mmol), stirred overnight at RT, treated with additional MeMgCl (0.3 mL, 0.9 mmol) and then quenched with H 2 O (25 mL) and diluted with EtOAc (25 mL) and 5% citric acid (10 mL). The organic phase was separated, washed with brine dried (Na 2 SO 4 ), filtered, concentrated and purified to yield 1-(3-t-butyl-1-(4-(l-hydroxyethyl)naphthalen-2- yl)-7H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 42% yield). 1 H-NMR (300 MHz, DMSO-^ 6 ): δ 1.31 (s, 9H), 1.49 (d, J= 6.2 Hz, 3H), 5.47-5.48 (m, 1H), 5.53-5.54 (m, 1H), 6.45 (s, 1H), 7.28-7.31 (m, 2H), 7.57-7.60 (m, 2H), 7.83 (s, 1H), 7.94 (s, 1H), 8.02-8.18 (m, 3H), 8.78 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z: 499.0 (M+H + ).

To a solution of 1-indanone (30 g, 0.23 mol) in cone. H 2 SO 4 (200 mL) was added a solution of KNO 3 (34 g, 0.34 mol) in cone. H 2 SO 4 (100 mL) at 0 °C. The resulting mixture was stirred for 2h, and then poured into ice-H2O (3 L). The mixture was extracted with EtOAc (3x500 mL). The combined organic layers were washed with brine (3x500 mL), dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford 6-nitro-indan-1-one (25 g, 61% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): D 8.45 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 3.20 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H).

A mixture of the 6-nitroindan-1-one (10 g, 56 mmol) and 10% Pd/C (2.Og) in MeOH (200 mL) was stirred under 30 psi of H 2 at RT for 3h. After filtration, the filtrate was concentrated to afford 6-aminoindan-1-one (7.2 g, 87% yield). 1 H NMR (300 MHz, DMSO-

d 6 ) δ 7.17 (d, J = 8.1 Hz, 1H), 6. 87 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 5.24 (s, 2H), 2.85 (t, J = 5.4 Hz, 2H), 2.49 (t, J = 5.7 Hz, 2H).

To a mixture of 6-aminoindan-1-one (7.2 g, 11.8 mmol) in cone. HCl (20 mL) at 0 °C was added dropwise an aqueous solution of NaNO 2 (0.9 g, 13 mmol). After 30 min, a solution of SnCl 2 -2H 2 O (5.9 g, 26.2 mmol) in cone. HCl was added dropwise at such a rate that the reaction temperature never rose above 5 °C. After the addition was completed, the mixture was stirred at RT for 2h. The mixture was extracted with Et 2 O to afford 6-hydrazinoindan-1- one. MS (ESI) m/z: 199 (M+H + ).

To a solution of the 6-hydrazinoindan-1-one (2.1g, 14.3mmol) and 4,4-dimethyl- 3- oxo-pentanenitrile (2.15g, 1.2eq) in EtOH (50 mL) was added cone. HC1 (5 mL). The resulting mixture was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 6-(5-amino-3-t-butylpyrazol-1-yl)indan-1-one (l. lg, 38.5% yield), which was put to the next reaction without further purification. MS (ESI) m/z: 270 (M+H + ).

To a solution of the 6-(5-amino-3-t-butyl-pyrazol-1-yl)indan-1-one (1.5 g, 5.6 mmol) in THF (30 mL) was added a solution of l,2-dichloro-3-isocyanato-benzene (1.2 g, 6.4 mmol) in THF (5.0 mL) at 0 °C under N 2 . The resulting mixture was stirred at RT overnight then poured into H2O. The mixture was extracted with CH 2 Cl 2 (3x100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford l-[5-t-butyl-2-(3-oxo-indan-5-yl)-2H-pyrazol-3-yl]-3-(2,3- dichlorophenyl)urea as a solid (l.lg, 43% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.22 (s, 1H), 8.68 (s, 1H), 7.94 (t, J = 5.1 Hz, 1H), 7.78 (d, / = 7.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.24 (d, J = 4.8 Hz, 2H), 6.34 (s, 1H), 3.14-3.05 (m, 2H), 2.78-2.66 (m, 2H), 1.22(s, 9H); MS (ESI) m/z: 457 (M+H + ).

A solution of Example 102 (120 mg, 0.26 mmol) in MeOH (20 ml) was treated with NaBH 4 (19 mg, 0.5 mmol) and stirred at RT for 2h. After removal of the solvent, the residue was purified by preparative HPLC to yield l-[5-t-butyl-2-(3-hydroxy-indan-5-yl)- 2H-pyrazol-3-yl]-3-(2,3-dichlorophenyl)urea (67 mg, 56% yield). 1 H NMR (300 MHz, CD 3 OD): δ 8.04 (m, 1H), 7.45-7.21 (m, 4H),

6.45 (s, 1H), 5.25 (t, J = 6.3 Hz, 1H), 3.10 (m, 1H), 2.85(m, 1H), 2.50 (m,l H), 2.00 (m, 1H),

1.34 (s, 9H); MS (ESI) m/z: 459 (M+H + ).

To a mixture of Example 102 (120 mg, 0.26 mmol) and K 2 CO 3 (0.1 g, 0.7 mmol) in EtOH (20 mL) was added HONH 2 HC1 (500 mg). The resulting mixture was heated at reflux for 3h, then concentrated and the residue was purified by reverse phase chromatography to yield l-[5-t-butyl-2-(3-hydroxyimino- indan- 5-yl)-2H-pyrazol-3-yl]-3-(2,3-dichlorophenyl)urea (75 mg, 61% yield). 1 H NMR (300 MHz, CD 3 OD): δ 8.04 (d, J = 5.4 Hz, 1H), 7.73 (s, 1H), 7.52-7.43 (m, 2H), 7.22-7.20 (m, 2H), 6.48 (s, 1H), 3.20-3.12 (m, 2H), 2.97 (m, 2H), 1.33 (s, 9H); MS (ESI) m/z: 473 (M+H + ).

A mixture of Example 104 (45 mg, 0.09 mmol) and Raney ® Ni (0.1 g) in EtOH (20 mL) was stirred under 30 psi of H 2 atmosphere for 3h. After filtration and removal of the solvent, the residue was purified by reverse phase chromatography to give 1- [2-(3-amino-indan-5-yl)-5-t-butyl-2H-pyrazol-3-yl]-3-(2,3- dichlorophenyl)urea (20 mg, 48% yield). 1 H NMR (300 MHz, CD 3 OD): δ 7.98 (t, / = 5.4 Hz, 1H), 7.62 (s, 1H), 7.50 (s, 2H), 7.22 (d, J = 4.5 Hz, 2H), 6.42 (s, 1H), 3.20 (m, 1H), 3.10-3.02 (m, 2H), 2.20-2.12 (m, 2H), 1.30 (s, 9H); MS (ESI) m/z: 458 (M+H + ).

To a solution of 5-nitroindoline (5.00 g, 30.5 mmol) in CH 2 Cl 2 (100 mL) at RT was added Et3N (4.25 mL, 3.08 g, 30.5 mmol) followed by the careful addition of TFAA (4.23 mL, 6.40 g, 30.5 mmol). The resulting solution was stirred at RT for Ih, followed by the addition of more Et 3 N (4.25 mL, 3.08 g, 30.5 mmol) and TFAA (4.23 mL, 6.40 g, 30.5 mmol). After 2h of stirring at RT, H 2 O (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3 x 100 mL). The combined organics were dried (MgSO 4 ), filtered, and concentrated and dried under vacuum to give 8.9 g (crude yield > 100%) of 2,2,2-trifluoro-1- (5-nitroindolin-1-yl)ethanone as a yellow-brown solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.33

(d, J = 8.8 Hz, 1H), 8.20 (dd, J = 8.4, and 2.0 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 4.42 (t, J = 8.4 Hz, 2H), 3.38 (t, J = 8.6 Hz, 2H); MS (ESI) m/z: 261.0 (M+H + ).

To a suspension of 2,2,2-trifluoro-1-(5-nitroindolin-1-yl)ethanone (7.92 g, 30.4 mmol) in MeOH (100 mL) was added 10% Pd/C (0.648 g, 0.609 mmol) and the slurry was stirred

under H 2 (1 atm) overnight. The mixture was filtered through a pad of Celite ® and the filtrate was concentrated and dried under vacuum to give 7.7 g (crude yield > 100%) of 1-(5- aminoindolin-1-yl)-2,2,2-trifluoroethanone as a yellow-brown solid. 1 HNMR (400 MHz, CDCl 3 ): δ 8.00 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.23 (t, J = 8.0 Hz,

2H), 3.69 (brs, 2H), 3.16 (t, J = 8.2 Hz, 2H); MS (ESI) m/z: 231.0 (M+H + ).

To an ice-cold solution of 1-(5-aminoindolin-1-yl)-2,2,2-trifluoroethanone (7.00 g, 30.4 mmol) in 6N HCl (50 mL) was dropwise added a solution of NaNO 2 (2.10 g, 30.4 mmol) in H 2 O (5 mL). The resulting slurry was stirred at 0 °C for 30 min. A solution of SnC12-2H 2 O (13.7 g, 60.8 mmol) in cone. HC1 (60 mL) was added dropwise and after the addition was complete the resulting slurry was stirred at RT for 2h. The mixture was filtered and the resulting solid was collected. The solid was redissolved in EtOH (200 mL), pivaloyl acetonitrile was added (4.57 g, 36.5 mmol) and the solution was heated at reflux temperature overnight. Water (100 mL) was added and the mixture was extracted with CH 2 C1 2 (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 1-(5-(5- amino-3-t-butyl-7H-pyrazol-1-yl)indolin-1-yl)-2,2,2-trifluor oethanone (492 mg, 4% yield). 1 H NMR (400 MHz, CD 3 OD): δ 8.39 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J = 8.8, and 2.0 Hz, 1H), 4.44 (t, J = 8.2 Hz, 2H), 3.40 (t, J = 8.6 Hz, 2H), 1.39 (s, 9H), pyrazolamine protons not visible; MS (ESI) m/z: 353.0 (M+H + ).

Using general method A, Example A29 (0.200 g, 0.514 mmol)and 2,3-dichlorophenyl isocyanate (0.145 g, 0.772 mmol) were combined and deprotected according to general method G to yield of 1 -(3-t-butyl- 1 -(indolin-5-yl)-2H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (229 mg, 93% yield) as a white solid. 1 H

NMR (400 MHz, CD 3 OD): δ 8.04 (t, J = 4.8 Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J = 8.4, and 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 4.8 Hz, 1H), 7.26 (d, / = 4.8 Hz, 1H), 6.67 (s, 1H), 3.91 (t, J = 7.8 Hz, 2H), 3.39 (t, / = 7.8 Hz, 2H), 1.39 (s, 9H), amine and urea protons not visible; MS (ESI) m/z: 444.0 (M+H + ).

To a solution of Example 106 (0.100 g, 0.208 mmol) in CH 2 Cl 2 (5 mL) was added pyridine (0.049 g, 0.624 mmol) and AcCl (0.033 g, 0.42 mmol) and the resulting solution was stirred at room temperature for 30 min. Water was added (20 mL) and the mixture was extracted with CH 2 C1 2 (3x20 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 1- (1-(l-acetylindolin-5-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (68 mg, 67% yield) as a white foam. 1 H NMR (400 MHz, acetone-d 6 ): δ 8.53 (brs, 1H), 8.28 (dd, J = 8.8, and 1.6 Hz, 1H), 8.20 (brs, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.35 (brs, 1H), 7.32-7.28 (m, 2H), 7.23 (dd, J = 8.0, and 1.6 Hz, 1H), 6.47 (s, 1H), 4.22 (t, J = 8.4 Hz, 2H), 3.25 (t, J = 8.6 Hz, 2H), 2.20 (s, 3H), 1.31 (s, 9H); MS (ESI) m/z: 486.2 (MH-H + ).

To a solution of Example 106 (0.077 g, 0.16 mmol) in CH 2 Cl 2 (5 mL) was added pyridine (0.038 g, 0.48 mmol) and MsCl (0.037 g, 0.32 mmol) and the resulting pink solution was stirred at RT for 2h. Water (20 mL) was added and the mixture was extracted with CH 2 Cl 2 (3 x 20 mL), dried (MgSO 4 ), concentrated and purified

Example 108 via column chromatography to yield 1-(3-t-butyl-1-(l- (methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (61 mg, 73% yield) as a white solid. 1 H-NMR (300 MHz, acetone-d 6 ): δ 8.52 (brs, 1H), 8.26 (dt, J = 8.4, and 2.0 Hz, 1H), 8.16 (brs, 1H), 7.42 (brs, 1H), 7.40-7.29 (m, 3H), 7.24 (dd, J = 8.4, and 1.6 Hz, 1H), 6.47 (s, 1H), 4.07 (t, J = 8.6 Hz, 2H), 3.23 (t, J = 8.6 Hz, 2H), 3.02 (s, 3H), 1.32 (s, 9H); MS (ESI) m/z: 522.0 (M+H + ).

Using general method D, Example A29 (0.150 g, 0.28 mmol) and 2,3,5-trifluoroaniline (0.125 g, 0.853 mmol) were combined and subsequently deprotected according to general method G to afford 1-(3-t-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,3,5- trifluorophenyl)urea, which was dissolved in CH 2 Cl 2 (3 mL). Pyridine (0.200 mL, 0.196 g, 8.70 mmol) and MsCl (0.296 g, 9.09

Example 109 mmol) were added sequentially at 0 °C. The mixture was allowed to reach RT and stirred for 3h. Water (20 mL) was added and the mixture was extracted with EtOAc (3x30 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to

yield of 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5-yl)-7H-pyrazol-5 -yl)-3-(2,3,5- trifluorophenyl)urea (25 mg, 17% yield ) as a light brown solid. 1 H-NMR (400 MHz, acetone-dβ): δ 8.62 (brs, 1H), 8.34 (brs, 1H), 8.01-7.96 (m, 1H), 7.42 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.88-6.81 (m, 1H), 6.47 (s, 1H), 4.07 (t, / = 8.4 Hz, 2H), 3.23 (t, / = 8.6 Hz, 2H), 3.03 (s, 3H), 1.32 (s, 9H); MS (ESI) m/z: 508.3 (M+H + ).

Using the same method as for Example 109, Example A29 (0.150 g, 0.28 mmol) and 2,4,5-trifluoroaniline ' (0.125 g, 0.853 mmol) were combined to afford 1 -(3-t-butyl- 1 -( 1 -

(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(2,4,5-tri- fluorophenyl)urea (38 mg, 26% yield) as a light brown solid. 1 H- NMR (400 MHz, acetone-d 6 ): δ 8.47 (brs, 1H), 8.34 (brs , 1H), 8.31-8.23 (m, 1H), 7.42 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.36-

7.25 (m, 2H), 6.46 (s, 1H), 4.06 (t, J = 8.8 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H), 3.02 (s, 3H),

1.31 (s, 9H); MS (ESI) m/z: 508.3 (M+H + ).

Using general method A, Example A29 (70 mg, 0.20 mmol) and 3-cyanophenyl isocyanate (30 mg, 0.20 mmol) were combined to yield 1 -(3-t-butyl- 1 -(indolin-5-yl)- 1H-pyrazol-5-yl)-3-(3- cyanophenyl)urea HCl salt (53 mg, 67% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.87 (s, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.62 (dt, J = 1.2, and 10.4 Hz, 1H), 7.56 (s, 1H), 7.43 (m,

2H), 6.39 (s, 1H), 3.73 (t, J = 8.0 Hz, 2H), 3.23 (t, J = 8.0 Hz, 2H), 1.28 (s, 9H); LC-MS (EI) m/z: 497.2 (M+H + ).

To a solution of 6-nitroindoline (5.00 g, 30.5 mmol) in CH 2 C1 2 (100 mL) was added Et 3 N (4.25 mL, 3.08 g, 30.5 mmol) and TFAA (4.23 mL, 6.40 g, 30.5 mmol) and the resulting solution stirred at RT for Ih. More Et 3 N (4.25 mL, 3.08 g, 30.5 mmol) and TFAA (4.23 mL, 6.40 g, 30.5 mmol) were added and the solution was stirred at RT for another 2h. Water (100 mL) was added and the mixture was extracted with CH 2 C1 2 (3x100 mL), dried (MgSO 4 ), and concentrated to yield 2,2,2-trifluoro-1-(6-nitroindolin-1- yl)ethanone (8.9 g, crude yield > 100%) as a yellow-brown solid. 1 H-NMR (300 MHz,

CDCl 3 ): δ 9.01 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.42 (t, J = 8.2 Hz,

2H), 3.38 (t, J = 8.4 Hz, 2H); MS (ESI) m/z: 261.0 (M+H + ).

To a suspension of 2,2,2-trifluoro-1-(6-nitroindolin-1-yl)ethanone (7.92 g, 30.4 mmol) in MeOH (100 mL) was added 10% Pd/C (0.648 g, 0.609 mmol) and the slurry was stirred under H 2 (1 atm)overnight. The mixture was filtered through a pad of Celite ® and the filtrate was concentrated and dried under vacuum to yield 1-(6-aminoindolin-1-yl)-2,2,2- trifluoroethanone (7.7 g, crude yield > 100%) as a yellow-brown solid. 1 H-NMR (400 MHz, CDCl 3 ): δ 7.64 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.49 (dd, , J = 8.4, and 2.0 Hz, 1H), 4.24 (t, J = 8.0 Hz, 2H), 3.85 (brs, 2H), 3,13 (t, / = 8.2 Hz, 2H); MS (ESI) m/z: 231.0 (M+H + ).

To an ice-cold solution of 1-(6-aminoindolin-1-yl)-2,2,2-trifluoroethanone (7.00 g, 30.4 mmol) in 6N HC1 (50 mL) was dropwise added a solution of NaNO 2 (2.10 g, 30.4 mmol) in H 2 O (5 mL). The resulting slurry was stirred at 0 °C for 30 min. A solution of SnC12-2H 2 O (11.5 g, 60.8 mmol) in cone. HCl (60 mL) was added dropwise and after the addition was complete the resulting slurry was stirred at RT for 2h. The mixture was filtered and the resulting solid was redissolved in EtOH (200 mL). Pivaloyl acetonitrile (4.57 g, 36.5 mmol) was added and the solution was heated at reflux overnight. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x100 mL), dried (MgSO 4 ), concentrated and purified by recrystallization from ethyl acetate/hexanes to yield 1-(6-(5-amino-3-t-butyl- 7H-pyrazol-1-yl)indolin-1-yl)-2,2,2-trifluoroethanone (3.2 g, 30% yield) as a light-brown solid. 1 H-NMR (400 MHz, acetone-^): δ 8.49 (d, / = 2.0 Hz, 1H), 7.51 (dd, J = 8.4, and 2.0 Hz, 1H), 4.41 (t, J = 8.2 Hz, 2H), 3.32 (t, J = 8.2 Hz, 2H), 1.32 (s, 9H), pyrazolamine protons not observed; MS (ESI) m/z: 353.2 (M+H + ).

To a solution of 2,3-dichloroaniline (0.200 g, 1.23 mmol) in EtOAc(5 mL) was added NaOH (IM, 2 mL, 2 mmol) and Troc- Cl (0.262 g, 1.23 mmol) and the resulting mixture was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (408 mg, 98%) as a yellow foam. 1 H NMR (400 MHz, CDCb): δ 8.11 (d, J = 6.4 Hz, 1H), 7.43 (brs, 1H), 7.25- 7.22 (m, 2H), 4.86 (s, 2H); MS (EI) m/z: 335.8 (M+H + ).

A solution of 2,2,2-trichIoroethyl-2,3-dichlorophenylcarbamate (0.400 g, 1.19 mmol)

and 3-amino-5-t-butylpyrazole (0.165 g, 1.19 mmol) in DMF (1 mL) was stirred at 80 °C overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 1-(3-t-butyl- ;H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (230 mg, 59% yield) as a pink foam. 1 H NMR (400 MHz, CDCb): δ 8.26 (d, J = 6.8 Hz 1 1H), 7.20-7.14 (m, 2H), 5.85 (brs, 1H), 1.34 (s, 9H), amine and urea protons not visible; MS (EI) m/z: 327.0 (MH-H + ).

A mixture of Example A9 (0.100 g, 0.386 mmol), Troc-Cl (0.164 g, 0.772 mmol), 2N NaOH (2.00 mL, 4.00 mmol) and EtOAc (2 mL) was stirred at RT overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 2,2,2-trichloroethyl-3-(pyridin-3-yloxy)phenylcarbamate (45 mg, 32% yield) as a yellow oil. 1 H NMR (CDCl.?): δ 8.42 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 7.36-7.24 (m, 5H), 7.17 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 8.2, and 1.8 Hz, 1H), 4.80 (s, 2H); MS (EI) m/z: 361.0 (M+H + ).

A mixture of 2,2,2-trichloroethyl-3-(pyridin-3-yloxy)phenylcarbamate (0.040 g, 0.11 mmol), 5-amino-3-t-butylpyrazole (0.031 g, 0.22 mmol) and i-Pr 2 NEt (0.029 g, 0.22 mmol) in DMF (2 mL) was stirred at 100 °C overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 1-(3-t-butyl-7H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)u rea (26 mg, 67% yield) of the desired product as a red-brown oil. 1 H-NMR (400 MHz, CDCl 3 ): δ 10.1 (brs, 1H), 8.40 (s, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.02 (s, 1H), 7.35-7.28 (m, 4H), 6.71 (dt, J = 6.4, and 2.2 Hz, 1H), 5.67 (brs, 1H), 1.32 (s, 9H), urea protons not visible; MS (EI) m/z: 352.3 (M+H + ).

Using general method A, Example A30 (0.400 g, 1.14 mmol) and 2,3-dichlorophenyl isocyanate (0.426 g, 2.28 mmol) were combined and deprotected according to general method G to yield 1-(3-t-butyl-1-(indolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (230 mg, 42% yield) as an off-white solid. 1 H-NMR (400 MHz, CD 3 OD): δ 8.01 (dd, J = 7.2, and 4.4 Hz, 1H), 7.64-7.58 (m, 3H), 7.25-7.23 (m, 2H), 6.51 (s, 1H), 3.91 (t, J = 7.8 Hz, 2H), 3.38 (t, J =

8.0 Hz, 2H), 1.37 (s, 9H); MS (ESI) m/z: 444.0 (M+H + ).

Using the same method as for Example 109, Example 112 (0.150 g, 0.312 mmol) was transformed to 1-(3-t-butyl-1-(l- (methylsulfonyl)indolin-6-yl)-7H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (100 mg, 61% yield) as a pink foam. 1 H- NMR (400 MHz, acetone-d 6 ): δ 8.58 (brs, 1H), 8.27 (dt, / = 8.4, 1.6 Hz, 1H), 8.17 (brs, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.35

(d, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.22-7.20 (m, 2H), 6.46 (s, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.23 (t, J = 8.6 Hz, 2H), 2.98 (s, 3H), 1.32 (s, 9H); MS (ESI) m/z: 522.0 (M+H + ).

Using general method A, Example A30 (70 mg, 0.2 mmol) and 3-cyanophenylisocyanate (29 mg, 0.2 mmol) were combined and deprotected according to general method G to yield 1-(3-t-butyl- 1-(indolin-6-yl)-/H-pyrazol-5-yl)-3-(3-cyanophenyl)urea HC1 salt (67 mg, 77% yield). 1 H-NMR (400 MHz, CD 3 OD): δ 7.94

(t, / = 1.6 Hz, 1H), 7.79 (s, 1H), 7.72 (m, 2H), 7.63 (m, 1H), 7.61 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 1.2 Hz, 1H), 7.38 (t, J = 1.6 Hz, 1H), 3.99 (t, J = 7.6 Hz, 2H), 3.45 (t, J = 7.6 Hz, 2H), 1.41 (s, 9H); LC-MS (EI) m/z: 497.2 (M + H + ).

A mixture of Example A31 (63 mg, 0.19 mmol), 1-N-Boc-indole- 5-boronic acid (75 mg, 0.28 mmol, commercially available from Anichem), Cu(OAc) 2 (53 mg, 0.28 mmol), pyridine (0.05 mL) and molecular sieves (activated, 4A) in CH 2 Cl 2 (12 mL) was stirred open to the air at RT for 3 days. The reaction mixture was filtered through a pad of Celite ® , concentrated, and purified via column chromatography to yield 1-(3-t-butyl-1-(7H-indol-5-yl)-7H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (50 mg, 48% yield). LC-MS (EI) m/z: 542.3 (M+η + ). This material was dissolved in CH 2 C1 2 (I mL) and TFA (0.5 mL) and stirred at RT overnight. Concentration and purification by column chromatography yielded 1-(3-t-butyl-1-(7H-indol-5-yl)-7H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (19 mg, 47 % yield). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 9.11 (s, 1H), 8.82 (s, 1H), 8.08 (dd, J = 2.4, and 9.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 (t, / = 2.8 Hz, 1H), 7.29 (m, 2H), 7.16 (dd, 7 = 1.6, and 8.4 Hz, 1H), 6.55 (brs, 1H), 6.38 (s, 1H), 3.86 (s, 3H), 1.28 (s, 9H); LC-MS (EI) m/z: 442.0 (M+H + ).

Using the same procedure as for Example 115, Example A32 (0.07 g, 0.2 mmol) and l-N-Boc-indole-5-boronic acid (0.05 g, 0.2 mmol, commercially available from Anichem),were combined to yield 1-(3-t-butyl-1-(/H-indol- 5-yl)-/H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (7 mg, 7% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.18 (s, 1H), 8.42 (brs, 2H), 8.26 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.46 (s, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.24 (t, J = 1.6 Hz, 1H), 7.13 (dd, J = 2.0, and 8.4 Hz, 1H), 7.05 (dd, J = 0.8, and 8.4 Hz, 1H), 6.67 (dd, J = 2.0, and 8.0 Hz, 1H), 6.53 (t, J = 2.0 Hz, 1H), 6.33 (s, 1H), 1.27 (s, 9H); LC-MS (EI) m/z: 467.3 (M+H + ).

Using the same procedure as for Example 115, Example A31 (63 mg, 0.19 mmol) and l-N-methylindole-5-boronic acid (51 mg, 0.28 mmol, commercially available from Anachem) were combined to yield 1-(3-t-butyl-1-(l-methyl-7H-indol-5-yl)-7H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white solid (54 mg, 61% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.10 (s, 1H), 8.80 (s, 1H), 8.08 (dd, J = 2.8, and 7.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.30 (m, 2H), 7.23 (dd, J = 2.0, and 8.8 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.38 (s, 1H), 3.86 (s, 3H), 1.26 (s, 9H); LC-MS (EI) m/z: 456.0 (M+H + ).

Commercially available N-Boc-5-indoleboronic acid (0.30 g, 1.1 mmol) was dissolved in CH 2 Cl 2 (20 mL) and pyridine (1 mL) with molecular sieves (activated 4A) and stirred overnight at RT. Commercially available ethyl 3-t- butyl-1H-pyrazole-5-carboxylate, Cu(OAc) 2 and molecular sieves (4A activated, powder) were added to the boronic acid solution and the whole stirred at RT open to the atmosphere for 2d. The reaction mixture was filtered through a pad of Celite ® , concentrated and purified by column chromatography to yield ethyl 5-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-1H-indole-1 -carboxylate (0.18 g, 38% yield). LC-MS (EI) m/z: 412.3 (M + H + ).

Using general method E, the material from the previous reaction was saponfied to yield lKHt-butoxycarbonyO-1H-indol-S-yl^-t-butyl-1H-pyrazole-S-car boxylic acid which was used directly in the next step.

To a solution of 1-(1-(t-butoxycarbonyl)-1H-indol-5-yl)-3-t-butyl-1H-pyrazole -5- carboxylic acid (0.09 g, 0.23 mmol) in toluene (2 raL) was added triethyl amine (0.026 mL, 0.26 mmol) and Example All (0.065 g, 0.26 mmol). The reaction mixture was stirred at RT and DPPA (71 mg, 0.26 mmol) was added. The reaction mixture was heated at 100 °C for 2h, cooled, concentrated and the residue purified via column chromatography to yield t-butyl 5- (3-t-butyl-5-(3-(3-(8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]p yrimidin-6-yl)phenyl)ureido)- 1 H-pyrazol - 1 -y I)- 1 H-indole- 1 -carboxylate.

Using general method F, t-Butyl 5-(3-t-butyl-5-(3-(3-(8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureido)-1H-pyrazol -1-yl)-1H-indole-1- carboxylate.was transformed to 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)u rea as a pale yellow solid (17 mg, 13% yield). 1 H-NMR (DMSO-(I 6 ): δ 9.20 (bs, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 2.8 Hz, 1H), 7.42 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.29 (dt, J = 1.2, and 8.0 Hz, 1H), 7.17 (dd, J = 2.4, and 8.8 Hz, 1H), 6.56 (m, 1H), 6.39 (s, 1H), 3.71 (s, 3H), 1.29 (s, 9H); LC-MS (EI) m/z: 594.2 (M + H + ).

To a solution of 5-bromoindoline (1.00 g, 5.05 mmol) in CH 2 C1 2 (20 mL) was added Et 3 N (0.7 mL, 0.51 g, 5.05 mmol). Trifluoroacetic anhydride (0.7 mL, 1.06 g, 5.05 mmol) was added dropwise into the reaction mixture and the resulting solution was stirred at RT for 4h. Water (20 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x100 mL). The organic layer was dried (Na 2 SO 4 ), concentrated and dried under vacuum to yield (1.42 g, 96% yield) as a yellow solid. 1 H NMR (400 MHz, CDC1 3 ): δ 8.11 (d, J = 9.6 Hz, 1H), 7.41 (m, 2H), 4.32 (t, J = 8.4 Hz, 2H), 3.28 (t, J = 8.4 Hz, 2H); LC-MS (EI) m/z: 294.0 (M+H + ), 296 (M+3H + ).

To a solution of 1-(5-bromoindolin-1-yl)-2,2,2-trifluoroethanone (0.70 g, 2.4 mmol) in DMF (10 mL) were added sequentially KOAc (0.70 g, 7.1 mmol), pinacoldiboron (0.91 g, 3.6 mmol) and PdCl 2 (dppf) (98 mg, 0.12 mmol). After flushing the reaction vessle with N 2 , the reaction mixture was sealed and heated at 80 °C for 3h. The reaction mixture was partitioned between H 2 O and EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to yield 2,2,2- trifluoro-1-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI) indolin-1-yl)ethanone (0.84 g, 100%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.20 (d, J = 7.6 Hz, 1H), 7.75 (d, J

= 7.6 Hz, 1H), 7.72 (s, 1H), 4.30 (t, J = 8.4 Hz, 2H), 3.27 (t, J = 8.4 Hz, 2H), 1.37 (s, 12H); LC-MS (EI) m/z: 342.3 (M+H + ).

To a solution of 2,2,2-trifluoro-1-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2- yl)indolin-1-yl)ethanone (0.7 g, 2.1 mmol) in THIVH 2 O (4/1, 15 mL) was added NaIO 4 (1.4 g, 6.4 mmol). The reaction mixture was stirred at RT for 30 min and then treated with 2N HC1 (18 mL). After stirring at RT for 3h, the reaction mixture was filtered and washed with THF. The filtrate was concentrated and the residue triturated with EtOAc (1 mL) to yield 1- (2,2,2-trifluoroacetyl)indolin-6-ylboronic acid (0.45g, 81% yield). 1 H NMR (400 MHz, DMSO-dβ): δ 8.04 (s, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.75 (brs, 1H), 7.72 (d, J = 8.4 Hz, 1H), 4.29 (t, J = 8.0 Hz, 2H), 3.27 (t, J = 8.0 Hz, 2H); LC-MS (EI) m/z: 260.0 (M+H + ).

Using the same procedure as for Example 115, Example A33 and Example A32 were combined to yield 1-(3-t-butyl-1- (indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3- yloxy)phenyl)urea (20 mg, 11% yield) as the HCl salt. 1 H NMR (400 MHz, OMSO-d 6 ): □ 9.62 (s, 1H), 8.74 (s, 1H), 8.56 (brm, 2H), 7.70 (m, 2H), 7.53 (brs, 1H), 7.42 (brd, / = 8.0 Hz, 1H), 7.34 (m, 2H), 7.13 (brd, J = 7.6 Hz, 1H), 7.12 (brm, 1H), 6.72 (dd, 7 = 6.8 Hz, 1H), 6.34 (s, 1H), 3.72 (brt, J = 7.2 Hz, 2H), 3.22 (brt, J = 7.2 Hz, 2H), 1.26 (s, 9H); LC-MS (EI) m/z: 469.2 (M+H + ).

A mixture of 6-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10% Pd/C (2.0 g) in MeOH was stirred under H 2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 1H-indazol-6-ylamine (18.5 g, 94% yield) as a yellow solid. 1 H NMR (300 MHz, DMSO-4): 12.20 (br s, 1 H), 7.70 (s, 1 H), 7.35 (d, J = 5.4 Hz, 1 H), 6.49-6.44 (m, 2 H), 5.17 (brs, 2 H). MS (ESI) m/z: 134 (M+H + ).

To a solution of 1H-indazol-6-ylamine (20 g, 153 mmol) in cone. HCl (50 mL) was added an aqueous solution (50 mL) of NaNO 2 (19 g, 158 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl 2 2H 2 O (90 g, 306 mmol) in cone. HCl (70 mL) pre-cooled to 0 °C was then added, and the mixture stirred for 2h at RT. The precipitate was filtered and washed with Et 2 O to yield (1H-indazol-6-yl)-hydrazine hydrochloride as a yellow solid, which was used without further purification.

A mixture of (1H-indazol-6-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo- pentanenitrile (17 g, 1.05eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1- (1H-indazol-6-yl)-1H-pyrazol-5-amine (21 g, 58% yield, for two steps). 1 H NMR (300 MHz, DMSO-d 6 ): 8.21 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.25 (d, / = 8.1 Hz, 1H), 5.71 (s, 1H), 1.31 (s, 9H); MS (ESI) m/z: 256 (M+H + ).

To a solution of 3-t-butyl-1-(1H-indazol-6-yl)-1H-pyrazol-5-arnine (15 g, 49 mmol) dissolved in dioxane (100 mL) at RT was added 10% NaOH (50 mL) and the mixture stirred for 0.5h. Boc anhydride (12 g, 1.2eq) was then added to the mixture and the solution stirred for 3h. The mixture was extracted with CH 2 Cl 2 (3x100 mL). The combined organic extracts were concentrated and purified by column chromatography to yield 6-(5-amino-3-t-butyl- pyrazol-1-yl)-indazole-1-carboxylic acid f-butyl ester (13.1 g, 75% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.41 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 5.42 (s, 1H), 5.38 (brs, 2H), 1.65 (s, 9H), 1.22 (s, 9H); MS (ESI) m/z: 356 (M+H + ).

Using general method A, the material from the previous reaction (0.150 g, 0.422 mmol, 1.00) and 2,3-dichlorophenyl isocyanate (0.0557 ml, 0.422 mmol, 1.00 eq) were combined to yieldof t-butyl 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-y l)- 1H-indazole-1-carboxylate (0.130 g, 57% yield). 1 H NMR (DMSO-d 6 ): δ 9.42 (s, 1H), 8.79 (s, 1H), 8.51-8.50 (m, 1H), 8.23-8.22 (m, 1H), 8.10-8.02 (m, 2H), 7.65-7.62 (m, 1H), 7.34- 7.29 (m, 2H), 6.46 (s, 1H), 1.60 (s, 9H), 1.31 (s, 9H); MS (ESI) m/z: 543.0 (M+H + ), 545.0 (M+2+H + ).

A solution of yieldof t-butyl 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H- pyrazol-1-yl)-1H-indazole-1-carboxylate (0.13 g, 0.239 mmol, 1.00 eq) in satd. HC1/EtOH (5.00 ml) and stirred at 65 °C for 2 h until the reaction was clear and homogeneous. It was cooled to RT and evaporated. The syrupy residue was dissolved in MeCNZH 2 O, frozen and lyopholized to yield 1-(3-t-butyl-1-(1H-indazol-6-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (97.1 mg, 85% yield) as the HCl salt. 1 H NMR (DMSO-d 6 ): δ 9.32 (s, 1H), 8.81 (s, 1H), 8.17-8.16 (m, 1H), 8.13-8.12 (m, 1H), 8.10-8.07 (m, 1H), 7.92-7.82 (m, 1H), 7.65-7.59 (m, 1H), 7.24-7.25 (m, 2H), 6.44 (s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 443.0 (M+H + ), 445.0 (M+2+H + ).

A mixture of 5-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10% Pd/C (2.0 g) in MeOH was stirred under H 2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 20 g (97%) of 1H-indazol-5-amine as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.50 (brs, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.74 (s, 1H), 4.71 (brs, 1H), 3.15 (d, J = 4.8 Hz, 2H); MS (ESI) m/z: 134 (M+H + ).

To a solution of 1H-indazol-5-yIamine (20 g, 153 mmol) in cone. HCl (50 mL) was added an aqueous solution (50 mL) of NaNO 2 (19 g, 158 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl 2 - 2H 2 O (90 g, 306 mmol) in cone. HCl (70 mL), pre-cooled to 0 °C, was then added. The reaction solution was stirred for 2h at RT. The precipitate was filtered and washed with ether to yield (1H-indazol-5-yl)-hydrazine hydrochloride as a yellow solid, which was used for the next reaction without further purification.

A mixture of (1H-indazol-5-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo- pentanenitrile (19 g, 1.05eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1- (1H-indazol-5-yl)-1H-pyrazol-5-amine (23 g, 60% of two steps). 1 H NMR (300 MHz, DMSO-d 6 ): 8.24 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.45 (dd, J = 9.0 Hz, 1.8 Hz, 1 H), 5.7 (s, 1 H), 1.31 (s, 9 H). MS (ESI) m/z: 256 (M+H + ).

To a solution of 3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-amine (14 g, 48 mmol) in dioxane (100 mL) was added 10 % NaOH (50 mL) at RT and the mixture stirred for 0.5h. Boc anhydride (12 g, 1.2eq) was added to the mixture and the solution stirred for 3h. The mixture was extracted with CH 2 Cl 2 (3x100 mL). The combined organic extracts were concentrated and purified by column chromatography to yield t-butyl 5-(5-amino-3-t-butyl- 1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (7.8 g, 46%). 1 H NMR (300 MHz, DMSO-d 6 ): 8.44 (s, 1 H), 8.10 (d, J = 9.0 Hz, 1 H), 8.00 (s, 1 H), 7.82 (d, J = 9.0 Hz, 1 H), 5.39 (s, 1 H), 5.24 (br s, 2 H), 1.65 (s, 9 H), 1.21 (s, 9 H). MS (ESI) m/z: 356 (M+H + ).

Using general method A, t-butyl 5-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-1H-indazole- 1-carboxylate (0.150 g, 0.422 mmol, 1.00 eq) and 2,3-dichlorophenyl isocyanate (0.0557 ml, 0.422 mmol, 1.00 eq). were combined to yield t-butyl 5-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carbox ylate (115.5 mg, 50% yield). 1 H NMR (DMSO-d 6 ): δ 9.25 (s, 1H), 8.73 (s, 1H), 8.53 (brs, 1H), 8.22-8.19 (m, 1H), 8.06-

8.01 (m, 2H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H), 6.43 (s, 1H), 1.67 (s, 9H), 1.30 (s, 9H); MS (ESI) m/z: 543.0 (M+H + ), 545.0 (M+2+H + ). t-Butyl 5-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)- 1 H-pyrazol- 1 -yl)- 1H-indazole- 1-carboxylate (0.1155 g, 0.213 mmol, 1.00 eq) was dissolved in satd. HC1/ EtOH. The solution was heated at 80 °C for 1 h. After cooling to RT, the reaction was concentrated to dryness and treated with 80:20 MeCN/H 2 O. The resulting suspension was thoroughly chilled. The solids were collected by filtration, rinsed with 80:20 MeCN/H 2 0, MeCN and dried on the filter to yield 1-(3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (55.5 mg, 54.4% yield) as the HCl salt. 1 H NMR (DMSO-d 6 ): 9.18 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8.08-8.06 (m, 1H), 7.89-7.88 (m, 1H), 7.70-7.67 (m, 1H), 7.47.7.44 (m, 1H), 7.33-7.28 (m, 2H), 6.40 (s, 1H), 1.29 (s, 9H); MS (ESI) m/z: 502.0 (M+H + ), 504.0 (M+2+H + ).

To a solution of phenethylamine (60.5 g, 0.5 mol) and Na 2 CO 3 (63.6 g, 0.6 mol) in EtOAc/H O (800 mL, 4:1) was added ethyl chloroformate dropwise (65.1 g, 0.6 mol) at 0 °C during a period of Ih. The mixture was warmed to RT and stirred for an additional Ih. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered and concentrated to a crude solid, which was purified by flash chromatography to afford ethyl phenethyl carbamate (90.2 g). 1 H NMR (400 MHz, CDCl 3 ): δ 7.32-7.18 (m, 5 H), 4.73 (brs, 1H), 4.14-4.08 (q, J = 6.8 Hz, 2H), 3.44-3.43 (m, 2H), 2.83-2.79 (t, J =6.8 Hz, 2H), 1.26-1.21 (t, 7 =6.8 Hz, 3H).

A suspension of ethyl phenethyl carbamate (77.2 g, 40 mmol) in polyphosphoric acid (300 mL) was heated to 140-160 °C and stirred for 2.5h. The reaction mixture was cooled to RT, carefully poured into ice-H 2 O and stirred for Ih. The aqueous solution was extracted with EtOAc (3x300 mL). The combined organic phases were washed with H 2 O, 5% K 2 CO 3 and brine, dried (Na 2 SO 4 ), filtered and concentrated to a crude solid which was purified by flash chromatography to afford 3,4-dihydro-2H-isoquinolin-1-one (24 g). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.91 (brs, 1H), 7.83 (d, J= 7.5 Hz, 1H,), 7.43 (t, J = 7.5 Hz, 1H), 7.33- 7.25 (m, 2H), 3.37-3.32 (m, 2H), 2.87 (t, / = 6.6 Hz, 2H).

To an ice-salt bath cooled mixture of cone. HNO 3 and cone. H 2 SO 4 (200 mL, 1 :1) was added 4-dihydro-2H-isoquinolin-1-one (15 g, 0.102 mol) dropwise over 15 min. After stirring for 2h, the resulting mixture was poured into ice-η 2 O and stirred for 30 min. The

precipitate was filtered, washed with H 2 O, and dried in air to afford 7-nitro-3,4-dihydro-2H- isoquinolin-1-one (13 g). 1 H NMR (300 MHz, OMS0-d 6 ): δ 8.53 (d, J = 2.4 Hz, 1H,), 8.31 (d, J =2.4 Hz, 1H), 8.29 (d, J =2.4 Hz, 1H), 7.62 (d, J =8.4 Hz, 1H), 3.44-3.39 (m, 2H), 3.04 (t, J= 6.6 Hz, 2H).

A suspension of 7-nitro-3,4-dihydro-2//-isoquinolin-1-one (11.6 g, 60 mmol) and 10%Pd/C (1.2 g,) in MeOH was stirred overnight at RT under H 2 (40 psi). The mixture was filtered through Celite ® and washed with MeOH. The filtrate was evaporated under vacuum to afford 8.2 g of 7-amino-3,4-dihydro-2H-isoquinolin-1-one, which was used without further purification.

To a suspension of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.1 g, 50 mmol) in cone. HC1 (100 mL) cooled in an ice-η 2 O bath was added a solution of NaNO 2 (3.45 g, 50 mmol) in H 2 O dropwise at such a rate that the reaction mixture never rose above 5 °C. After stirring for 30 min, to the resulting mixture was added a solution of SnCl 2 -2H 2 O(22.5 g, 0.1 mol) in cone. HCl (150 mL) dropwise at 0 °C in an ice-H 2 O bath. The resulting mixture was stirred for another 2h at 0 °C. The precipitate was collected by suction, washed with ether to afford 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.3 g), which was used for the next reaction without further purification.

A mixture of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.0 g, 37.6 mmol) and 4,4- dimethyl-3-oxo-pentanenitrile (5.64 g, 45 mmol) in EtOH (100 mL) and cone. HC1 (10 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 7-(5-Amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinoli n-1-one hydrochloride as a yellow solid (11.5 g, 96% yield), which was used without further purification.

Using general method A, Example A34 (2.0 g, 6.2 mmol) and l,2-dichloro-3-isocyanato-benzene (1.42 g, 7.5 mmol) were combined to afford 1.2 g l-[3-t-butyl-1-(l-oxo-l,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-di- chlorophenyl)urea (1.2 g, 41% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 9.08 (brs, 1H), 8.34 (brs, 1H), 8.15 (brs, 1H), 8.02 (m, 1H), 7.60 (brs, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.29 (d, J =8.7 Hz, 1H), 7.15-7.09 (m, 2H), 6.62

(s, 1H), 3.5 (brm, 2H), 3.94 (brm, 2H), 1.34 (s, 9H).

Using general method C, Example 122 (120 mg, 0.25 mmol) was reduced to yield l-[3-t-butyl-1-(l, 2,3,4- tetrahydroisoquinolin-7-yl)-/H-pyrazol-5-yl]-3-(2,3-dichloro - phenyl)urea (80 mg, 70% yield). 1 H NMR (300 MHz, CD 3 OD): δ 7.98 (t, J = 4.8 Hz, 1H), 7.45-7.39 (m, 3 H), 7.23 (d, 7 = 5.1 Hz, 2H), 6.41 (s, 1H), 4.41 (s, 2H), 3.52 (t, 7 = 6.3 Hz, 2H), 3.19 (t, 7 = 6.3 Hz, 2H), 1.33 (s, 9H).

Using general method A, Example A34 (2.0 g, 6.2 mmol) and 1- chloro-4-isocyanatobenzene (1.15 g, 7.5 mmol) were combined to afford l-[3-t-butyl-1-(l-oxo-l,2,3,4-tetrahydroisoquinolin-7- yl)-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (1.5 g, 55% yield). 1 H NMR (300 MHz, CDCl 3 ): 5 9.03 (s, 1H), 8.77 (s, 1H), 7.90 (s, 1H), 7.54 (d, 7 = 7.5 Hz, 1H), 7.30 (d, 7 = 9 Hz, 3H), 7.19 (d, 7 = 9 Hz, 2H), 6.88 (brs, 1H), 6.74 (s, 1H), 3.45 (brs, 2H), 2.88 (t, 7 =6 Hz, 2H), 1.37 (s, 9H). Using general method C, l-[3-t-butyl-1-(l-oxo-l,2,3,4-terrahydroisoquinolin-7-yl)- /H-pyrazol-5-yl]-3-(4-chlorophenyl)urea (1.0 g, 2.3 mmol) was reduced to afford l-[3-t- butyl-1-(l,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrazol-5-yl ]-3-(4-chloro-phenyl)urea (0.8 g, 82% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.13 (brs, 1H), 8.34 (brs, 1H), 7.41-7.12 (m, 7H), 6.31 (s, 1H), 3.88 (s, 2H), 2.95 (t, 7 = 6.0 Hz, 2H), 2.70 (t, 7 = 6.0 Hz, 2H), 1.24 (s, 9H).

To a solution of Example A34 (20 g, 0.070 mol) in THF (400 mL) was added LAH (15 g, 0.395 mol) in portions at 0-5 °C. The resulting mixture was heated at reflux overnight, followed by the addition of 10% NaOH solution. After stirring for Ih at RT, BoC 2 O (23g, 0.106 mol) was added and the solution stirred overnight. After filtration, the filtrate was concentrated to afford the crude product, which was purified by reverse pahse chromatography to give 7-(5- amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-7H-isoquinoline-2- carboxylic acid t-butyl ester (12 g, 75 % yield). 1 H NMR (300 MHz, DMSO-rf 6 ): 7.32 (s, 1H), 7.29 (d, 7 = 2.7 Hz, 1H), 7.18 (d, 7 = 8.4 Hz, 1H), 5.32 (s, 1H), 5.15 (s, 1H), 4.51 (s, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.75 (t, 7 = 5.6 Hz, 2H), 1.40 (s, 9H), 1.17 (s, 9H); MS (ESI) m/z: 371(M+H + ).

Using general method D, 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-/H- isoquinoline-2-carboxylic acid t-butyl ester (0.250 g, 0.675 mmol) and 3-aminobenzonitrile

(0.0796 g, 0.674 mmol, 1.00 eq) were combined to yield 0.34 g (98%) of t-butyl 7-(3-t-butyl- 5-(3-(3-cyanophenyl)ureido)-/H-pyrazol- 1 -yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as an oil. MS (ESI) m/z: 515.2 (M-I-H + ).

To t-butyl 7-(3-t-butyl-5-(3-(3-cyanophenyl)ureido)-7H-pyrazol-1-yl)-3, 4- dihydroisoquinoline-2(1H)-carboxylate (0.34 g, 0.66 mmol) in EtOAc (5.0 ml) was added 3M ηCl/EtOAc (1.1 mL, 3.3 mmol). The resulting mixture was stirred at 20-25 °C for 6.5h. The suspension was diluted with Et 2 O to fully precipitate the solids. These were collected by filtration, rinsed with Et 2 O and dried to yield 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-7- yl)-7H-pyrazol-5-yl)-3-(3-cyanophenyl)urea (0.1377 g, 46% yield) of as an off-white solid. 1 H NMR (400 MHz, DMSO-J 6 ): 10.1 (s, 1H), 9.47 (brs, 2H), 8.97 (s, 1H), 7.94-7.93 (m, 1H), 7.63-7.60 (m, 1H), 7.49-7.33 (m, 5H), 6.37 (s, 1H), 4.36 (brs, 2H), 3.37 (brs, 2H), 3.06-3.03 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 415.3 (M-I-H + ).

Using the same method as for Example 107, Example 123 (100 mg, 0.22 mmol) was converted to l-[1-(2-acetyl-l,2,3,4- tetrahydroisoquinolin-7-yl)-3-t-butyl-7H-pyrazol-5-yl]-3-(2, 3- dichlorophenyl)urea (55 mg, 50 % yield). 1 H NMR (300 MHz, DMSO-d 6 ): D 9.16 (m, 1 H), 8.74 (s, 1H), 8.00 (s, 1H), 7.20-7.36 (m, 5H), 6.33 (s, 1H), 4.66 (s, 2H), 4.61 (s, 2H), 2.76-2.86 (m, 2H), 2.04 (s, H), 1.22 (s, 9 H); MS (ESI) m/z:

500 (M+H + ).

Using the same method as for Example 108, Example 123 (100 mg, 0.22 mmol) was converted to l-{3-t-butyl-1-[2- (methanesulfonyl)-l,2,3,4-tetrahydroisoquinolin-7-yl]-1H- pyrazol-5-yl}-3-(2,3-dichlorophenyl)urea (45 mg, 38% yield). 1 H NMR (300 MHz, DMSO-d 6 ): D9.18 (s, 1H), 8.75 (s, 1H), 8.03 (m, 1H), 7.26-7.33 (m, 5H), 6.35 (s, 1H), 4.40 (s, 2H), 3.42 (s, 2H), 2.94 (s, 2H), 2.93 (s, 3H), 1.23 (s, 9H); MS

(ESI) m/z: 536 (M+H + ).

A mixture of CDI (810 mg, 5.0 mmol) and methanesulfonamide (500 mg, 5.0 mmol) in DMF (10 mL) was stirred at 60 °C for 5 h. To 1 mL of the reaction mixture was added Example 123 (100 mg, 0.23 mmol). The resulting mixture was stirred overnight at RT. After

removal of the solvent, the residue was purified by reverse phase chromatography to afford N-(7-{ 3-t-butyl-5-[3-(4- chloro-phenyl)ureido]pyrazol-1-yl }-3,4-dihydro-/H- isoquinoline-2-carbonyl)methane-sulfonamide (55 mg, 44% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.6 (s, 1H), 9.09 (s, 1H), 8.37 (s, 1H), 7.41-7.26 (m, 7H), 6.33 (s, 1H), 4.60 (s, 2H), 3.62 (brm, 2H), 3.24 (s, 3H), 2.88-2.85 (m, 2H), 1.24 (s,

9H).

A suspension of Example A34 (1.00 g, 3.12 mmol), Et 3 N (0.43 mL, 0.315 g, 3.12 mmol) and Lawesson's reagent (1.26 g, 3.12 mmol) in dioxane (30 mL) was heated at reflux. After Ih, the mixture was cooled to RT. Water (50 mL) was added and the mixture was extracted with EtOAc (3xl00mL), dried (MgSO 4 ) and filtered. The filtrate was filtered through a pad of silica gel and the silica gel was thoroughly rinsed with MeOH. The solvents were evaporated under reduced pressure and the residue purified by column chromatography to yield of 7-(3-t-butyl- 5-amino-7H-pyrazol-1-yl)-3,4-dihydroisoquinoline-l(2H)-thion e as a yellow solid (310 mg, 33% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.6 (brs, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.0, and 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 5.38 (s, 1H), 5.16 (brs, 2H), 3.42-3.38 (m, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.21 (s, 9H); MS (ESI) m/z: 301.2 (M+H + ).

A suspension of 7-(3-t-butyl-5-amino-7H-pyrazol-1-yl)-3,4-dihydroisoquinolin e- l(2H)-thione (0.150 g, 0.499 mmol) in TηF (3 mL) was added to a solution of 2,3- dichlorophenyl isocyante (0.141 g, 0.749 mmol), pyridine (0.061 mL, 0.059 g, 0.749 mmol) and TηF (3 mL). The flask which contained the starting material was again rinsed with TηF (4 mL) and the solution was added to the reaction flask. The resulting yellow suspension was briefly heated with a heat gun, causing the reaction mixture to become clear. After 18h, the solution was concentrated and the residue was purified by column chromatography to yield 1- [3-t-butyl-1-(l-thioxo-l,2,3,4-tetτahydroisoquinolin-7-yl)- 7H-pyrazol-5-yl]-3-(2,3- dichlorophenyl)urea as a yellow solid (203 mg, 83% yield). 1 H NMR (400 MHz, acetone- d 6 ): δ 9.60 (brs, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.61 (brs, 1H), 8.26 (dd, J = 8.4, and 2.0 Hz, 1H), 8.17 (brs, 1H), 7.68 (dd, J = 8.0, and 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.23 (dd, J = 7.6, and 1.2 Hz, 1H), 6.48 (s, 1H), 3.62-3.58 (m, 2H), 3.07 (t, / = 6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 488.0 (M+H + ).

l-[3-t-Butyl-1-(l-thioxo-l,2,3,4-tetrahydroisoquinolin-7-yl) -7H-pyrazol-5-yl]-3-(2,3- dichlorophenyl)urea (0.170 g, 0.348 mmol) was dissolved in 0.5M Nη 3 /dioxane (30 mL). Mercuric chloride (0.142 g, 0.522 mmol) was added and the mixture was stirred at 80 °C. After 18 h, H 2 O (2 mL) was added. The mixture was stirred for 30 min and filtered through a pad of Celite ® . The solvent was removed under vacuum and the residue was purified by reverse-phase chromatography to yield l-[1-(l-amino-3,4-dihydroisoquinolin-7-yl)-3-t-butyl- /H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (25 mg, 15% yield). 1 H NMR (400 MHz, CD 3 OD): D 8.14 (d, J = 2.0 Hz, 1H), 7.99-7.96 (m, 1H), 7.84 (dd, / = 8.0, and 2.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.23-7.21 (m, 2H), 6.46 (s, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.14 (t, / = 6.8 Hz, 2H), 1.35 (s, 9H); MS (ESI) m/z: 471.3 (M+H + ).

Example 123 (crude, 0.241 mmol) was suspended in DMF (1 mL). Triethylamine (0.1 mL, 0.073 g, 0.072 mmol), di-t- butoxycarbonylthiourea (67 mg, 0.241 mmol) and mercuric chloride (72 mg, 0.265 mmol) were added and the mixture was stirred for 20 min. The mixture was filtered through a pad of Celite ® and concentrated to afford a crude solid which was purified by column chromatography to yield l-[3-t-butyl-1-(N,N'-(t-butyloxycarbonyl)- 2-amidino-l,2,3,4-tetrahydroisoquinolin-7-yl)-7H-pyrazol-5-y l]-3-(2,3-dichlorophenyl)-urea (76 mg, 45% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 10.1 (brs, 1H), 8.07 (dd, J = 6.4, and 3.2 Hz, 1H), 8.03 (brs, 1H), 7.97 (brs, 1H), 7.22 (dd, J = 8.4, and 1.6 Hz, 1H), 7.12-7.10 (m, 3H),

7.06 (d, J = 8.0 Hz, 1H), 6.36 (s, 1H), 4.57 (brs, 2H), 3.63 (brs, 2H), 2.79 (brs, 2H), 1.48 (s, 18H), 1.30 (s, 9H); MS (ESI) m/z: 700.3 (M+H + ). l-[3-t-Butyl-1-(N,N'-(t-butyloxycarbonyl)-2-amidino-l,2,3,4- tetrahydroisoquinolin- 7-yl)-7H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)-urea (0.076 g, 1.1 mmol) and TFA (0.7 mL,

8.7 mmol) were dissolved in CH 2 C1 2 (4 mL), stirred overnight, concentrated under reduced pressure and the resulting solid purified by reverse-phase chromatography to yield l-[3-t- butyl-1-(2-carbamimidoyl-l,2,3,4-tetrahydroisoquinolin-7-yl) -7H-pyrazol-5-yl]-3-(2,3- dichlorophenyl)urea (51 mg,77% yield). 1 H NMR (400 MHz, CD 3 OD): δ 8.02 (dd, 1H, J = 6.4, 3.2 Hz), 7.44-7.43 (m, 2H), 7.37 (br s, 1H), 7.25 (d, 1H, J = 2.8 Hz), 7.24 (s, 1H), 6.45 (s, 1H), 4.67 (s, 2H), 3.70 (t, 2H, J = 6.0 Hz), 3.09 (t, 2H, J = 5.8 Hz), 1.35 (s, 9H); MS (ESI) m/z: 500.3 (M+H + ).

To a solution of hydrocarbostyril (9.00 g, 61.2 mmol) in cone. H 2 SO 4 (180 mL) cooled to -10 °C was slowly added H 2 O (45 mL), followed by HNO 3 (65%, 4.5 mL). The yellow solution was stirred at -10 °C for 10 min and then carefully quenched at -10 °C with H 2 O (500 mL). The precipitated yellow solid was filtered off, washed with H 2 O and dried in vacuo to yield l,2-dihydro-6-nitroisoquinolin-3(4H)-one (10.3 g, 88% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 9.35 (brs, 1H), 8.12-8.09 (m, 2H), 6.95-6.92 (m, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.8 Hz, 2H); MS (ESI) m/z: 193.0 (M+H + ).

To a suspension of l,2-dihydro-6-nitroisoquinolin-3(4H)-one (10.3 g, 53.6 mmol) in MeOH (150 mL) was added 10% Pd/C (1.14 g, 1.07 mmol) and the mixture was stirred overnight under H 2 (1 atm). After filtration, the filtrate was concentrated and the residue was suspended in acetone, filtered and precipitated with cone. HCl (10 mL). The resulting precipitate was collected, washed with H 2 O and acetone and recrystallized from MeOH/H 2 O to yield 6-amino-l,2-dihydroisoquinolin-3(4H)-one as a grey solid (6.7 g, 63 % yield). 1 H NMR (400 MHz, CD 3 OD): δ 7.22 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.4, and 2.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.01 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H); MS (ESI) m/z: 163.0 (M+H + ).

To a suspension of 6-amino-l,2-dihydroisoquinolin-3(4H)-one (4.00 g, 20.1 mmol) in 2M HC1 (40 mL) at -10 °C was added solid NaNO 2 (1.39 g, 20.1 mmol) causing all solids to dissolve. The mixture was stirred at -10 °C for 30 min and then solid SnCl 2 2η 2 O (9.09 g, 40.3 mmol) was added at -10 °C. The mixture was allowed to warm to RT over a period of 30 min and then stirred for 2h. Ethanol (160 mL) and pivaloylacetonitrile (2.52 g, 20.1 mmol) were added and the solution was heated at reflux overnight under Ar atm. The EtOH was removed under reduced pressure, H 2 O (200 mL) was added, and the mixture was extracted with CH 2 C1 2 (3x200 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 6-(3-t-butyl-5-amino-1H-pyrazol-1-yl)-l,2-dihydroisoquinolin - 3(4H)-one (1.98 g, 35% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (brs, 1H), 7.40 (brs, 1H), 7.35 (dd, J = 8.4, and 2.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.52 (s, 1H), 3.67 (brs, 2H), 3.01 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.4 Hz, 2H), 1.30 (s, 9H); MS (ESI) m/z: 285.2 (M+H + ).

Using general method A, Example A35 and 2,3-dichlorophenyl isocyanate (0.145 g, 0.774 mmol) were combined to yield l-[3-t- butyI-1-(2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-/H-pyrazol-5 -yl]- 3-(2,3-dichlorophenyl)urea (307 mg, 92% yield). 1 H NMR (400 MHz, acetone-rfό): δ 9.26 (brs, 1H), 8.55 (brs, 1H), 8.28 (dd, J = 8.4, and 1.6 Hz, 1H), 8.21 (brs, 1H), 7.36 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.24 (dd, 7 = 8.4, and 1.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.47 (s, 1H), 3.01 (t, J = IA Hz, 2H), 2.53 (t, J = 7.6 Hz, 2H),

1.31 (s, 9H); MS (ESI) m/z: 472.2 (M+H + ).

Using general method D, Example A35 (0.075 g, 0.16 mmol) and Example All (0.04 g, 0.16 mmol) were combined to yield 1-(3-t-butyl-1-(2-oxo-l,2,3,4- tetrahydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(3-(8-methyl-

7-0X0-7, 8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)urea (0.065 g, 63%) as a solid; 1 H NMR (400 MHz, DMSO-4): δ 10.29 (s, 1H), 9.32 (s, 1H), 9.16 (s, 1H), 9.12 (s, 1H), 8.48 (s, 1H), 8.17 (s, 2H), 7.82 (s, 1H), 7.46-7.27 (m, 5H), 6.98 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 3.71 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 1.27 (s, 9H); MS (ESI) m/z: 563.3 (M+H + ).

6-Hydrazinyl-3,4-dihydroquinolin-2(7H)-one (1.0Og, 4.68 mmol, available from Example A35) was dissolved in EtOH (10 mL) and 3- cyclopentyl-3-oxopropanenitrile (0.706 g, 5.15 mmol) was added. The reaction mixture was heated at 80 °C for 22h. The reaction mixture was concentrated and the residue was suspended in EtOAc (30 mL) and treated slowly with satd. Na 2 CO 3 (30 mL). The solution was extracted with EtOAc (3x), and the combined organics were washed H 2 O and dried (Na 2 SO 4 ), filtered, concentrated and dried to yield 6-(5-amino-3-cyclopentyl-/H- pyrazol-1-yl)-3,4-dihydroquinolin-2(1H)-one (1.2 g, 87% yield) which was used without further purification. LC-MS (EI) m/z: 297.2 (M+η + ).

Using general method D, Example A36 (0.15 g, 0.32 mmol) and Example A9 (70 mg, 0.38 mmol) were combined to yield 1-(3-cyclopentyl-1-(2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)- 1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (60 mg, 28% yield, 2 steps) as an off-white solid HCl salt. 1 H-NMR (DMSO-de): δ 10.3 (s, 1H), 9.41 (s, 1H), 8.56 (bs, 1H), 8.52 (s, 1H), 8.51 (bs, 1H), 7.71 (m, 2H), 7.33 (m, 2H), 7.25 (dd, J

= 2.4, and 8.8 Hz, 1H), 7.12 (dd, J = 1.6, and 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.73 (dd, J = 2.0, and 8.0 Hz, 1H), 6.26 (s, 1H), 2.98 (m, 1H), 2.93 (t, J = 7.6 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H), 1.95 (m, 2H), 1.64 (m, 6H); LC-MS (EI) m/z: 509.2 (M + H + ).

Using general method D, Example A36 and Example Al l were combined to yield 1-(3-cyclopentyl-1-(2-oxo- l,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 (11 mg, 6% yield, 2 steps). 1 H-NMR (DMSOd 6 ): δ 10.3 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 7.82 (bt, 1H),

7.46 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.31 (m, 1H), 7.26 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 3.71 (s, 3H), 2.96 (m, 3H), 1.96 (m, 2H), 1.68 (m, 6H); LC-MS (EI) m/z: 575.2 (M + H + ).

Using general method C, Example 131 was reduced to yield l-[3- f-butyl-1-(l,2,3,4-tetrahydroquinolin-6-yl)-7H-pyrazol-5-yl] -3- (2,3-dichlorophenyl)urea hydrochloride (204 mg, 70% yield). 1 H NMR (400 MHz, CD 3 OD): δ 8.11 (dd, J = 6.0, and 4.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.27 (s, 1H), 7.11 (d, / = 8.0 Hz, 1H), 6.85 (s, 1H), 3.48 (t, J = 5.8 Hz, 2H), 2.95 (t, / =

6.2 Hz, 2H), 2.08 (quintet, J = 5.8 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 458.3 (M+H + ).

To a suspension of Example 135 (0.151 g, 0.305 mmol), Et 3 N (0.124 g, 1.22 mmol) and di-t-butoxycarbonyl-thiourea (0.084 g, 0.305 mmol) in DMF (2 mL) at RT was added HgCl 2 (0.091 g, 0.336 mmol) and the resulting mixture was stirred overnight. Water (20 mL) was added and the mixture extracted with Et 2 O (3x20 mL), dried (MgSO 4 ), concentrated, and purified via column chromatography to yield 1-(3-t-butyl-1-(N,N'-(t-butyloxycarbonyl)-1-amidino-l,2,3,4- tetrahydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(2,3-dichlorophe nyl)urea as a colorless solid (92 mg, 43% yield). 1 H NMR (400 MHz, acetone-d 6 ): δ 9.64 (brs, 1H), 8.56 (brs, 1H), 8.27 (dd, J = 8.0, and 1.6 Hz, 1H), 8.16 (brs, 1H), 7.37-7.33 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.0, and 1.2 Hz, 1H), 6.46 (s, 1H), 3.78 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.01 (quintet, / = 6.4 Hz, 2H), 1.37 (brs, 18H), 1.32 (s, 9H); MS (ESI) m/z: 700.3 (M-HH + ).

A solution of 1-(3-t-butyl-1-(N,N'-(t-butyloxycarbonyl)-1-amidino- 1,2,3,4- tetrahydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophe nyl)urea (0.088 g, 0.13 mmol) in 3 N ηCl/EtOAc (10 mL) was stirred overnight at RT. The solvent was evaporated and the residue was redissolved in η2O/MeCN 2: 1 (5 mL) and lyopholized to yield 1 -[3-t-butyl- 1 -( 1 - amidino-l,2,3,4-tetrahydroquinolin-6-yl]-7H-pyrazol-5-yl)-3- (2,3-dichlorophenyl)urea as the hydrochloride salt (65 mg, 96% yield). 1 H NMR (400 MHz, CD 3 OD): δ 7.99 (t, J = 4.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52-748 (m, 2H), 7.26-7.25 (m, 2H), 6.68 (s, 1H), 3.81 (t, J = 6.4 Hz, 2H), 2.90 (t, / = 6.6 Hz, 2H), 2.09 (quintet, J = 6.4 Hz, 2H), 1.40 (s, 9H); MS (ESI) m/z: 501.2 (M+H + ).

To an ice-cold solution of 2-(3-methoxyphenyl)-1-ethanamine (5.00 g, 33.1 mmol) and Et 3 N (5.10 mL, 3.70 g, 36.6 mmol) in CH 2 Cl 2 (100 mL) was added ethyl chloroformate (3.50 mL, 3.62 g, 33.4 mmol). The resulting solution was allowed to warm to RT and was stirred for 2h. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x50 mL), dried (MgSO 4 ) and concentrated to yield ethyl 3- methoxyphenethylcarbamate (7.32g, 99% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.22 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 4.65 (brs, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.44 (q, J = 6.4 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H); MS (ESI) m/z: 224.2 (M+H + ).

A mixture of ethyl 3-methoxyphenethylcarbamate (7.32 g, 32.8 mmol) and polyphosphoric acid (30 g) was heated at 120 °C for 2h after which H 2 O (100 mL) was added

and the mixture was cooled to RT. The mixture was extracted with EtOAc (6x100 mL), dried (MgSO 4 ) and concentrated to yield crude 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (8.0 g, 138%) as a sticky gum. 1 H NMR (400 MHz, acetone- d 6 ): δ 7.88 (d, J = 8.4 Hz. 1H), 7.04 (brS, 1H), 6.87 (dd, J = 8.4, and 2.4 Hz, 1H), 6.82 (d, / = 2.4 Hz, 1H), 3.84 (s, 3H), 3.49 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H); MS (ESI) m/z: 178.0 (M+H + ).

A mixture of 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (6.40 g, 35.6 mmol) and pyridinium hydrochloride (41. Ig, 356 mmol) was heated at 200 °C for 3h. Water was added (200 mL) and the mixture was extracted with CH 2 Cl 2 (3x200 mL), dried (MgSO 4 ) and concentrated to yield 6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one (1.6Og, 39%, 2 steps) as a yellow solid. 1 H NMR (400 Mhz, acetone- d 6 ): δ 8.91 (brs, 1H), 7.81 (d, / = 8.4 Hz, 1H), 7.40 (brs, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 3.47 (dt, J = 6.8, and 3.2 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H); MS (ESI) m/z: 164.0 (M+H + ).

To a suspension of 6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one (1.60 g, 9.81 mmol) and Et 3 N (1.37 mL, 0.992 g, 9.81 mmol) in CH 2 Cl 2 (100 mL) was added triflic chloride (1.65 g, 9.81 mmol). After 2h of stirring, H 2 O (100 mL) was added and the mixture was extracted with CH 2 C1 2 (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.70 mg, 59% yield) as a colorless solid. 1 H NMR (400 MHz, CDCb): δ 8.19 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.4, and 2.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.58 (brs, 1H), 3.64 (dt, / = 6.8, and 2.4 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H); MS (ESI) m/z: 296.0 (M+H + ).

To a suspension of l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.70 g, 5.76 mmol), benzophenone hydrazone (1.36 g, 6.91 mmol), Cs 2 CO 3 (2.81 g, 8.64 mmol) and DPPF (0.048 g, 0.086 mmol) in degassed PhMe (40 mL) was added Pd(OAc) 2 (0.013 g, 0.058 mmol) and the resulting mixture was stirred at RT for 30 min and then heated at 90 °C. After 16h, the mixture was cooled to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (3x50 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 6-(2- (diphenylmethylene)hydrazinyl)-3,4-dihydroisoquinolin-l(2H)- one (980 mg, 50% yield). 1 H NMR (400 MHz, acetone-rf 6 ): δ 8.69 (brs, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.63-7.54 (m, 5H), 7.37-7.31 (m, 5H), 7.11-7.08 (m, 2H), 6.67 (brS, 1H), 3.47 (dt, J = 7.2, and 3.2 Hz, 2H), 2.90 (t, / = 6.6 Hz, 2H); MS (ESI) m/z: 342.0 (M+H + ).

A solution of 6-(2-(diphenylmethylene)hydrazinyl)-3,4-dihydroisoquinolin-l (2H)-one (0.980 g, 2.87 mmol), pivaloylacetonitrile (0.539 g, 4.31 mmol) and p-TsOη (4.04 g, 28.8 mmol) in EtOH (20 mL) was heated at reflux overnight. The reaction was cooled and H 2 O

was added (20 mL). The mixture was extracted with CH 2 Cl 2 (3x50 mL), dried (MgSO 4 ), concentrated and recrystallized to yield 6-(5-amino-3-t-butyl-7H-pyrazol-1-yl)-3,4- dihydroisoquinolin-l(2η)-one (387 mg, 48% yield). Purification of the mother liquors via column chromatography yielded an additional 330 mg (40%) of 6-(5-amino-3-t-butyl-7H- pyrazol-1-yl)-3,4-dihydroisoquinolin-l(2η)-one. 1 H NMR (400 MHz, acetone-J 6 ): δ 7.99 (d, J = 8.4 Hz, 1H), 7.65 (dd, / = 8.4, and 2.0 Hz, 1), 7.60 (s, 1H), 6.99 (brs, 1H), 5.53 (s, 1H), 4.92 (brs, 2H), 3.55 (dt, J = 6.8, and 2.8 Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 285.2 (M+H + ).

Using general method A, Example A37 (0.070 g, 0.069 mmol) and 2,3-dichlorophenyl isocyanate (0.069 g, 0.37 mmol) were combined to yield 1-(3-t-butyl-1-(l-oxo-l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichloro - phenyl)urea (90 mg, 77% yield) as a pale yellow solid. 1 H NMR

Example 137 (400 Mhz, acetone-dό): δ 9.01 (brs, 1H), 8.54 (brs, 1H), 8.30 (d, J

= 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.33-7.29 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 3.55 (dt, J = 6.4, and 1.6 Hz, 2H), 3.05 (t, / = 6.2 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 472.0 (M+H + ).

Using general method C, Example A37 (0.200 g, 0.703 mmol) was reduced to 3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrazol- 5- amine which was used without further purification. MS (ESI) m/z: 446.3 (M+η + ), 271.3 (M+2H + ).

To a solution of 3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)- 7H-pyrazol-5-amine in CH 2 Cl 2 (20 mL) was added Boc anhydride (0.154 g, 0.703 mmol) and the solution was stirred at RT for 30 min. Evaporation and column chromatography yielded t-butyl 6-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(7H)-carboxylate (154 mg, 59% yield, 2 steps) as a yellow oil. 1 H NMR (400 MHz, acetone-J 6 ): δ 7.44-7.39 (m, 2H), 7.21 (d, / = 7.6 Hz, 1H), 5.47 (s, 1H), 4.76 (brs, 2H), 4.56 (brs, 2H), 3.64 (t, J = 5.8 Hz, 2H), 2.85 (t, / = 6.0 Hz, 2H), 1.46 (s, 9H), 1.24 (s, 9H); MS (ESI) m/z: 371.2 (M+H + ).

Using general method A, Example A38 (0.150 g, 0.405 mmol) and 2,3-dichlorophenyl isocyanate (0.100 g, 0.532) were combined, and the product deprotected using general method F to yield 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-1H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (125 mg, 88% yield). 1 H NMR (400 MHz, CD 3 OD): δ 8.07-8.05 (m, 1H), 7.55-7.50 (m,

3H), 7.28-7.27 yield (m, 2H), 6.69 (brs, 1H), 4.50 (s, 2H), 3.58 (t, 7 = 6.2 Hz, 2H), 3.27-3.23

(m, 2H), 1.41 (s, 9H); MS (ESI) m/z: 460.0 (M+lT).

Starting with Example A38, the following compounds were made using either general method A or D and deprotection using general method F. Yields are reported over two (general method A) or three (general method D) steps starting from Example A38.

Using general method D, Example A38 (0.08 g, 0.15 mmol) and Example A12 (0.04 g, 0.16 mmol) were combined and the product deprotected using general method F to yield 1- (3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-7H- pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea (54 mg, 52% yield, 3 steps) as the HCl salt. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.78 (s, 1H), 9.55 (brs, 2H), 8.87 (brs, 2H), 8.52 (d, J = 5.6 Hz, 1H), 7.55-7.43 (m, 5H), 7.39-7.34 (m, 2H), 7.16-7.14 (m, 2H), 6.35 (s, 1H), 4.30 (brs, 2H), 3.39-3.37 (m, 2H), 3.12-3.09 (m, 2H), 2.78 (d, J = 5.6 Hz, 3H), 1.28 (s, 9H); MS (ESI) m/z: 540.3 (M+H + ).

Using general method D, Example A38 (0.08 g, 0.15 mmol) and Example Al l (0.037 g, 0.15 mmol) were combined and the product deprotected using general method F to yield 1 -(3-t-buty 1- 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 (32 mg, 29% yield, 3 steps) as the HCl salt. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.46 (s, 1H), 9.29 (brs, 2H), 9.16 (s, 1H), 9.11 (s, 1H), 8.65 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.38-7.34 (m, 2H), 7.29-7.23 (m, 2H), 7.18-7.16 (m, 1H), 6.36 (s, 1H), 4.31 (brs, 2H), 3.71 (s, 3H), 3.41-3.37 (m, 2H), 3.09 (t, J = 6.0 Hz, 2H), 1.28 (s, 9H); MS (ESI) m/z:549.3 (M+H + ).

Using general method D, Example A38 (0.1 g, 0.22 mmol) and Example Al 3 (0.037 g, 0.15 mmol) were combined and the product deprotected using general method F to yield 1- (1-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-7H-pyrazol-5- yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-/H- pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)phenyl)urea (27 mg, 51%, 2 steps) as the HCl salt. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.77 (s, 1H), 9.49 (brs, 2H), 8.83 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.63-7.62 (m, 1H), 7.43- 7.41 (m, 2H), 7.34-7.29 (m, 3H), 7.15-7.13 (m, 1H), 6.72 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.32 (s, 1H), 4.29 (brs, 2H), 3.38-3.35 (m, 2H), 3.08 (t, / = 6.0 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 517.3 (M+H + ).

Using general method H, 4-(4-aminophenyl)isoindolin-1-one (150 mg, 0.67 mmol, made according to literature procedures) was transformed to yield prop-1-en-2-yl 4-(l-oxoisoindolin-4- yl)phenylcarbamate (176 mg, 85% yield). 1 H NMR (400

MHz, DMSO-d 6 ): δ 10.1 (s, 1H), 8.67 (s, 1H), 7.65 (apparent td, J = 7.6, 1.2 Hz, 2H), 7.61- 7.55 (m, 5H), 4.77 (brt, J = I. Q Hz, 1H), 4.76 (s, 1H), 4.50 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 309.0 (M+H + ).

A solution of Example A39 (58.5 mg, 0.19 mmol), Example A38 (70 mg, 0.019 mmol) and N-methyl pyrrolidine (8.9 mg, 0.10 mmol) in THF (0.4 mL) was heated at 55 °C for 24h. The crude reaction mixture was chromatographed on silica gel to provide t-butyl 6-(3-t- butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-lH- pyrazol-1-yl)-3,4-dihydroiso-quinoline-2(1H)- carboxylate (76 mg). MS (ESI) m/z: 621.3 (M+η + ).

Using general method F, t-butyl 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4- yl)phenyl)ureido)-/H-pyrazol-1-yl)-3,4-dihydroiso-quinoline- 2(7H)-carboxylate (74 mg, 0.12 mmol) was deprotected to yield 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-lH- pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyI) urea hydrochloride (45 mg, 43% yield, 2 steps). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.59 (s, 1H), 9.36 (brs, 2H), 8.75 (s, 1H), 8.67 (s,

1H), 7.64 (m, 2H), 7.59-7.51 (m, 5H), 7.45 (m, 2H), 7.36 (d, J = 9.2 Hz, 1H), 6.37 (s, 1H), 4.50 (s, 2H), 4.31 (brs, 2H), 3.39 (m, 2H), 3.10 (t, J = 6.1 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 519.2 (M+H + ).

Using general method H, Example A39 (665 mg, 1.79 mmol) was transformed to yield t-butyl 6-(3-t-butyl-5-((prop-1-en-2- yloxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(7 H)- carboxylate (843 mg, 100% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.30-7.22 (m, 3H), 6.71 and 6.45 (brs, 1H total), 4.77 (brs, 1H), 4.74 (m, 1H), 4.63 (s, 2H), 3.68 (m, 2H), 2.91 (t, / = 5.6 Hz, 2H), 1.98 (s,

3H), 1.52 (s, 9H), 1.36 (s, 9H); MS (ESI) m/z: 455.3 (M+H + ).

Using the same procedure as for Example 151, Example A40 (145 mg, 0.32 mmol) and 3-amino-5-fluorobenzonitrile (50 mg, 0.37 mmol) were combined to yield 1-(3-t-butyl-l -(1,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-cyano-5- fluorophenyl)urea hydrochloride (55 mg, 38% yield, 2 steps). 1 H NMR (400 MHz, DMSO-rfβ): δ 10.2 (s, 1H), 9.36 (brs, H), 8.96 (s, 1 H), 7.65 (dt, J = 11.2, and 2.0 Hz, 1H), 7.62 (t, J = 1.9

Hz, 1H), 7.44-7.40 (m, 3H), 7.34 (d, J = 9.1 Hz, 1H), 6.37 (s, 1H), 4.30 (s, 2H), 3.39 (m, 2H),

3.09 (t, J = 6.0 Hz, 2H), 1.28 (s, 9H); MS (ESI) m/z: 433.3 (M+H + ).

Using the same procedure as for Example 151, Example A40 (136 mg, 0.30 mmol) and 6-methyl- N 1 -(4-(pyridin-3-yl)pyrimidin-2-yl)ben-zene- 1 ,3- diamine (80 mg, 0.29 mmol, made according to literature procedures) were combined to afford 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-yla mino)phenyl)urea dihydrochloride (109 mg, 56% yield). 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.56 (s, 1H), 9.50 (brs, 2H), 9.43 (d, J = U Hz, 1H), 9.10 (s, 1H), 8.99 (brd, J = 8.3 Hz, 1H), 8.92 (dd, J = 5.4, 1.3 Hz, 1H), 8.83 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 7.94 (dd, / = 8.0, 5.4 Hz, 1H), 7.98 (s, 1H), 7.57 (d, J = 5.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.14-7.08 (m, 2H), 6.35 (s, 1H), 4.29 (m, 2H), 3.37 (m, 2H), 3.09 (t, / = 6.0 Hz, 2H), 2.18 (s, 3H), 1.28 (s, 9H);

MS (ESI) m/z: 574.2 (M+H + ).

Using the same procedure as for Example 108, Example 138 (0.070 g, 0.14 mmol) and MsC1 (0.032 g, 0.28 mmol) were combined to yield 1-(3-t-butyl-1-(2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (57 mg, 75%) as a colorless solid. 1 H NMR (400 Mhz, acetone-d 6 ): δ 8.56 (brs, 1H), 8.26 (dd, J = 8.4, and 1.6 Hz, 1H), 8.17 (brs, 1H), 7.42-7.40 (m, 2H), 7.33-7.29 (m, 2H), 7.24 (dd, J = 8.4, and 2.0 Hz, 1H), 6.48 (s, 1H), 4.49 (s, 2H), 3.56 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.93 (s, 3H), 1.32 (s, 9H); MS (ESI) m/z: 536.0 (M+H + ).

To a solution of hydrocarbostyril (7.8 g, 0.53 mol) in cone. H 2 SO 4 (200 mL) was slowly added H 2 O (50 mL) at -10 °C. Cone. HNO 3 (70%, 4.0 mL) was added dropwise at -10 °C. The yellow solution was stirred at -10 °C for 10 min and then carefully quenched with ice H 2 O (500 mL). The precipitated yellow solid was filtered, washed with H 2 O and dried under vacuum to obtain 6-nitro-3,4-dihydroquinolin-2(7H)-one (7.9 g, 78% yield). 1 H NMR (400 Mhz, CDCl 3 ): δ 9.28 (s, 1H), 8.12 (m, 2H), 6.95 (d, J = 9.2 Hz, 1H), 3.12 (t, J = 7.2 Hz, 2H), 2.75 (d, J = 7.2 Hz, 2H).

To a solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (0.46 g, 2.4 mmol) and NBS (0.53 g, 3.0 mmol) in CHCl 3 (20 mL) was added benzoyl peroxide (cat. amount) at RT. The mixture was refluxed at 80 °C for 3h. More NBS (0.25 g) was added and the reaction mixture was refluxed at 80 °C for Ih. The solvent was evaporated and the residue was dissolved in EtOH. The solid was filtered, washed with EtOH and dried under vacuum to obtain 6-nitroquinolin-2-ol as a pale yellow solid (0.36 g, 79% yield). 1 H NMR (400 MHz, DMSO-Ci 6 ): δ 8.71 (d, J = 2.0 Hz, 1H), 8.34 (dd, J = 2.8, and 9.2 Hz, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 6.68 (dd, J = 1.6, and 9.6 Hz, 1H). LC-MS (EI) m/z: 191.0 (M+H + ).

A mixture of 6-nitroquinolin-2-ol and PtO 2 (20 mg) in EtOH (30 mL) was stirred under H 2 (1 atm) for 2Oh. More PtO 2 (10 mg) was added and was stirred under H 2 (1 atm) for 2 days. The solution was filtered and washed with MeOH and CHCl 3 . The solvent was evaporated and the residue was dried under vacuum to obtain 6-aminoquinolin-2(7H)-one as a yellow solid (0.28 g, 92% yield). LC-MS (EI) m/z: 161.0 (M+η + ).

To a solution of 6-aminoquinolin-2(/H)-one in cone. HCl (1.5 mL) was added an aqueous solution (0.75 mL) of NaNO 2 dropwise at 0 °C. The reaction mixture was stirred at 0 °C for Ih, and then added a soultion of SnCl 2 -2η 2 O in cone. HCl (0.75 mL) dropwise at 0 °C. The reaction mixture was allowed to reach RT over a period of 30 min and then stirred for additional 2h. The reaction mixture was diluted with EtOH. The mixture was filtered to remove some solids and then pivaloylacetonitrile was added into the solution. The reaction mixture was heated at 80 °C for 16h. The reaction mixture was evaporated and the residue was suspended in ethyl acetate (30 mL) and treated slowly with satd. Na 2 CO 3 (30 mL). The solution was extracted with EtOAc (3x). The combined organics were washed H 2 O and dried (Na 2 SO 4 ). Filtration, evaporation, and drying under vacuum provided crude 6-(5-amino-3-t- butyl-1H-pyrazol-1-yl)quinolin-2(1H)-one which was used as is in the next reaction. LC-MS (EI) m/z: 283.0 (M+H + ).

Using general method A, Example A41 (90 mg, 0.32 mmol) in THF (3 mL) and 2,3-dichlorophenyl isocyanate (72 mg, 0.38 mmol) were combined to yield 1-(3-t-butyl-1-(2-oxo-l,2- dihydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(2,3-dichlorophenyl )- urea as a yellow solid (52 mg, 35% yield). 1 H NMR (400 MHz, DMSO-Ct 6 ): δ 9.22 (s, 1H), 8.74 (s, 1H), 8.07 (dd, J = 3.2, and 6.4 Hz, 1H), 8.01 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 2.4, and 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 3.24 Hz, 1H), 7.30 (s, 1H), 6.59 (dd, J = 1.6, and 9.2 Hz, 1H), 6.41 (s, 1H), 1.28 (s, 9H); MS (EI) m/z: 470.0 (M+H + ).

To a solution of (S)- 1,2,3,4- tetrahydroisoquinolone-3-carboxylic acid (5.00 g, 28.2 mmol) in cone. H 2 SO 4 (20 mL) at RT was added dropwise a solution of KNO 3 (2.95 g, 29.2 mmol) in cone. H 2 SO 4 (10 mL) without cooling. When the addition was complete, the mixture was stirred for 5 min and then carefully diluted with H 2 O and neutralized with cone. NH 4 OH (about 100 mL). The precipitate was filtered, washed with H 2 O and acetone and dried in vacuo to give 6.60 g (crude yield > 100%) of a mixture of nitrated compounds which was used as is in the next reaction. MS (EI) m/z: 223.0 (M+H + ).

To a solution of the mixture from the previous reaction (4.40 g, 18.6 mmol) in CH 2 C1 2 (100 mL) was added TFAA (3.89 mL, 5.87 g, 27.9 mmol) and the resulting solution was stirred at RT for 30 min. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x100 mL). The organic layer was dried (MgSO 4 ), concentrated, and dried to yield 6.2 g (100%) of (S)-methyl 7-nitro-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquino line-3- carboxylate and the 6-nitro isomer as a mixture. MS (EI) m/z: 333.0 (M+H + ).

To a solution of the two regioisomers (6.20 g, 18.7 mmol) in MeOH (100 mL) was added 10% Pd/C (0.397 g, 0.161 mmol) and the mixture was stirred under H 2 (1 atm). The mixture was filtered through Celite ® and concentrated to yield a yellow syrup of (S)-methyl 7-amino-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquino line-3-carboxylate and the 6- amino isomer as a mixture (6.1 g, crude yield > 100%) which was used without further purification. MS (EI) m/z: 303.0 (M+H + ).

To a solution of the mixture from the previous reaction (5.60 g, 16.5 mmol) in 2N HCl(30 mL) at 0 °C was added in portions solid NaNO 2 (1.14 g, 16.5 mmol) and the resulting solution was stirred for 45 min at 0 °C. SnCl 2 ^H 2 O (7.46 g, 33.1 mmol) was then added and the mixture was allowed to reach RT and was stirred for 90 min. Ethanol (270 mL) and pivaloylacetonitrile (3.10 g, 24.8 mmol) were added and the resulting solution was heated at reflux overnight. Ethanolwas removed under reduced pressure and 2N HC1 (500 mL) was added to the residue. The mixture was extracted with CH 2 Cl 2 (3 x 500 ml), the organic layer was dried (MgSO 4 ), concentrated, and purified via column chromatography to yield (3S)- methyl 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-2-(2,2,2-trifluoroacet yl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxylate and (3S)-methyl 6-(5-amino-3-t-butyl-1H-pyrazol-1- yl)-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline -3-carboxylate as a mixture (3.10 mg, 44%) heavily contaminated with pivaloylacetonitrile (around 70 mol%). This material was used directly for the next step. MS (EI) m/z: 425.2 (M+η + ).

Using general method A, the previous mixture (1.60 g, 3.77 mmol) and 2,3- dichlorophenyl isocyanate (4.50 g, 23.9 mmol) were combined and the mixture of two compounds separated by column chromatography to yield (3S)-methyl 7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-7H-pyrazol-1-yl)-2-(2,2,2-trifluoroac etyl)-l,2,3,4-tetrahydroiso- quinoline-3-carboxylate (275 mg, 12% yield), MS (EI) m/z: 612.1 (M+η + ) and (3S)-methyl 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-7H-pyrazol-1-y l)-2-(2,2,2-trifluoroacetyl)- l,2,3,4-tetrahydroisoquinoline-3-carboxylate (80 mg, 4% yield), MS (EI) m/z: 612.0 (M+η + ).

Using general method D, Example A41 (50 mg, 0.18 mmol) and Example A9 (34 mg, 0.18 mmol) were combined to yield 1 -(3-t-butyl- 1 -(2-oxo- 1 ,2-dihydroquinolin-6-yl)-1H- pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea as an off- white solid (34 mg, 45 % yield). 1 H NMR (DMSO-de): δ 9.01 (s, 1H), 8.40 (s, 1H), 8.37 (m, 2H), 7.98 (d, J = 9.6 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 2.4, and 8.8 Hz, 1H), 7.43 (m, 3H), 7.29 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 2.4 Hz, 1H), 7.08 (dd, J = 1.6, and 8.4 Hz, 1H), 6.70 (dd, J = 2.4, and 8.4 Hz, 1H), 6.58 (dd, J = 2.0, and 10.0 Hz, 1H), 6.36 (s, 1H), 1.27 (s, 9H); LC-MS (EI) m/z: 495.2 (M + H + ).

Using general method D, Example A41 (0.090 g, 0.20 mmol, 1.0 eq) and Example A12 (0.053 g, 0.22 mmol, 1.10 eq) and i-Pr 2 NEt (0.044 ml, 0.25 mmol, 1.25 eq) were combined to yield 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 (11.2 mg. 10% yield, 2 steps. 1 H NMR (acetone-^): 9.04 (s, 1H), 8.49-8.48 (m, 1H), 8.44 (s, 1H), 8.35 (brs, 1H), 7.96-7.94 (m, 1H), 7.87-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65-7.64 (m, 1H), 7.59-7.58 (m, 1H), 7.47-7.39 (m, 2H), 7.31-7.29 (m, 1H), 7.31-7.29 (m, 1H), 7.14-7.12 (m, 1H), 6.85-6.82 (m, 1H), 6.55 (s, 1H), 6/52 (s, 1H), 2.94 (s, 3H), 1.33 (s, 9H); MS (ESI) m/z: 552.2 (M+H + ).

Using general method D, Example A41 (0.075 g, 0.16 mmol) and Example All (0.04 g, 0.16 mmol) were combined to afford 1 -(3-t-butyl- 1 -(2-oxo- 1,2- dihydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(3-(8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

(0.062 g, 60%) as as the HC1 salt. 1 H NMR (400 MHz, DMSOd 6 ): D 9.37 (brs, 1H), 9.17 (s, 1H), 9.12 (s, 1H),

8.65 (brs, 1H), 8.16 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.81 (brs, 1H),

7.66 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.30-7.28 (m, 1H), 6.58 (d, J = 9.6 Hz, 1H), 6.40 (s, 1H), 3.70 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 561.3 (M+H + ).

Using general method D, Example A41 (0.081 g, 0.19 mmol) and Example A 12 (0.05 g, 0.21 mmol) were combined to afford 1-(3-t-butyl-1-(2-oxo-l,2- dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2- (rnethylcarbamoyl)pyridin-4-yloxy)phenyl)urea (0.04 g, 60%, 2 steps) as a white solid HC1 salt. 1 H NMR (400 MHz, DMSO-^ 6 ): δ. 9.48 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.88 (s, 1H), 7.66 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.47-7.43 (m, 3H), 7.18-7.13 (m, 3H), 6.59 (d, J = 9.6 Hz, 1H), 6.37 (s, 1H), 2.79 (d, J = 4.8 Hz, 3H), 1.29 (s, 9H); MS (ESI) m/z:552.2 (M+H + ).

To a degassed solution of l-iodo-3-nitrobenzene (0.35 g, 1.4 mmol) in DME (5 mL) was added Pd(PPh 3 ) 4 (0.08 g, 10% mol). After stirring for 5 min, 3-pyridylboronicacid (0.2 g, 1.65 mmol) and 2M Na 2 CO 3 (1 mL) solution were added. After refluxing for 16h under an Ar atmosphere, the reaction mixture was poured into H 2 O (15 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), concentrated and purified via column chromatography to yield 3-(3-nitrophenyl)pyridine (0.22 g, 78%) as a white solid. 1 H NMR (CDCl 3 ): δ 8.94 (brs, 1H), 8.73 (brs, 1H), 8.48 (t, J = 1.6 Hz, 1H), 8.32 - 8.29 (m, 1H), 7.98 - 7.93 (m, 2H), 7.72 - 7.68 (m, 1H), 7.48 (brs, 1H); Exact mass: 200.0, Found: 201.0 (M+l) + .

To a solution of 3-(3-nitrophenyl)pyridine (0.22 g, 1.1 mmol) in EtOAc (10 mL) was added PtO 2 (0.025 g, 10% mol) and the mixture was stirred for 4h under H 2 (1 atm). It was filtered through Celite ® and the combined filtrates were concentrated to yield 3-(pyridin-3- yl)benzenamine (0.175 g, 94%) as a semi solid which was used without further purification. 1 H NMR (DMSO-de): δ 8.77 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.57- 7.52 (m, 1H), 7.46-7.43 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.86 - 6.80 (m, 2H), 6.63 - 6.60 (m, 1H), 5.23 (s, 2H); Exact mass: 170.0, Found: 171.0 (M+l) + .

Using the same procedure as for Example A43, 5-iodo-2- aminopyridine (0.31 g, 1.4 mmol) and 3-nitrophenylboronic acid (0.28 g, 1.7 mmol) were combined to yield 5-(3- nitrophenyl)pyridin-2-amine (0.18 g, 60%) as a white solid. 1 H NMR (DMSO-d 6 ): δ 8.37 (d, J = 2.4 Hz, 1H), 8.34 (t, J = 2.0 Hz, 1H), 8.11 - 8.04 (m, 2H), 7.83 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 6.55 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 6.26 (s, 2H); Exact mass: 215.0, Found: 216.0 (M+l) + .

To a solution of 5-(3-nitrophenyl)pyridin-2-amine (0.17 g, 0.8 mmol) in CH 2 C1 2 (10 mL) was added pyridine (0.12 g, 1.6 mmol) and TFAA (0.2 g, 0.9 mmol). After stirring for Ih at RT, 3M HCl (20 mL) was added to the reaction and the product was extracted with CH 2 C1 2 (2x20 mL). The combined organic extracts were washed with satd. NaHCO 3 solution (1x25 mL) and brine, then dried (Na 2 SO 4 ) and concentrated to yield a solid. This solid was dissolved in EtOAc, and PtO 2 was added to this mixture which was stirred under H 2 (1 atm) for 4h. The mixture was filtered through Celite ® , and the combined filtrates were concentrated to yield N-(5-(3-aminophenyl)pyridin-2-yl)-2,2,2-trifluoroacetamide (0.21 g, 95%) as a solid which was used without further purification. 1 H NMR (DMSO-d ό ): δ 8.65 (d, J = 2.4 Hz, 1H), 8.11 - 8.09 (m, 1H), 8.03 - 8.01 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.92 - 6.88 (m, 2H), 6.66 - 6.64 (m, 1H); Exact mass: 281.1, Found: 282.3 (M+l) + .

Using general procedure D, Example A35 (0.09 g, 0.2 mmol) and Example A44 (0.05 g, 0.20 mmol) were combined and deprotected using general method G to yield 1 -(3-(6-aminopyridin-3-yl)phenyl)-3-(3-t-butyl- 1 -(2-oxo- l,2,3,4-tetrahydroquinolin-6-yl)-7//-pyrazol-5-yl)urea (47 mg, 45% yield) as a solid. 1 H NMR ( 400 MHz, DMSO-4): δ 10.27 (s, 1H), 9.40 (s, 1H), 8.58 (s, 1H), 8.23-8.21 (m, 2H), 8.11 (brs, 1H), 7.77 (s, 1H), 7.38-7.33 (m, 2H), 7.28-7.24 (m, 2H), 7.10 (d, J = 0.8 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.35 (s, 1H), 2.95 (t, J = 6.4 Hz, 2H), 1.27 (s, 9H); MS (ESI) m/z: 496.3 (M+H + ).

Using general method D, Example A35 (0.09 g, 0.2 mmol) and Example A43 (0.034 g, 0.2 mmol) were combined to yield 1-(3-t-butyl- 1 -(2-oxo- 1 ,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrazol-5-yl)-3-(3-(pyridin-3-yl)phenyl)urea (76 mg, 74%) as a white solid as the HCl salt. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.27 (s, 1H), 9.70-9.67 (m, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 8.77 (brs, 2H), 8.11-8.08 (m, 1H), 7.95 (s, 1H), 7.47 (s, 2H),

7.35 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 2.95 (t, J = 7.6

Hz, 2H), 1.27 (s, 9H); MS (ESI) m/z: 481.2 (M+H + ).

To a suspension of 6-aminoquinolin-2(1H)-one (0.72 g, 4.5 mmol, see Example A41) in cone. HC1 (5 mL) was slowly added NaNO 2 (0.43 g, 6.3 mmol) solution in H 2 O (5 mL) at 0 °C. After stirring for Ih, SnC1 2 2H 2 O (2.0 g, 9.0 mmol), dissolved in cone. HCl (7 mL), was slowly added at such a rate that the temperature of the mixture did not rise above 5 °C. After stirring for 2h, the resultant solid was filtered, dried, and suspended in EtOH. To this were added 3-cyclopentyl-3-oxopropanenitrile (0.68 g, 4.9 mmol) and a few drops of HC1 and the mixture was heated at 80 °C for 16h. The solution was concentrated, dissolved in satd. NaHCO 3 solution and the product was extracted with EtOAc (2x30 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), concentrated and the resultant solid triturated with toluene (10 mL) and filtered to yield 6-(5- amino-3-cyclopentyl-/H-pyrazol-1-yl)quinolin-2(7H)-one (0.75 g, 57% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.95 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.32 (s, 1H), 5.24 (brs, 2H), 2.92-2.84 (m, 1H), 1.94-1.86 (m, 2H), 1.73-1.57 (m, 6H); MS (ESI) m/z: 295.2 (M+H + ).

Using general method D, Example A45 (0.075 g, 0.16 mmol)) and Example All (0.04 g, 0.16 mmol) were combined to yield 1-(3-cyclopentyl-1-(2-oxo-l,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 (0.075 g, 47% yield, 2 steps) as a solid HCl salt. 1 H NMR (400 MHz, DMSOd 6 ): δ 9.71 (brs, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.56 (brs, 1H), 8.15 (s, 1H), 8.11 (d, / = 9.6 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.79 (brs, 1H), 7.67 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.46-7.41 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.28-7.26 (m, 1H), 6.57 (d, J = 9.6 Hz, 1H), 6.33 (s, 1H), 3.70 (s, 3H), 3.06-2.98 (m, 1H), 1.99-1.94 (m, 2H), 1.72-1.59 (m, 6H); MS (ESI) m/z: 573.3 (M+H + ).

Using general method D, Example A45 (0.075 g, 0.16 mmol) and Example A12 (0.04 g, 0.16 mmol) were combined to yield 1-(3-cyc!opentyl-1-(2-oxo-l,2- dihydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (0.038 g, 31% yield, 2 steps) as a solid HC1 salt. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.59 (brs, 1H), 8.88 (brs, 1H), 8.81 (s, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.54-7.42 (m, 4H), 7.17-7.13 (m, 3H), 7.58 (d, J = 9.6 Hz, 1H), 6.33 (s, 1H), 3.06-2.98 (m, 1H), 2.78 (d, J = 6.0 Hz, 3H), 1.99-1.94 (m, 2H), 1.72-1.59 (m, 6H); MS (ESI) m/z: 564.3 (M+H + ).

Using general method D, Example A45 (0.075 g, 0.16 mmol) and Example A9 (0.03 g, 0.16 mmol) were combined to yield 1-(3-cyclopentyl-1-(2-oxo-l,2- dihydroquinolin-6-yl)-7H-pyrazol-5-yl)-3-(3-(pyridin-3- yloxy)phenyl)urea (0.07 g, 52%, 2 steps) as a solid. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.63-9.61 (m, 1H), 8.80- 8.79 (m, 1H), 8.65-8.64 (m, 1H), 8.57-8.56 (m, 1H), 7.98 (d, J = 10.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.86 (d, / = 4.4 Hz, 1H), 7.83-7.79 (m, 1H), 7.64 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.15-7.13 (m, 1H),

6.76 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.57 (d, J = 10.0 Hz, 1H), 6.29 (s, 1H), 3.04-2.97 (m, 1H), 1.98-1.93 (m, 2H), 1.72-1.60 (m, 6H); MS (ESI) m/z: 507.2 (M+H + ).

To a solution of 8-amino-l,2,4,5-tetrahydrobenzo[c]azepin-3-one (0.5 g, 2.8 mmol) in cone. HCl (3 mL) was added an aqueous solution (2 mL) of NaNO 2 dropwise at 0 °C. The reaction mixture was stirred at 0 °C for Ih, and then treated dropwise with a solution of SnC1 2 -2H 2 O in cone. HCl (2 mL) at 0 °C. The reaction mixture was allowed to reach room temperature over a period of 30 min and then stirred for an additional 2h at RT. This solution was concentrated and used directly for the next step. The material from the previous reaction (0.65 g, 2.8 mmol) was dissolved in EtOH (10 mL) and some solid was filtered off. Pivaloylacetonitrile (0.36 g, 2.8 mmol) was added to the solution. The reaction mixture was heated at 80 °C overnight, then evaporated and the residue was suspended in EtOAc (30 mL) and treated slowly with satd. Na 2 CO 3 (30 mL). The solution was extracted with EtOAc (3x), and the combined organics were washed with H 2 O, dried (Na 2 SO 4 ), filtered, concentrated and dried under vacuum to provide crude product in 65% yield. This was dissolved in toluene (10 mL) with molecular sieves (4 A). The reaction mixture was refluxed overnight, concentrated and the residue dried under vacuum. This was used for the next reaction without further purification. MS (EI) m/z: 299.0 (M + H + ).

Using general method A, Example A46 (23 mg, 0.077 mmol) and 2,3-dichlorophenylisocyanate (17 mg, 0.092 mmol) were combined to yield 1-(3-t-butyl-1-(2-oxo-2,3,4,5-tetrahydro-7H- benzo[d]azepin-7-yl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (23 mg, 61% yield) as a pale yellow powder. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.20 (s, 0.84H), 9.04 (s, 0.26H), 8.76 (s, 0.84H), 8.75 (s, 0.26H), 8.06 (m, 1H), 7.66 (t, J = 5.6 Hz, 0.84H), 7.51 (t, J = 5.6 Hz, 0.26H), 7.31 (m, 4H), 6.38 (s, 0.26H), 6.37 (s, 0.84H), 3.88 (s, 0.48H), 3.82 (s, 1.72H), 3.48 (dd, / = 5.6, and 11.6 Hz, 1.72H), 3.41 (m, 0.48H), 3.07 (U J = 6.0 Hz, 2H), 1.27 (s, 7.56H), 1.26 (s, 2.16H); MS (EI) m/z: 487.0 (M+H + ).

beta-Tetralone (34 mmol) was suspended in 300 mL of 85% H 3 PO 4 and treated portion wise with NaN 3 (68 mmol) with vigorous stirring over a period of 1 h. During this time the reaction mixture was brought slowly to about 70 °C. After stirring for a further 2h at 70 °C, no more N 2 evolution was observed. The reaction mixture was cooled to RT, then poured into cold H 2 O (400 mL) and extracted with CHCl 3 (3x). The organic layer was dried (MgSO 4 ), concentrated and the residue was dissolved in EtOAc and the solid was filtered and washed with EtOAc to yield 4,5-dihydro-7H-benzo[d]azepin- 2(3H)-one as a white solid (20% yield) along with a varying amount of the other region isomer 1 ,2,4,5-tetrahydrobenzo[c]azepin-3-one.

To a solution of regioisomers from the previous reaction (16.6 mmol) in CH 2 Cl 2 were added Et 3 N (16.6 mmol), di-t-butyl dicarbonate (33.1 mmol) and DMAP (16.6 mmol), and the mixture stirred at RT for 24h. The reaction mixture was purified by column chromatography to yield Boc-protected 4,5-dihydro-7H-benzo[d]azepin-2(.3H)-one as white solid in 20% yield. A solution of this material (2.7 mmol) in 3N ηCl/EtOAc (4 mL) was stirred at 0 °C for 3h. The solvent was neutralized by 20% NaOH. The solution was extracted with CHCl 3 (3x) and washed with H 2 O. The organic layer was dried (MgSO 4 ), and concentrated to afford 4,5-dihydro-1H-benzo[d]azepin-2(JH)-one (0.64 g, 91% yield) as a white solid. LC-MS (EI) m/z: 162.2 (M+η + ).

A solution of 4,5-dihydro-7H-benzo[d]azepin-2(5H)-one (3.5 mmol) was in TηF (25 mL) was stirred at 0 °C for 5 min. A solution of IM BH 3 THF (4 mL) was added dropwise to the reaction mixture at 0 °C over a period of 30 min. The ice bath was removed and the reaction stirred at RT for 30 min. The reaction mixture was heated at 60 °C overnight, then cooled to 0 °C and additional IM BH 3 -THF (2.5 mL) was added dropwise into the reaction mixture at 0 °C over a period of 15 min. The ice bath was removed and it was stirred at RT for 30 min then heated at 60 °C for 7h. The reaction mixture was cooled to RT, then further cooled with an ice-bath. The reaction was quenched by the addition of 2M HCl (15 mL). The mixture was heated for 30 min and then 20% NaOH (7.5 mL) was added with ice cooling. The solution was extracted with chloroform (3x) and the organic layer was washed with H 2 O. The organic layer was dried (Na 2 SO 4 ), concentrated and redissolved in 2 mL of EtOAc and acidified with 3M HCl/EtOAc. The solid was filtered and dried under vacuum to obtain 2,3,4,5-tetrahydro-7H-benzo[d]azepine as a shiny powder (0.36 g, 69% yield). LC- MS (EI) m/z: 148.2 (M+η + ).

A solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine dissolved in cone. H 2 SO 4 (1.5 mL) was cooled to 0 °C and a mixture of concentrated H 2 Sθ4 (0.12 mL) and fuming HN03 (0.06 mL) (also cooled to 0 °C) was added dropwise. After the addition was complete, the mixture was stirred for 15-30 min. The reaction mixture was poured onto 1Og of crushed ice, followed by the dropwise addition of 20% NaOH solution. The mixture was extracted with EtOAc (3x). The organic layer was washed with H 2 O, dried (Na 2 SO 4 ), concentrated and under vacuum to afford 7-nitro-2,3,4,5-tetrahydro-7H-benzo[d]azepine as a brown liquid (0.12 g, 46 % yield). LC-MS (EI) m/z: 193.0 (M+η + ).

To a solution of 7-nitro-2,3,4,5-tetrahydro-/H-benzo[d]azepine (1.1 mmol) in CH 2 Cl 2 (5 mL) was added TFAA (1.7 mmol) and the resulting solution was stirred at RT for 30 min. Water (10 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x10 mL), dried (MgSO 4 ), and concentrated under vacuum to yield 2,2,2-trifluoro-1-(7-nitro- 1,2,4,5- tetrahydrobenzo[d]azepin-3-yl)ethanone as a yellow syrup (0.32 g, 96% yield). LC-MS (EI) m/z: 299.3 (M+H + ).

To a suspension of 2,2,2-trifluoro-1-(7-nitro-l,2,4,5-tetrahydrobenzo[d]azepin- 3- yl)ethanone (1.1 mmol) in MeOH (5 mL) was added 10% Pd/C and the mixture was stirred at RT under H 2 (1 atm) for 24h. After filtration, the filtrate was concentrated to afford 1-(7- amino-l,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,2,2-trifluoro ethanone (0.27g, 95% yield). LC-MS (EI) m/z: 259.0 (M+H + ).

To a solution of 1-(7-amino-l,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,2,2-trif luoroethanone (1.6 mmol) in cone. HCl (2 mL) was added an aqueous solution (1 mL) Of NaNO 2 (2.4 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for Ih, and was followed by the addition of a solution of SnCl 2 -2H 2 O (5.0 mmol) in cone. HCl (1 mL) dropwise at 0 °C. The reaction mixture was allowed to reach RT over a period of 30 min and then stirred for additional 2h. The solution was concentrated and redissolved in EtOH, and pivaloylacetonitrile (3.7 mmol) was added. The reaction mixture was heated at reflux for 16h. The reaction mixture was evaporated and the residue suspended in EtOAc (30 mL) and treated slowly with satd. NaHCO 3 (30 mL). The biphasic mixture was stirred at RT for 2h. The aqueous layer was treated with 6M NaOH to pH 8 and filtered to remove the tin salts. The filtrate was extracted with EtOAc (3x). The combined organics were washed with satd. NaHCO 3 (Ix), brine (Ix) and dried (Na 2 SO 4 ). Filtration, evaporation and drying under vacuum provided crude product (0.21 g, 71% yield). LC-MS (EI) m/z: 285.2 (M + H + ).

This material (0.74 mmol) was dissolved in CH 2 Cl 2 and Boc anhydride (0.74 mmol) was added. The resultant solution was stirred at RT for 30 min and evaporated to yield t-butyl

7-(5-amino-3-t-butyl-i//-pyrazol-1-yl)-l,2,4,5-tetrahydroben zo[d]azepine-3-carboxylate (0.26 g, 98 % yield). LC-MS (EI) m/z: 385.2 (M+H + ).

Using general method A, Example A47 (65 mg, 0.17 mmol) and 2,3-dichlorophenyl isocyanate (32 mg, 0.17 mmol) were combined and the product deprotected using general method F to yield 1-(3-t-butyl-1-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)- 7H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (50 mg, 58% yield). 1 H NMR (400 MHz, DMSOd 6 ): δ 9.28 (s, 1H), 8.89 (m, 1H), 8.81 (s, 1H), 8.03 (dd, J = 4.0, and 5.6 Hz, 1H), 7.42 (brs, 1H), 7.31 (m,4H), 6.37 (s, 1H), 3.20 (m, 4H), 3.14 (m, 4H), 1.26 (s, 9H); LC-MS (EI) m/z: 472.0 (M+H + ).

Using general method A, Example A47 (70 mg, 0.18 mmole) and 3-cyanophenylisocynate (26 mg, 0.18 mmol) were combined and the product deprotected using general method F to yield 1-(3-t- butyl-1-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-;H- pyrazol-5-yl)-3-(3-cyanophenyl)urea HC1 salt (24 mg, 29% yield). 1 H NMR (DMSO-de): δ 9.78 (s, 1H), 9.04 (m, 1H), 8.73 (s, 1H), 7.93 (t, J = 1.6 Hz, 1H), 7.61 (dt, J = 1.2, and 9.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (m, 2H), 7.34 (s, 1H), 6.37 (s, 1H), 3.19 (m, 4H), 3.14 (m, 4H), 1.27 (s, 9H); LC-MS (EI) m/z: 429.2 (M+H + ).

To a solution of commercially available 6-bromo- 1,2,3, 4-tetrahydro-2- quinolinone (5.0 g, 22 mmol) and NBS (4.9 g, 27 mmol) in CHCl 3 (80 mL) was added a catalytic portion of benzoyl peroxide at RT. The mixture was refluxed at 80 °C for 3h, after which additional NBS (2.0 g) was added and the reaction refluxed overnight at 80 °C. Additional NBS (0.9 g) was added into the reaction mixture which was refluxed at 80 °C for 5h. The solid was filtered, washed with EtOH and dried to yield 6-bromoquinolin-2(7H)-one (4.35 g, 88% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.93 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.64 (dd, J = 2.0, and 8.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.55 (dd, J = 2.0, and 9.6 Hz, 1H); LC-MS (EI) m/z: 224.0 (M+H + ).

6-Bromoquinolin-2(7H)-one (4.0 g, 18 mmol), 4-methoxybenzyl chloride (3.6 g, 23 mmol), and tetrabutylammonium bromide (1.2 g, 3.6 mmol) were dissolved in PhMe (200

mL) and then KOH (powder, 1.8 g, 32 mmol) was added into the reaction mixture. The reaction mixture was stirred at RT for 4h, then poured into H 2 O and extracted with EtOAc (3x50 mL). The organic layer was washed with H 2 O, dried (Na 2 SO 4 ), and concentrated. Trituration with hexane, followed by collection of the solids yielded 1-(4-methoxybenzyl)-6- bromoquinolin-2(7H)-one (5.4 g, 87% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.70 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.52 (dd, J = 2.0, and 8.8 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.85(d, J = 8.8 Hz, 2H), 6.83 (d, J = 9.4 Hz, 1H), 5.48 (brs, 2H), 3.78 (s, 3H), 1.36 (s, 12H); LC-MS (EI) m/z: 344.0 (M+H + ).

Potassium acetate (54.3 g, 44 mmol), pinacol diboron (5.5 g, 22 mmol) and PdCl 2 (dppf) (0.60 mg, 0.73 mmol) were added sequentially to a solution 1-(4- methoxybenzyl)-6-bromoqumolin-2(1H)-one (5.0 g, 15 mmol) in DMF (70 mL). After flushing with N 2 , the reaction vessel was sealed and heated at 80 °C for 14h andthen partitioned between H 2 O and EtOAc. The combined organic extracts were washed with brine, dried (MgSO 4 ) concentrated and purified via column chromatography to yield 1-(4- methoxybenzyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)quinolin-2(7H)-one (38 g, 67% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.04 (brs, 1H), 7.86 (dd, J = 1.2, and 8.4 Hz, 1H), 7.76 (d, / = 9.6 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.83 (d, 7 = 8.8 Hz, 2H), 6.80 (d, J = 9.6 Hz, 1H), 5.52 (brs, 2H), 3.77 (s, 3H), 1.36 (s, 12H); LC-MS (EI) m/z: 392.3 (M+H + ).

Sodium periodate (5.9 g, 28 mmol) was added to a solution of 1-(4-methoxybenzyl)- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-2(/H )-one (3.6 g, 9.2 mmol) in TηF/η 2 O (4/1, 40 mL). The reaction mixture was stirred at RT for 30 min, after which 2N HCl (9.2 mL) was added and the solution was then stirred at RT for 3h. The solution was extracted with EtOAc (3x50 mL) and the organic layer was dried (MgSO 4 ), and concentrated to yield crude 1-(4-methoxybenzyl)-2-oxo-l,2-dihydroquinolin-6-ylboronic acid (2.6 g, 90% yield) which was used without further purification. 1 H NMR (400 MHz, DMSO-4): δ 8.10 (brs, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.88 (dd, J = 1.6, and 8.8 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 9.6 Hz, 1H), 5.45 (brs, 2H), 3.69 (s, 3H); LC-MS (EI) m/z: 310.0 (M+H + ). 1-(4-Methoxybenzyl)-2-oxo-l,2-dihydroquinolin-6-ylboronic acid (1.8 g, 5.8 mmol) was dissolved in CH 2 Cl 2 (120 mL) and pyridine (10 mL) with molecular sieves (activated, 4A) and the solution was kept overnight at RT. Commercially available ethyl 3-t-butyl-7H- pyrazole-5-carboxylate (1.2 g, 5.8 mmol), Cu(OAc) 2 (1.1 g, 5.8 mmol) and molecular sieves (4A activated, powder) were added to the boronic acid solution and the reaction mixture was

stirred open to the air at RT for 3 days. The reaction mixture was filtered through a pad of Celite ® , and the filtrate was evaporated under reduced pressure and purified by silica gel column chromatography to yield ethyl 1-(1-(4-methoxybenzyl)-2-oxo-l,2-dihydroquinolin-6- yl)-3-t-butyl-7H-pyrazole-5-carboxylate (2.5 g, 94% yield). LC-MS (EI) m/z: 460.3 (M+η + ).

A solution of ethyl 1-(1-(4-methoxybenzyl)-2-oxo-l,2-dihydroquinolin-6-yl)-3-t- butyl-7H-pyrazole-5-carboxylate (1.5 g, 3.3 mmol) in TFA (25 mL) was heated in a sealed tube at 100 °C for 7h. The mixture was cooled, concentrated and purified by silica gel column chromatography to yield ethyl 3-t-butyl-1-(2-oxo-l,2-dihydroquinolin-6-yl)-7H- pyrazole-5-carboxylate (1.0 g, 90% yield). 1 H NMR (400 MHz, CDC1 3 ): δ 7.95 (d, J = 9.6 Hz, 1H), 7.77 (d, 7 = 2.0 Hz, 1H), 7.66 (dd, J = 2.4, and 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.82 (d, J = 9.2 Hz, 1H). LC-MS (EI) m/z: 340.3 (M+H + ).

To a stirred suspension of ethyl 3-t-butyl-1-(2-oxo-l,2-dihydroquinolin-6-yl)-7H- pyrazole-5-carboxylate (1.0 g, 2.95 mmol) and Et 3 N (0.45 g, 4.45 mmol) in CH 2 Cl 2 (30 ml) was added triflic anhydride (1.66 g, 5.9 mmol) at -78 °C and then maintained at this temperature for 30 min. The reaction was allowed to warm to RT over a period 1.5h, then quenched by pouring onto ice. The organic layer was washed with 10% NaOH, extracted with CH 2 Cl 2 (3x50 mL). washed with brine, dried (Na 2 SO 4 ), concentrated and purified by coulmn chromatography to yield ethyl 3-t-butyl-1-(2-(trifluoromethylsulfonyloxy)quinolin-6- yl)-7H-pyrazole-5-carboxylate (1.3 g, 94% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.40 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.04 (d, / = 2.0 Hz, 1H), 7.90 (dd, J = 2.4 and, 9.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.41 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H); LC-MS (EI) m/z: 472.0 (M+H*).

To a solution of Example A48 (0.10 g, 0.21 mmol) in DMSO (1 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (0.055 g, 0.47 mmol). The reaction mixture was heated at 40 °C for Ih. Ethyl acetate was added and the resulting solution was washed with brine, dried (Na 2 Sd) and concentrated under reduced pressure to yield ethyl 3-t-butyl-1-(2-((R)-3- (dimethylamino)pyrrolidin- 1 -yl)quinolin-6-yl)-/H-pyrazole-5- carboxylate (88 mg, 95% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 2.0 and, 8.4 Hz, 1H), 6.92 (s, 1H), 6.76 (d, J = 9.2 Hz, 1H), 4.21 (q, J = 7.6 Hz, 2H), 4.03 (m, 1H), 3.88 (m. 1H), 3.60 (m, 1H), 3.49 (m, 1H), 2.98 (m, 1H), 2.63 (s, 6H), 2.33 (m, 1H), 2.04 (m, 1H), 1.40 (s, 9H), 1.21 (t, J = 7.6 Hz, 3H); LC-MS (EI) m/z: 436.2 (M+H*).

Using the same procedure as for Example A49, Example A48 (0.2 g, 0.42 mmol) and t-butyl piperazine-1-carboxylate (0.17 g, 0.93 mmol) were combined to yield t-butyl 4-(6-(5-amino-3-t-butyl-/H-pyrazol-1- yl)quinolin-2-yl)piperazine-1-carboxylate (210 mg, 98% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.94 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.71 (d, / = 2.4 Hz, 1H), 7.58 (dd, J = 2.4 and, 8.8 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 6.92 (s, 1H), 4.22 (q, / = 7.2 Hz, 2H), 3.77 (m, 4H), 3.61 (m. 4H), 2.64 (s, 6H), 1.52 (s, 9H), 2.33 (m, 1H), 1.40 (s, 9H), 1.22 (t, J = 7.6 Hz, 3H); LC-MS (EI) m/z: 508.3 (M+H + ).

Using the same procedure as for Example A49, Example A48 (0.20 g, 0.42 mmol) and t-butyl 2-aminoethylcarbamate (0.15 g, 0.93 mmol) were combined to yield ethyl 1-(2-(2-(t-butoxycarbonyl)ethylamino)quinolin-6- yl)-3-t-butyl-7H-pyrazole-5-carboxylate (0.20 mg, 98% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.4 and, 8.8 Hz, 1H), 6.93 (s, 1H), 6.73 (m, 1H), 5.57 (brs, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.70 (brq, J = 5.2 Hz, 2H), 3.45 (brq, J = 5.2 Hz, 2H), 1.45 (s, 9H), 1.40 (s, 9H), 1.24 (t, 7 = 7.2 Hz, 3H); LC-MS (EI) m/z: 482.2 (M+H + ).

Using the same procedure as for Example A49, Example A48 (0.20 g, 0.42 mmol) and MeNH 2 HCl (0.043 g, 0.64 mmol) were combined to yield ethyl 3-t-butyl-1-(2-(dimethylamino)quinolin-6-yl)-1H-pyrazole-5- carboxylate (82 mg, 55% yield). 1 H NMR (400 MHz, CDC1 3 ): δ 7.90 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 2.0, and 8.8 Hz, 1H), 7.17 (q, J = 4.8 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 2.92 (d, J = 4.8 Hz, 1H), 1.32 (s, 9H); LC-MS (EI) m/z:

353.2 (M+H + ).

Using the same procedure as for Example A49, Example A48 (0.20 g, 0.42 mmol) and Me 2 NH HCl (0.026 g, 0.32 mmol) were combined to yield ethyl 3-t-butyl- 1 -(2-(dimethylamino)quinolin-6-yl)-./H-pyrazole-5- carboxylate (82 mg, 55% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.04 (s, 1H), 7.88 (m, 1H), 7.73 (m, 1H), 7.68 (brs, 1H), 7.57 (m, 1H), 6.94 (d, / = 8.8 Hz, 1H), 6.92 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.40 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); LC-MS (EI) m/z: 367.3

(M+H + ).

Using the same procedure as for Example A49, Example A48 (0.15 g, 0.42 mmol) and 4-methoxybenzylamine (0.13 g, 0.93 mmol) were combined to yield ethyl 1 -(2-(4-methoxybenzylamino)quinolin-6-yl)-3-t-butyl-1H- pyrazole-5-carboxylate (150 mg, 77%). LC-MS (EI) m/z: 459.2 (M+η + ). Using general method E, this material was saponified to yield 1-(2-(4- methoxybenzylamino)quinolin-6-yl)-3-t-butyl-7H-pyrazole-5-ca rboxylic acid in quantitative yield. A solution of this material in TFA (25 mL) was heated in sealed tube at 100 °C for 7h. The mixture was cooled, concentrated and purified by silica gel column chromatography to yield 1-(2-aminoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5- carboxylic acid (0.1 g, 99% yield). LC-MS (EI) m/z: 311.2 (M+η + ).

To a solution of Example A50 (0.21 g, 0.41 mmol) in a mix of EtOH:dioxane:H 2 O (1 :1:1) (1 mL) was added LiOH (40 mg, 1.7 mmol). The mixture was stirred overnight at RT then diluted with EtOAc (50 mL) and 5% citric acid (50 mL). The organic phase was separated, washed with brine (20 mL), dried (Na 2 SO 4 ), concentrated and dried to yield 1-(2-(4-(t- butoxycarbonyl)piperazin-1-yl)quinolin-6-yl)-3-t-butyl-/H- pyrazole-5-carboxylic acid as a yellow solid in quantitative yield. LC-MS (EI) m/z: 480.2 (M+η + ).

To a solution of 1-(2-(4-(t-butoxycarbonyl)piperazin-1-yl)quinolin-6-yl)-3-t- butyl-7H- pyrazole-5-carboxylic acid (0.1 g, 0.21 mmol) in toluene (2 mL) was added Et 3 N (0.032 mmL, 0.23 mmol) and 2,3-dichloroaniline (84 mg, 0.52 mmol). The reaction mixture was stirred at RT and DPPA (63 mg, 0.23 mmol) was added. The reaction mixture was heated at

100 °C for 2h, cooled, quenched with H 2 O, and extracted with EtOAc (3x50 mL). The organic extracts were washed with brine, dried (Na 2 SO 4 ), concentrated and purified by column chromatography to yield t-butyl 4-(6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H- pyrazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate (0.11 g, 83% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.26 (s, 1H), 8.77 (s, 1H), 8.17 (d, / = 9.6 Hz, 1H), 8.07 (dd, J = 3.2, and 6.8 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.68 ( m, 2H), 7.31 (m, 3H), 6.42 (s, 1H), 3.74 (m, 4H), 3.47 (m, 4H), 1.44 (s, 9H), 1.30 (s, 9H); LC-MS (EI) m/z: 638.3 (M+H + ).

The material from the previous reaction (0.11 g, 0.17 mmol) was dissolved in EtOAc, 3M HC1/EtOAc (2 mL) was added and the solution was stirred at RT for 5h. The solution was concentrated and the residue was dissolved in H 2 O/CH 3 CN (1:1, 4 mL) and lyopholized to obtain 1-(3-t-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol- 5-yl)-3-(2,3- dichlorophenyl)urea (65 mg, 66% yield) as a white solid HCl salt. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.55 (brs, 1H), 9.37 (brs, 2H), 8.89 (s, 1H), 8.40 (brd, J = 7.6 Hz, 1H), 8.07 (brs, 1H), 8.00 (m, 2H), 7.87 (m, 1H), 7.53 (brd, J = 8.4 Hz, 1H), 7.29 (d, J = 4.8 Hz, 2H), 6.42 (s, 1H), 4.10 (m, 4H), 3.29 (m, 4H), 1.30 (s, 9H); LC-MS (EI) m/z: 538.3 (M+H + ).

Using the same procedure as for Example 168 Example

A50 (100 mg, 0.21 mmol), and Example All (58 mg, 0.23 mmol) were combined to yield 1 -(3-t-butyl- 1 -(2-

(piperazin- 1 -yl)quinolin-6-yl)-7H-pyrazol-5-yl)-3-(3-(8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)urea (69 mg, 42% yield, 3 steps) as the HCl salt.

1 H NMR (400 MHz, DMSO-d 6 ): δ 9.30 (brm, 1H), 9.15 (s, 1H), 9.11 (s, 1H), 8.96 (brm, 2H), 8.60 (brm, 2H), 8.27

(brm, 1H), 8.15 (s, 1H), 7.97 (brm, 1H), 7.81 (brs, 1H), 7.78 (brm, 1H), 7.43 (m, 1H), 7.35 (brt, J = 7.6 Hz, 1H), 7.28 (m, 1H), 6.41 (s, 1H), 4.01 (m, 4H), 3.97 (m, 4H), 3.71 (s, 3H), 3.26 (m, 4H), 1.30 (s, 9H); LC-MS (EI) m/z: 629.2 (M+H + ).

Using the same procedure as for Example 168, Example A50 (0.10 g, 0.21 mmol) and Example A12 (0.13 g, 0.52 mmol) were combined to yield 1-(3-t-butyl-1-(2-(piperazin- l-yl)quinolin-6-yl)-7H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (90 mg, 59% yield, 3 steps) as an off-white solid HCl salt. 1 H NMR (400 MHz, DMSOd 6 ): δ 9.33 (brs, 1H), 9.02 (brs, 2H), 8.78 (m, 2H), 8.63 (brs, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.30 (m, 1H), 7.94 (m, 1H), 7.80 (m, 1H), 7.52 (m, 2H), 7.45 (m, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.13 (m, 2H), 6.41 (s, 1H), 4.01 (m, 4H), 3.27 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 620.2 (M+H + ).

Using the same procedure as for Example 168,

Example A50 (0.10 g, 0.21 mmol), and Example A7

(0.14 g, 0.52 mmol) were combined to yield 1-(3-t- butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-7H-pyrazol-

5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)phenyl)urea (94 mg, 57% yield, 3 steps) as the

HCl salt. 1 H NMR (400 MHz, 400 MHz, DMSOd 6 ): δ 9.36 (brm, 1H), 9.27 (brm, 1H), 8.99 (brs, 1H), 8.82

(brd, J = 4.8 Hz, 1H), 8.78 (brm, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.37 (brd, J = 9.2 Hz, 1H), 8.04 (brs, 1H), 7.95 (brm, 1H), 7.83 (m, 1H), 7.76 (brm, 1H), 7.49 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 7.06 (dd, J = 2.0, and 8.4 Hz, 2H), 6.41 (s, 1H), 4.14 (brm, 4H), 3.28 (brm, 4H), 3.15 (brd, J = 4.8 Hz, 3H), 2.18 (s, 3H), 1.32 (s, 9H); LC-MS (EI) m/z: 654.3 (M+H + ).

Using the same procedure as for Example 168, Example

A51 (0.10 g, 0.21 mmol) and Example A12 (0.11 g, 0.44 mmol) were combined to yield 1-(1-(2-(2- aminoethylamino)quinolin-6-yl)-3-t-butyl-7//-pyrazol-5- yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea

(100 mg, 75% yield, 3 steps) as a pale yellow solid HCl salt. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.51 (brs, 1H),

8.80 (brs, 1H), 8.78 (m, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.39 (m, 1H), 8.15 (m, 3H), 7.98 (m, 1H), 7.52 (m, 2H), 7.36 (d, J = 2.8 Hz, 1H), 7.21 (m, 1H), 7.14 (m, 3H), 6.42 (s, 1H), 3.92 (m, 2H), 3.18 (m, 2H), 2.78 (d, J = 4.8 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 594.2 (M+H + ).

Using the same procedure as for Example 168, Example A49 (0.08 g, 0.21 mmol) and Example A12 (0.13 g, 0.52 mmol) were combined to yield 1 -(3-t-butyl- 1-(2-((R)-3- (dimethylamino)pyrrolidin- 1 -yl)quinolin-6-yl)-7H- pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea (30 mg, 20% yield) as a yellow solid HCl salt. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.77 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 7.14 (m, 3H), 6.41 (s, 1H), 4.15 (brs, 1H), 4.06 (brs, 1H), 3.95 (brs, 1H), 3.64 (brs, 1H), 2.87 (brt, J = 5.6 Hz, 6H), 2.78 (d, J = 4.8 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 648.2 (M+H + ).

Using the same procedure as for Example 168, Example A52 (0.04 g, 0.11 mmol) and Example A12 (0.07 g, 0.27 mmol) were combined to yield 1 -(3-t-butyl- 1 -(2- (methylamino)quinolin-6-yl)-7H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (53 mg, 74% yield) as the HC1 salt. 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.87 (brm, 1H), 9.38 (brs, 1H), 8.78 (brm, 1H), 8.74 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.35 (brd, J = 9.2 Hz, 1H), 8.13 (brs, 1H), 8.11 (brm, 1H), 7.97 (dd, J = 2.0, and 9.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.14 (m, 3H), 6.42 (s, 1H), 3.15 (brd, J = 4.8 Hz, 3H), 2.78 (d, J = 5.2 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 565.3 (M+H + ).

Using the same procedure as for Example 168, Example A53 (0.08, 0.21 mmol) and Example A12 (0.13 g, 0.52 mmol) were combined to yield 1 -(3-t-butyl- 1 -(2- (dimethylamino)quinolin-6-yl)-7H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (61mg, 51% yield) as a pale yellow solid HCl salt. 1 H NMR (400

MHz, DMSO-d 6 ): δ 9.30 (brs, 1H), 8.78 (q, J = 4.4 Hz, 1H), 8.69 (brs, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.15 (m, 2H), 7.98 (m, 1H), 7.52 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.14 (m, 3H), 6.42 (s, 1H), 3.38 (brs, 6H), 2.78 (d, J = 4.8 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 579.2 (M+H + ).

Using the same procedure as for Example 168, Example A54 (0.085 g, 0.27 mmol) and Example A12 (0.10 g, 0.41 mmol) were combined to yield 1-(1-(2-aminoquinolin-6- yl)-3-t-butyl-;H-pyrazol-5-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (48 mg, 33% yield) as the HCl salt. 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.59 (brs, 1H), 9.20 (brs, 1H), 8.90 (brs, 1H), 8.79 (q, J = 4.4 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.48 (d, / = 9.2 Hz, 1H), 8.17 (d, / = 2.4 Hz, 1H), 7.97 (dd, J = 2.0, and 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.52 (m, 2H), 7.37 (m, 3H), 7.17 (m, 4H), 6.41 (s, 1H), 2.78 (d, J = 4.4 Hz, 3H), 1.31 (s, 9H); LC-MS (EI) m/z: 551.2 (M+H + ).

To a solution of (S)-l,2,3,4-tetrahydroisoquinolone-3-carboxylic acid (5.00 g, 28.2 mmol) in cone. H 2 SO4 (20 mL) at RT was added dropwise a solution of KNO 3 (2.95 g, 29.2 mmol) in cone. H 2 SO 4 (10 mL). The mixture was stirred for 5 min, then carefully diluted with H 2 O and neutralized with cone. NH 4 OH (100 mL). The precipitate was filtered, washed with HO and acetone and dried in vacuo to yield 6.60 g (crude yield > 100%) of nitrated compounds. The crude mixture was used directly without further purification. MS (ESI) m/z: 223.0 (M+H + ).

To a suspension of the mixture from the previous reaction (6.60 g, 29.7 mmol) in MeOH (50 mL) was added dropwise cone. H 2 SO 4 (5.0 mL, 9.2 g, 3.16 mmol). The mixture was heated at 60 °C for 5h, neutralized and basified with 2N NaOH and extracted with EtOAc (3x100 mL). The combined organic layers were dried (MgSO 4 ), filtered and evaporated to yield 2.85 g (43%, 2 steps) of a mixture as a yellow solid. MS (ESI) m/z: 237.0 (M+H + ).

To a stirring solution of the mixture from the previous reaction (2.80 g, 1.9 mmol) in CH2C1 2 was added Boc anhydride (3.10 g, 14.2 mmol) and the resulting mixture was stirred for 3h. The mixture was concentrated and the residue was purified by column

chromatography to yield 1.15 g (29%) of (S)-2-t-butyl-3-methyl-3,4-dihydro-7- nitroisoquinoline-2,3(7H)-dicarboxylate. MS (ESI) m/z: 359.2 (M+Na + ).

To a suspension of (S)-2-t-butyl-3-methyl-3,4-dihydro-7-nitroisoquinoline- 2,3(1H)- dicarboxylate (1.15 g, 3.42 mmol) in MeOH (15 mL) was added 10% Pd/C (0.073 g, 0.068 mmol) and the mixture was stirred under H 2 (1 atm). After 18h, the mixture was filtered through a pad of Celite ® , acidified with cone. HCl (0.060 mL, 0.072 mmol) and concentrated to yield 970 mg (83%) of (S)-2-t-butyl-3-methyl-7-amino-3,4-dihydroisoquinoline-2,3(1 H)- dicarboxylate as the hydrochloride salt. MS (ESI) m/z: 329.2 (M+Na + ).

To a solution of (S)-2-t-butyl-3-methyl-7-amino-3,4-dihydroisoquinoline-2,3- (IH)- dicarboxylate (0.960 g, 2.80 mmol) in 2M HCl (10 mL) was at -10 °C added solid NaNO 2 (0.190 g, 2.80 mmol) and the resulting solution was stirred for 45 min at a temperature below 0 °C. Solid SnCl 2 -2H 2 O (1.26 g, 5.60 mmol) was added and the mixture was allowed to warm to RT and stirred for 2h. Ethanol (80 mL) and pivaloylacetonitrile (0.350 g, 2.80 mmol) were added and the resulting solution was heated at reflux overnight. Ethanol was removed under reduced pressure and H 2 O (100 mL) was added to the residue. The mixture was extracted with CH 2 Cl 2 (3x100 ml), dried (MgSO 4 ), and concentrated. The residue was dissolved in MeOH (200 mL) and cone. H2SO 4 (15 mL) was added and the mixture was heated at reflux for 4h. After cooling, the mixture was neutralized with 3N NaOH (approx. 150 mL) and MeOH was removed under reduced pressure. The mixture was extracted with CH 2 C1 2 (3x100 mL), dried (MgSO 4 ), and concentrated. The residue was dried in vacuo overnight and resuspended in CH 2 Cl 2 (30 mL). A solution of Boc anhydride (0.611 g, 2.80 mmol) in CH 2 Cl 2 (5 mL) was added dropwise at 0 °C and the resulting mixture was allowed to reach RT and stirred for 3h. Water (100 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified by column chromatography to yield 118 mg (10%) of (3S)-2-t-butyl 3-methyl-7-(3-t-butyl-5-amino-1H- pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(./H)-dicarboxylate as a yellow foam. MS (ESI) m/z: 429.2 (M+η + ).

Using general method A, Example A55 (0.215 g, 0.501 mmol) and 2,3-dichlorophenyl isocyanate (0.104 g, 0.552 mmol) were combined, and the product deprotected using general methods F and E to yield (3S)-7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-7H-pyrazol-1-yl)-l,2,3,4-tetra- hydroisoquinoline-3-carboxylic acid (128 mg, 60% yield) as a

colorless solid. 1 H-NMR (400 MHz, acetone-d ό ): δ 8.60 (brs, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.19 (brS, 1H), 7.40 (d, / = 8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 4.12 (d, J = 14.4 Hz, 1H), 3.89 (d, J = 14.8 Hz, 1H), 3.63 (d, J = 10.4 Hz, 1H), 3.17 (d, J = 15.6 Hz, 1H), 2.90 (dd, J = 16.0, and 10.8 Hz, 1H), 1.32 (s, 9H); MS (ESI) m/z: 502.0 (M+H + ).

A solution of (3S)-2-t-butyl 3-methyl 7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-7H-pyrazol- 1 -yl)-3,4-dihydroiso- quinoline-2,3(1H)-dicarboxylate (from Example 177, 0.100 g, 0.163 mmol) in 7N Nη 3 /MeOη (3 mL) was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was dissolved in CH 2 Cl 2 (2 mL). Boc anhydride (0.036 g, 0.163 mmol) was added and the solution was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)- 7H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(i//)- carboxylate (85 mg, 87% yield) as a white solid. 1 H-NMR (400 MHz, acetone-^): δ 8.66 (brs, 1H), 8.27 (dd, J = 8.4, and 2.0 Hz, 1H), 8.21 (brs, 1H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.24 (dd, J = 8.0, and 1.6 Hz, 1H), 6.88 (brs, 1H), 6.49 (s, 1H), 6.33 (brs, 1H), 4.97-4.45 (m, 3H), 3.36-3.09 (m, 2H), 1.47-1.45 (m, 9H), 1.32 (s, 9H); MS (ESI) m/z: 601.2 (M+H + ).

(3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-y l)-3- carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.085 g, 0.14 mmol) was dissolved in 4N HCl in dioxane (5 mL) and the solution was stirred at RT for 30 min. The solvent was removed under reduced pressure and the residue was dissolved in η 2 O/MeCN (1:1) and lyopholized to yield 1-(3-t-butyl-1-((3S)-3-carbamoyl-l,2,3,4-tetrahydroisoquinol in-7-yl)- 1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 85% yield) as a white solid. 1 H-NMR (CD 3 OD) shows rotameric mixture. MS (ESI) m/z: 501.2 (M+H + ).

To a suspension of DL-m-tyrosine (5.00 g, 11.0 mmol) in 0.05 N HCl (50 mL) was added 37% aq. formaldehyde (5.00 mL, 5.2 g, 64.0 mmol) and the resulting slurry was heated at 90 °C for Ih and then cooled to RT. The mixture was filtered and the resulting solid was washed with H 2 O and acetone and dried in vacuo to yield 6-hydroxy- 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (3.31 g, 52% yield) as an off-

white solid. MS (EI) m/z: 194.0 (M+H + ). 1 H NMR (400 MHz, CD 3 OD): δ 7.03 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 8.8, and 2.4 Hz, 1H), 7.00 (s, 1H), 4.28-4.19 (m, 2H), 3.80 (dd, J = 11.6, and 5.2 Hz, 1H), 3.31-3.27 (m, 1H), 3.05 (dd, J = 16.8, and 11.2 Hz, 1H), acid, hydroxy and amine protons not visible.

Acetyl chloride (30 mL, 33 g, 422 mmol) was added carefully to ice-cold anhydrous EtOH and the resulting solution was stirred at RT for 10 min. 6-Hydroxy- 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (3.30 g, 14 mmol) was added and the mixture was stirred at 50 °C for 5 h. The solvent was evaporated and the residue was dried under vacuum to yield ethyl 6-hydroxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (4.35 g, crude yield > 100%) as a yellow solid. MS expected 222.1 found 222.0. 1 H NMR (400 MHz, CD 3 OD): δ 7.06 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.0, and 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 4.44- 4.29 (m, 5H), 3.35 (dd, / = 17.2, and 5.2 Hz, 1H), 3.15 (dd, J = 17.2, and 11.6 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H).

To a solution of the material from the previous reaction (3.70 g, 14.4 mmol) and Et 3 N (6.00 mL, 4.36 g, 43.1 mmol) in CH 2 C1 2 (100 mL) was added Boc anhydride (3.76 g, 17.2 mmol) at RT and the resulting mixture was stirred for Ih. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3 x 100 mL), dried (MgSO 4 ), and concentrated under vacuum to yield 2-t-butyl 3-ethyl 6-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (5.80 g, crude yield > 100%) as a light brown foam. MS (EI) m/z: 344.3 (M+Na + ). 1 H NMR (400 Mhz, CDCb) shows rotameric mixture.

To a solution of material from the previous reaction (4.61 g, 14.3 mmol) in CH 2 Cl 2 (100 mL) at RT was added Et 3 N (3.00 mL, 2.18 g, 21.5 mmol) and triflic chloride (2.29 mL, 3.63 g, 21.5 mmol) and the resulting solution was stirred at RT for 1 h. Water (100 mL) was added and the mixtrue was extracted with CH 2 Cl 2 (3x100 mL), dried (MgSO 4 ), concentrated and purified by column chromatography to yield 2-t-butyl 3-ethyl 6- (trifluoromethylsuIfonyloxy)-3,4-dihydroisoquinoline-2,3(/H) -dicarboxylate (6.30 g, 97% yield, 3 steps) as a white wax-like solid. MS (EI) m/z: 476.0 (M+Na + ). 1 H NMR (400 MHz, CDClj) shows rotameric mixture.

To a degassed solution of the material from the previous reaction (3.270 g, 7.21 mmol), bis(pinacolato)diboron (2.75 g, 0.662 mmol), and KOAc (2.12 g, 21.6 mmol) in DMF (10 mL) was added PdC1 2 (dppf) 2 (0.2945 g, 0.361 mmol) and the resulting mixture was stirred at 80 °C overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified by column chromatography to yield 2-t-butyl 3-ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-

dihydroisoquinoline-2,3(1H)-dicarboxylate (2.77g, 89%) as a colorless oil. MS (EI) m/z: 454.2 (M+Na + ).

To a solution of the material from the previous reaction (0.105 g, 0.243 mmol) in TηF/η2O (4: 1) (2 mL) was added NaIO 4 (0.160 g, 0.730 mmol) and the thick mixture was stirred for 30 min. Hydrochloric acid (2N, 0.24 mL, 0.48 mmol) was added and the resulting solution was stirred at RT overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and dried under vacuum to yield 2-(t-butoxycarbonyl)-3-(ethoxycarbonyl)-l,2,3,4-tetrahydrois oquinolin-6-ylboronic acid (66 mg, 78%) of the crude boronic acid as an orange-yellow solid. MS (EI) m/z: 372.3 (M+Na + ). This material was used without further purification.

To a solution of Example A32 (0.025 g, 0.071 mmol), Example A56 (0.064 g, 0.180 mmol) and pyridine (0.011 g, 0.14 mmol) in CH 2 Cl 2 (2 mL) was added Cu(OAc) 2 (0.019 g, 0.11 mmol) and the resulting green solution was stirred at RT open to air for 72h, replacing evaporated solvent as needed. Water (20 mL) was added and the mixture was extracted with CH 2 Cl 2 (3x20 mL), dried (MgSO 4 ), concentrated and purified by column chromatography to yield 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3- (pyridin-3-yloxy)phenyl)ureido)-/H-pyrazol-1-yl)-3,4-dihydro isoquinoline-2,3(1H)- dicarboxylate (13 mg, 28% yield) as a yellow oil. MS (EI) m/z: 655.2 (M+η + ).

A solution of the material from the previous reaction (0.013 g, 0.020 mmol) in 2N HC1 in EtOH (5 mL) was stirred overnight. The solvent was evaporated and the residue was dissolved in 7N NH 3 /Me0H and the solution was stirred in a sealed vessel at 60 °C overnight. The solvent was evporated and the residue was purified by reverse phase chromatography. Basic reextraction and acidification with HCl yielded 1-(3-t-butyl-1-(3- carbamoyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrazol-5-y l)-3-(3-(pyridin-3- yloxy)phenyl)urea (7 mg, 59% yield) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.66 (d, J = 2.8 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.21 (ddd, J = 8.8, 2.4, and 1.2 Hz, 1H), 8.04 (dd, J = 8.4, and 5.4 Hz, 1H), 7.58 (t, , / = 2.2 Hz, 1H), 7.52 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (d, J = 10.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.19 (ddd, J = 8.0, 1.8, and 0.8 Hz, 1H), 6.89 (ddd, J = 8.0, 2.4, and 1.2 Hz, 1H), 6.50 (s, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 4.29 (dd, J = 12.0, and 5.0 Hz, 1H), 3.54 (dd, J = 17.2, and 4.8 Hz, 1H), 1.36 (s, 9H), one proton is buried under the MeOH peak; MS (EI) m/z: 526.2 (M+H + ).

Using the same procedure as for Example 179, 2-t-butyl 3- ethyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)- 7H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1H)- dicarboxylate (0.053 g, 0.081 mmol), available from Example 188) in 3N hydrochloric acid in MeOH (10.0 mL) was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in 8N MeNη 2 /Me0η (3 mL) and the solution was stirred in a sealed vessel at 50 °C overnight. The solvent was evaporated and the residue was purified by reverse phase chromatography and coevaporated with THF/4N HCl to yield 1-(3-t-butyl-1-(1-(methylcarbamoyl)-l,2,3,4-tetrahydroisoqui nolin-6- yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (43 mg, 87% yield) as a yellow solid. 1 H-NMR (MeOH-d 4 ): δ 8.66 (d, 1H, J = 2.4 Hz), 8.59 (d, 1H, J = 5.6 Hz), 8.22 (ddd, 1H, J = 9.2, 2.4, 1.2 Hz), 8.05 (dd, 1H, J = 8.0, 6.0 Hz), 7.60-7.54 (m, 4H), 7.42 (t, 1H, J = 8.0 Hz), 7.20 (dd, 1H, J = 7.6, 1.2 Hz), 6.90 (dd, 1H, J = 8.4, 2.0 Hz), 6.53 (s, 1H), 5.23 (s, 1H), 3.80- 3.74 (m, 1H), 3.56-3.49 (m, 1H), 3.26-3.14 (m, 2H), 2.88 (s, 3H).1.36 (s, 9H). MS expected 540.3 found 540.3

To a solution of 4-(4-aminophenyl)isoindolin-1-one (0.327 g, 1.46 mmol, made according to literature procedures) in EtOAc (5 mL) was added NaOH (2N, 2 mL, 4 mmol) and Troc-Cl (0.618 g, 2.92 mmol) and the resulting mixture was stirred at RT for 6h. Water (20 mL) was added and the mixture was extracted with EtOAc (3x20 mL), dried (MgSO 4 ) and concentrated. The residue was dissolved in DMF (2 mL) to which was added 5-amino-3-t-butylpyrazole (0.831 g, 5.97 mmol, made according to literature procedures) and 1-Pr 2 NEt (0.406 g, 2.92 mmol) and the solution was stirred at 90 °C overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ) and concentrated. Addition of CH 2 Cl 2 to the residue resulted in precipitation of the product. The product was collected and dried to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phe nyl)urea (270 mg, 48% yield) as a light brown powder. 1 H-NMR (DMSO-d 6 ): δ 9.31 (s, br, 1H), 8.95 (s, br, 1H), 8.65 (s, br, 1H), 7.65-7.63 (m, 2H), 7.58-7.52 (m, 5H), 6.00 (s, br, 1H), 4.51 (s, 2H), 1.25 (s, 9H), one NH is not visible. MS expected 390.2 found 390.2.

To a solution of the material from the previous reaction (0.200 g, 0.514 mmol) and Example A54 (0.179 g, 0.514 mmol) in DMF (2 mL) was added pyridine (0.122 g, 1.54 mmol) and Cu(OAc) 2 (0.140 g, 0.770 mmol) and the resulting solution was stirred under a balloon of air at RT for 96h. Water (20 mL) was added and the mixture was extracted with EtOAc (3x20 mL), dried (MgSO^, concentrated and purified by column chromatography to yield 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-1H -pyrazol- l-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (50 mg, 14%) as a yellow powder. MS expected 693.3 found 693.2.

A solution of the material from the previous reaction (0.025 g, 0.036 mmol) in 3N HCl/MeOH was stirred at RT for 1 h. The solvent was evaporated and the residue was dried in vacuo. The residue was dissolved in THF (3 mL) and 2N NaOH (2 mL) was added. MeOH was added until the mixture became homogenous. After 1 h, the mixture was acidified with cone. HCl, concentrated and purified by reverse phase chromatography to yield 6-(3-t-butyl-5-(3-(4-(l-oxoisoindolin-4-yl)phenyl)ureido)-1H -pyrazol-1-yl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (16 mg, 74%) as a white solid. 1 H-NMR (MeOH- d 4 ): δ 7.79 (d, 1H, J = 7.2 Hz), 7.66-7.48 (m, 9H), 6.63 (s, 1H), 4.62-4.47 (m, 5H), 3.61 (dd, 1H, J = 17.6, 4.8 Hz), 3.38-3.31 (m, 1H), 1.40 (s, 9H). MS expected 565.3 found 565.3.

Using the same method as for Example 184, a solution of methyl 6-(3-t-butyl-5-(3-(3-(pyridin-3- yloxy)phenyl)ureido)-1H-pyrazol-1-yl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxylate (0.017 g, 0.026 mmol, available in Example 179) in 3N HCl in MeOH (2 mL) was stirred at RT overnight. The solvent was evaporated and the residue was dissolved in MeOH (0.5 mL). 3-Amino-l,2- dihydroxypropane (0.200 g, 2.20 mmol) was added and the solution was kept at RT overnight. The mixture was directly loaded on to a reverse phase column and purified to yield 1-(1-(3-((2,3-dihydroxypropyl)carbamoyl)-l,2,3,4-tetrahydroi soquinolin-6-yl)-3-t- butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (16 mg, 97% yield) as a yellow solid. 1 H-NMR (MeOH-^ 4 ): δ 8.66 (s, 1H), 8.60 (d, 1H, J = 5.6 Hz), 8.23-8.20 (m, 1H), 8.05 (dd, 1H, J = 8.8, 5.6 Hz), 7.57 (t, 1H, J = 2.0 Hz), 7.52-7.40 (m, 4H), 7.23 (d, 1H, J = 8.4 Hz), 6.89 (dd, 1H, J = 7.6, 1.6 Hz), 6.54 (s, 1H), 4.56 (d, 1H, J = 16.8 Hz), 4.51 (d, 1H, / = 16.8 Hz), 4.29 (dd, 1H, 7 = 12.0, 4.4 Hz), 3.78-3.72 (m, 1H), 3.54-3.45 (m, 5H), 1.36 (s, 9H), one proton is buried under the MeOH peak, urea, amide, amine and hydroxy protons not

visible. MS expected 600.3 found 600.2

A solution of Example 181 (0.025 g, 0.036 mmol) was dissolved in 7N ammonia in MeOH (3 mL) and the solution was kept at RT overnight, then purified via reverse phase column chromatography to yield 1-(3-t- butyl- 1 -(3-carbamoyl- 1 ,2,3,4-tetrahydroisoquinolin-6-yl)- 1H-pyrazol-5-yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea (8 mg, 37%) as a white solid. 1 H-NMR (MeOH-dt): δ 7.78 (dd, 1H, J = 7.4, 1.4 Hz), 7.65 (dd, 1H, J = 8.0, 1.0 Hz),

7.61 (d, 1H, J = 7.6 Hz), 7.58-7.45 (m, 7H), 6.51 (s, 1H), 4.55 (s, 2H), 4.54 (d, 2H, J = 16.0 Hz), 4.49 (d, 2H, J = 16.0 Hz), 4.28 (dd, 1H, J = 11.6, 5.2 Hz), 3.53 (dd, 1H, J = 17.2, 5.2 Hz), 1.38 (s, 9H), one proton is buried under the MeOH peak, urea, amine and amide protons not visible. MS expected 564.3 found 564.3

Using the same procedure as for Example 179, 2-t-butyl 3- ethyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)- 1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(7H> dicarboxylate (0.029 g, 0.044 mmol), available from experimental 184) in 3N hydrochloric acid in MeOH (10.0 mL) was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in 3-amino-l,2- dihydroxypropane (0.200 g, 2.2 mmol) in MeOH (0.5 mL) and the solution was stirred at RT for 2 d. The solvent was evaporated and the residue was purified by reverse phase chromatography and coevaporated with TηF/4N HCl to yield 1-(1-(1-((2,3- dihydroxypropyl)carbamoyl)-l,2,3,4-tetrahydroisoquinolin-6-y l)-3-t-butyl-1H-pyrazol-5-yl)- 3-(3-(pyridin-3-yloxy)phenyl)urea (24 mg, 81% yield) as a pale yellow solid. 1 H-NMR (MeOH-d 4 ): δ 8.68 (d, 1H, J = 3.2 Hz), 8.60 (d, 1H, J = 7.6 Hz), 8.23 (ddd, 1H, J = 8.8, 2.6,

1.0 Hz), 8.06 (dd, 1H, / = 8.4, 1.4 Hz), 7.70 (dd, 1H, / = 9.0, 1.8 Hz), 7.58-7.54 (m, 3H), 7.42 (t, 1H, J = 8.0 Hz), 7.22 (dt, 1H, J = 8.4, 1.0 Hz), 6.90 (dd, 1H, J = 6.8, 1.6 Hz), 6.58 (d, 1H, J = 1.2 Hz), 5.29 (s, 1H), 3.84-3.63 (m, 2H), 3.63-3.51 (m, 5H), 3.30-2.87 (m, 2H), 1.37 (s, 9H), urea, amine, hydroxy and amide protons not visible. MS expected 600.3 found 600.2.

To a solution of benzyl 3-t-butyl-1H-pyrazole-5- carboxylate (0.100 g, 0.387 mmol, synthesized by trans-esterification of commercially available ethyl β-t-butyl-1H-pyrazole-S-carboxylate), 2-(t- butoxycarbonyl)-3-(methoxycarbonyl)- 1,2,3,4- tetrahydroisoquinolin-6-ylboronic acid (0.195 g, 0.581 mmol, made analogously to Example A56) and pyridine (0.092 g, 1.16 mmol) in methylene chloride (4 mL) was added copper(II)-acetate (0.105 g, 0.581 mmol) and the resulting mixture was stirred at Rt for Id. The mixture was directly loaded on a silica gel column, chromatographed and concentrated to yield 2-t-butyl 3-methyl 6-(5-(benzyloxycarbonyl)-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihy droisoquinoline- 2,3(1H)-dicarboxylate (171 mg, 81% yield) as a colorless foam. MS expected 548.3 found 548.3. To this material (0.136 g, 0.248 mmol) in EtOAc (5 mL) was added palladium on charcoal (10%, 0.013 g, 0.012 mmol) and the mixture was stirred under an atmosphere of H 2 overnight. The mixture was filtered and the filtrate was concentrated to yield 1-(2-(t- butoxycarbonyO-S-^ethoxycarbony^-l^^^-tetrahydroisoquinolin- ό-yO-S-t-butyl-1H- pyrazole-5-carboxylic acid (114 mg, 100%) as a colorless foam. MS expected 458.2 found 458.3.

To a solution of the material from the previous reaction (0.070 g, 0.153 mmol) and Example All (0.062 g, 0.245 mmol) in toluene (2 mL) was added triethylamine (0.031 g, 0.306 mmol) and diphenylphosphonic azide (0.063 g, 0.229 mmol) and the resulting solution was stirred at 100 °C for 1 h. The mixture was directly loaded on a column and purified via column chromarography to yield 2-t-butyl 3-methyl 6-(3-t-butyl-5-(3-(3-(8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureido)-1H-pyr azol-1-yl)-3,4- dihydroisoquinoline-2,3(1H)-dicarboxylate (89 mg, 82%) as a yellow oil. MS expected 707.3 found 707.2

A solution of material from the previous reaction (0.088 g, 0.120 mmol) in 3N HCl in MeOH was stirred at RT for Ih. The solvent was evaporated and the residue was dried in vacuo. The residue was dissolved in 7N ammonia in MeOH and the mixture was kept at RT overnight. The mixture purified via reverse phase column chromatography to yield 1-(3-t- butyl-1-(3-carbamoyl-l,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 dihydrochloride (63 mg, 76%) as a yellow crystalline solid. 1 H-NMR (MeOH-d 4 ): δ 9.27 (s, br, 2H), 8.17 (s, 1H), 7.89 (s, 1H), 7.60-7.49 (m, 4H), 7.42-7.38 (m, 2H), 6.71 (s, 1H), 4.58 (d, 1H, J = 16.4 Hz), 4.53 (d, 1H, J

= 16.4 Hz), 4.33 (dd, 1H, J = 11.6, 4.4 Hz), 3.89 (s, 3H), 3.57 (dd, 1H, J = 17.6, 5.2 Hz), 1.40 (s, 9H), one proton is buried under the MeOH peak, urea, amide and amine protons not visible. MS expected 592.3 found 592.3.

Using general method G, followed by general method E, (3S)- methyl 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-7H- pyrazol-1-yl)-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydro- isoquinoline-3-carboxylate from Example A42 (0.080 g, 0.13 mmol) was deprotected and lyophilized to yield (3S)-6-(3-t- butyl-5-(3-(2,3-dichlorophenyl)ureido)-/H-pyrazol-1-yl)- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (42 mg, 60% yield) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.98 (t, J = 4.8 Hz, 1H), 7.49 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (d, , J = 8.4 Hz, 1H), 7.24 (d, J = 4.8 Hz, 1H), 7.24 (d, J = 4.8 Hz, 1H), 6.42 (s, 1H), 4.55 (d, / = 16.4 Hz, 1H), 4.48 (d. / = 16.4 Hz, 1H), 4.41 (dd, J = 10.8, and 4.8 Hz, 1H), 3.56 (dd, / = 17.6, and 4.4 Hz, 1H), 1.35 (s, 9H), one aliphatic proton is buried under the MeOH peak; MS (EI) m/z: 504.0 (M+H + ).

A solution of (3S)-methyl 7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-7H-pyrazol-1-yl)-2-(2,2,2-trifluoro- acetyl)-l,2,3,4-tetrahydroiso-quinoline-3-carboxylate from

Example A42 (0.153 g, 0.250 mmol), methylamine hydrochloride (1.000 g, 14.8 mmol) and triethylamine (2.05 mL, 1.49 g, 14.7 mmol) in MeOH (5 mL) was stirred at 60 °C for 24h. η2O was added (50 mL) and the mixture was extracted with CH 2 C1 2 (3x50 mL), dried (MgSO 4 ) and concentrated. The residue was redisolved in CH 2 Cl 2 (5 mL). Boc anhydride (0.055 g, 0.250 mmol) was added and the solution was stirred at RT for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-y l)-3-(methyl- carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (52 mg, 34% yield) as a white solid. 1 H NMR (400MHZ, acetone-^) shows rotameric mixture. MS (EI) m/z: 615.2 (M+H + ).

Using general method F, the material from the previous reaction (0.050 g, 0.14 mmol) was deprotected and lyophilized to yield 1-(3-t-butyl-1-((3S)-3-(methylcarbamoyl)- 1,2,3,4- tetrahydroisoquinolin-7-yl)-7H-pyrazol-5-yl)-3-(2,3-dichloro phenyl)urea (42 mg, 94% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD) shows rotameric mixture. MS (EI) m/z:

515.0 (M+H + ).

To a solution of Example A31 (0.066 g, 0.200 mmol), Example A56 (0.070 g, 0.200 mmol) and pyridine (0.032 g, 0.401 mmol) in CH 2 Cl 2 (2 mL) was added copper(II)-acetate (0.055 g, 0.301 mmol) and the resulting green solution was stirred at RT open to air for 96h, replacing evaporated solvent as needed. H2O was added (20 mL) and the mixture was extracted with CH 2 Cl 2 (3x20 mL), EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via reverse phase column chromatography to yield 2-t-butyl 3-ethyl-6-(3-t-butyl-5- (3-(2,3-dichlorophenyl)ureido)-7H-pyrazol-1-yl)-3,4-dihydroi soquinol-ine-2,3(7H)- dicarboxylate (50 mg, 40%) as an off-white solid. MS (EI) m/z: 630.2 (M+η + ).

A solution of the material from the previous reaction (0.040 g, 0.063 mmol) in 7N ammonia in MeOH (3 mL, 21 mmol) was heated at 70 °C for 8h. The solvent was evaporated and the residue was purified by reverse phase chromatography to yield 1-(3-t-butyl-1-(3- carbamoyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrazol-5-y l)-3-(2,3-dichloro-phenyl)urea (17 mg, 50% yield) as an off-white solid. 1 H NMR (400 Mhz, CD 3 OD): δ 8.03 (t, J = 4.8 Hz, 1H), 7.56-7.54 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.26-7.25 (m, 2H), 6.61 (s, 1H), 4.57 (d, / = 16.8 Hz, 1H), 4.51 (d, J = 16.4 Hz, 1H), 4.30 (dd, / = 12.0, and 4.6 Hz, 1H), 3.54 (dd, / = 17.6, and 4.8 Hz, 1H), 1.38 (s, 9H), one proton is buried under the MeOH peak, urea, amide and amine protons not visible; MS (EI) m/z: 501.2 (M+H + ).

A solution of 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3- (pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol- 1 -yl)-3,4- dihydroisoquinoline-2,3(7H)-dicarboxylate (available from Example 179, 0.102 g, 0.160 mmol) in 3N HCl in MeOH (5 mL) was stirred for Ih. The solvent was evaporated. The residue was dissolved in TηF (2 mL). 2N NaOH was added (2 mL) and then MeOH until homogenous. The solution was stirred at RT for Ih. The solvents were evaporated, the residue was purified by reverse phase chromatography followed by coevaporation with TηF/ηC1 to yield 6-(3-t-butyl-5-(3-(3- (pyridin-3-yloxy)phenyl)ureido)-7H-pyrazol-1-yl)-l,2,3,4-tet rahydroisoquinoline-3- carboxylic acid (20 mg, 100%) as a white solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.66 (d, J = 2.8 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.22 (ddd, J = 9.2, 2.8, and 0.8 Hz, 1H), 8.05 (dd, J =

8.8, 5.6 Hz, 1H), 7.58 (t, / = 2.0 Hz, 1H), 7.54-7.46 (m, 3H), 7.42 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.89 (dd, J = 8.4, and 2.4 Hz, 1H), 6.57 (s, 1H), 6.59 (d, J = 16.0 Hz, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.49 (dd, J = 11.2, and5.2 Hz, 1H), 3.60 (dd, J = 18.0, and 4.8 Hz, 1H), 1.37 (s, 9H), acid, amine and urea protons not visible, one proton is buried under the MeOH peak; MS (EI) m/z: 527.2 (M+H*).

A solution of 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3- (pyridin-3-yloxy)phenyl)ureido)-7H-pyrazol-1-yl)- 3,4-dihydroisoquinoline-2,3(7H)-dicarboxylate (available from Example 179, 0.102 g, 0.160 mmol) in 3N HCl in MeOH (5 mL) was stirred for Ih. The solvent was evaporated and the residue was redissolved in 8N methylamine in EtOH and stirred at RT overnight. The solvent was evaporated, the residue was purified by reverse phase chromatography and coevaporation with TηF/ηCI to yield 1-(3-t-butyl-1-(3- (methylcarbamoyl)-l,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyr azol-5-yl)-3-(3-(pyridin-3- yloxy)phenyl)urea (20 mg, 92% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.67 (d, J = 2.8 Hz, 1H), 8.60 (d, / = 5.6 Hz, 1H), 8.23 (ddd, J = 8.8, 2.8, and 1.0 Hz, 1H), 8.06 (dd, J = 8.8, and 5.6 Hz, 1H), 7.58 (t, J = 2.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 8.2 Hz, 1H), 7.26 (dd, J = 8.0, and 1.6 Hz, 1H), 6.90 (ddd, J = 8.4, 2.0, and 0.8 Hz, 1H), 6.64 (s, 1H), 4.56 (d, J = 16.4 Hz, 1H), 4.52 (d, J = 16.4 Hz, 1H), 4.28 (dd, y = 11.6, and 4.8 Hz, 1H), 3.50 (dd, J = 17.2, and 4.8 Hz, 1H), 2.86 (s, 3H), 1.38 (s, 9H), amide, urea and amine protons not visible, one proton is buried under the MeOH peak, methylamide protons split due to rotation barrier; MS (EI) m/z: 540.3 (M+H + ).

Using general method H, Example A29 (116 mg, 0.30 mmol) was transformed to prop-1-en-2-yl 3-t-butyl-1-(l- (2,2,2-trifluoroacetyl)indolin-5-yl)-7H-pyrazol-5- ylcarbamate (119 mg, 91% yield). MS (ESI) m/z: 437.3 (M+η + ). Using the same procedure as for Example 151, this material (117 mg, 0.27 mmol) and 4-(4- aminophenyl)isoindolin-1-one (61 mg, 0.27 mmol) were combined to yield 1-(3-t-butyl-1-(l- (2,2,2-trifluoroacetyl)indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-( l-oxoisoindolin-4-yl)phenyl)urea (152 mg, 94% yield). MS (ESI) m/z: 603.3 (M+η + ). To this material (149 mg, 0.25 mmol)

was added NH 3 /MeOH (7.0 M, 3.0 mL, 21 mmol) and the resultant mixture was stirred at RT overnight. Ether (9 mL) was added, the reaction was filtered and the precipitate was washed with 3: 1 Et 2 O-MeOH (10 mL) and Et 2 O (10 mL). The tan-colored solid was dried in vacuo to provide 1 -(3-t-butyl- 1 -(indolin-5-yl)-1H-pyrazol-5-yl)-3-(4-( 1 -oxoisoindolin-4- yl)phenyl)urea (100 mg, 79% yield). 1 H NMR (400 MHz, DMSO-dβ): δ 9.21 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.66-7.62 (m, 2H), 7.56 (m, 1H), 7.54-7.50 (m, 4H), 7.08 ( brs, 1H), 6.97 (dd, J = 8.2, and 2.1 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.32 (s, 1H), 5.81 (s, 1H), 4.51 (s, 2H), 3.50 (td, J = 8.5, and 1.5 Hz, 2H), 2.99 (t, J = 8.5 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 507.2 (M+H + ).

Using the same procedure as for Example 108, Example 191 (55 mg, 0.11 mmol) was transformed to yield 1 -(3-t- butyl- 1 -( 1 -(methylsulfonyl)indolin-5-yl)-1H-pyrazol-5- yl)-3-(4-(l-oxoisoindolin-4-yl)phenyl)urea (5 mg, 8% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-Cf 6 ): δ 9.15 (s, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 7.66-7.62 (m, 2H), 7.56 (m, 1H), 7.54-7.52 (m, 4H), 7.43

(m, 1H), 7.36-7.32 (m, 2H), 6.38 (s, 1H), 4.50 (s, 2H), 4.02 (t, J = 8.5, 2H), 3.20 (t, J = 8.5

Hz, 2H), 3.07 (s, 3H), 1.286 (s, 9H); MS (ESI) m/z: 585.3 (M+H + ).

To a solution of Example A27 (500 mg, 1.5 mmol) in absolute THF was added powder LiA1H 4 (300 mg, 7.5 mmol) in portions at 0 °C under N 2 atmosphere. After stirring for 3h, the reaction was quenched by addition of H 2 O and 2N NaOH. The suspension was filtered and the filtrate was concentrated to the crude product, which was purified by reverse phase chromatography to yield 2- (3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)naphthalen-1-yl) (400mg, 86% yield) as a white solid. 1 H NMR (300 MHz, DMSO-^ 5 ): 58.02-8.05 (m, 1H), 7.90-7.93 (m, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.50-7.47 (m, 2H), 5.38 (s, 1H), 5.27 (s, 2H), 4.73 (t, J = 5.4 Hz, 1H), 3.69 (t, J = 6.9Hz, 2 H), 3.20 (t, J = 6.9Hz, 2H), 1.20 (s, 9H); MS (ESI) m/z: 310 (M+H + ).

To a stirred solution of the material from the previous reaction (400 mg, 1.3 mmol) and DPPA (0.419 mL, 2mmol) in dry THF (10 mL) at 0 °C was added DBU (0.293 mL, 2mmol). The resulting mixture was allowed to warm to 25 °C and stirred under N 2 for 18h. The mixture was concentrated and purified by column chromatography to yield 1-(4-(2-

azidoethyl)naphthalen-2-yl)-3-t-butyl-7H-pyrazol-5-amine (150 mg, 30% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 8.75-8.78 (m, 1H), 7.90-7.95 (m, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.55-7.50 (m, 2H), 5.39 (s, 1H), 5.30 (s, 2H), 3.68 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H), 1.21 (s, 1H); MS (ESI) m/z: 335 (M+lT).

To a mixture of the material from the previous reaction (150 mg, 0.45 mmol) and Et 3 N (0.186 mL, 1.3 mmol) in CH 2 Cl 2 (10 mL) was added a solution of l,2-dichloro-3- isocyanatobenzene (84 mg, 1.5 mmol) in CH 2 Cl 2 dropwise at 0 °C under N 2 atmosphere. The mixture was allowed to come to room temperature and stirred overnight before being poured into ice cold 1.0N HCl. The mixture was extracted with CH 2 Cl 2 (3x100 mL), and the combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give a dark oil, which was purified by column chromatography to yield 1-(1-(4-(2- azidoethyl)naphthalen-2-yl)-3-t-butyl-/H-pyrazol-5-yl)-3-(2, 3-dichlorophenyl)urea (200 mg, 30% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.29 (s, 1H), 8.74 (s, 1H), 8.12-8.15 (m, 1H), 8.12-8.00 (m, 2H), 7.93-7.96 (m, 1H), 7.62-7.53 (m, 3H), 7.30-7.24 (m, 2H), 6.42 (s, 1H), 3.69 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz, 2H), 1.23 (s, 1H); MS (ESI) m/z: 522 (M+H + ).

To a solution of the material from the previous reaction (200 mg, 0.38 mmol) in absolute THF was added LiAlH 4 powder (77 mg, 1.9 mmol) in portions at 0 °C under N 2 . After stirring for 3h, the reaction was quenched by addition of H 2 O and 2N NaOH. The suspension was filtered and the filtrate was concentrated to give the crude product, which was purified by reverse phase chromatography to yield 1-(1-(4-(2-aminoethyl)naphthalen-2-yl)-3- t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (20 mg, 10% yield) as a white solid. 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.30 (s, 1H), 8.71 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.03-7.98 (m, 3H), 7.84 (s, 2H), 7.60-7.56 (m, 3H), 7.25-7.24 (m, 2H), 6.40 (s, 1H), 3.43-3.46 (m, 2H), 3.10-3.15 (m, 2H), 1.25(s, 9H); MS (ESI) m/z: 496 (M+H + ).

A mixture of formamide (7.91 g, 176 mmol) and 4-nitroanthranilic acid (4.00 g, 22.0 mmol) was warmed to 160 °C and stirred for 7h then cooled to RT and stirred overnight. The mixture was diluted with H 2 O (30 mL) and stirred overnight. The brown solid was collected by filtration and dried to yield 7-nitroquinazolin-4-ol (3.62 g, 86% yield). 1 H NMR (300 MHz, DMSO-<4): 8.38-8.33 (m, 2 H), 8.27-8.23 (m, 2 H).

A solution of 7-nitroquinazolin-4-ol (3.62 g, 18.9 mmol) with 10% Pd/C (0.25 g) in

DMF (15 mL) was stirred under H 2 (1 atm) for 18h, then partially concentrated at elevated temperature, filtered warm through Celite ® to remove catalyst and then concentrated to a brown solid. The solid was triturated with EtOAc (50 mL), filtered, dried, redissolved in DMF (25 mL), treated with 10% Pd/C (0.25 g) and stirred overnight under an H 2 atmosphere. The mixture was filtered free of catalyst and the filtrate evaporated at reduced pressure to yield a brown solid which was triturated with EtOAc (50 mL) and filtered to yield 7- aminoquinazolin-4-ol (2.27g, 74% yield). MS (ESI) m/e (M+H + ) 162.3. To a stirred suspension of 7-aminoquinazolin-4-ol (2.00 g, 12.4 mmol) in cone. HC1 (20.0 ml) at 0 °C was added dropwise NaNO 2 (0.98 g, 14.3 mmol, 1.15 eq) as a solution in H 2 O (15.0 ml). The resulting mixture was stirred at 0 °C for Ih, and then treated with a solution of SnCl 2 -2H 2 O (12.0 g, 53.4 mmol, 4.30 eq) in cone. HCl (15.0 ml). The reaction was stirred at 0 °C for Ih and then at RT for 2h. The reaction was diluted with EtOH (130 ml) and 4,4- dimethyl-3-oxopentanenitrile (2.02 g, 16.1 mmol, 1.30 eq) added, heated at reflux overnight, then cooled to RT and concentrated. The residue was diluted with EtOAc (100 mL), placed in an ice/H20 bath and the stirred solution made basic (pH 8) with solid NaOH. The mixture was filtered through Celite ® , washed with H 2 O (50 mL) and then EtOAc (100 mL). The organic phase washed with brine, dried (Na 2 SO 4 ) and concentrated to yield a tan solid, which was dried then stirred in ether (100 mL) and allowed to stand. The solid was collected by filtration and dried to yield 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (1.69g, 48% yield). 1 H NMR (300 MHz, DMSO-^ 5 ): 8.17-8.11 (m, 2 H), 7.90-7.83 (m, 2 H), 5.47 (m, 3 H), 1.23 (s, 9 H). MS (ESI) m/e (M+H + ) 284.2.

Using general method A, 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (120 mg, 0.424 mmol) and 2,3-dichlorophenylisocyanate (79 mg, 0.487 mmol) were combined to yield 1-(3-t-butyl-1-(4-oxo-3,4-dihydroquinazolin-7-yl)-1H-pyrazol -5-yl)-3- (2,3-dichlorophenyl)urea (102 mg, 51% yield) as a white solid. 1 H NMR (300 MHz, DMSO- d 6 ): 9.41 (s, 1 H), 8.79 (s, 1 H), 8.25-8.23 (s, 1 H), 8.16 (s, 1 H), 8.08-8.02 (m, 1 H), 7.82- 7.75 (m, 2 H), 7.32-7.30 (m, 2 H), 6.46 (s, 1 H), 1.30 (s, 9 H). MS (ESI) m/e (M+H + ) 471.0.

A mixture of formamide (14 g, 0.3 mol) and 2-amino-5- nitrobenzoic acid (9.1 g, 0.05 mol) was heated at 155 °C for 7h, cooled to RT and stirred overnight. The mixture was diluted with H 2 O (30 mL) and filtered. The resultant brown solid was dissolved in i-PrOH (300 mL), warmed to reflux, cooled to RT and filtered and dried to yield 6-nitroquinazolin-4(3H)-one, (5.85

g, 61% yield). MS (ESI) m/e (M+H + ) 192.0

A mixture of 6-nitroquinazolin-4(3H)-one (4.15 g, 21.7 mmol) and 10% Pd/C (0.3 g) in MeOH (25 mL) and THF (50 mL) was stirred under H 2 (1 atm) at 40 °C for 18h. The mixture was diluted with DMF (50 mL), stirred overnight under H 2 , then placed under an Ar atmosphere. After the addition of Pd/C (0.4 g), the mixture was placed under an H 2 atmosphere and warmed to 50 °C and stirred for 4h. The reaction mixture was filtered through Celite ® , washed with warm DMF (75 mL) and the combined filtrates evaporated to yield 6-aminoquinazolin-4(3H)-one (3.10 g, 88% yield) as a yellow solid. MS (ESI) m/e (M+H + ) 162.3

To a suspension of 6-aminoquinazolin-4(3H)-one (3.07 g, 19.0 mmol, 1.0 eq) in cone. HC1 (30.0 ml) at 0 °C was added dropwise NaNO 2 (1.51 g, 21.9 mmol, 1.15 eq) as a solution in H 2 O (20.0 ml). The resulting mixture was stirred at 0 °C for Ih, and then treated with a solution of SnC1 2 -2H 2 O (18.5 g, 81.9 mmol, 4.30 eq) in cone. HC1 (20.0 ml). The reaction was stirred at 0 °C for Ih and then at RT for 2h. The reaction was diluted with EtOH (200 ml), treated with 4,4-dimethyl-3-oxopentanenitrile (3.10 g, 24.8 mmol, 1.30 eq), heated at reflux overnight, then cooled to RT and concentrated. The residue was diluted with EtOAc (100 mL), then strirred in an ice/H2O bath and made basic (pH 8) with solid NaOH. The mixture was filtered through Celite ® , washed with H 2 O (50 mL) and then EtOAc (100 mL). The organic phase was washed with brine, dried (Na 2 SO 4 ) and concentrated to yield a yellow solid, which was triturated from Et 2 O (100 ml) to yield 6-(5-amino-3-t-butyl-1H-pyrazol-1- yl)quinazolin-4(3H)-one (1.2 g, 22% yield). MS (ESI) m/e (M+H + ) 284.2

Using general method A, the material from the previous reaction (120 mg, 0.424 mmol) and 2,3-dichlorophenyl isocyanate (96 mg, 0.508 mmol) were combined to yield 1-(3- t-butyl-1-(4-oxo-3,4-dihydroquinazolin-6-yl)-1H-pyrazol-5-yl )-3-(2,3-dichlorophenyl)urea as a tan solid (107 mg, 53% yield). 1 H-NMR (OMSO-d 6 ): δ 1.30 (s, 9H), 6.42 (s, 1H), 7.27- 7.32 (m, 2H), 7.80-7.83 (m, 1H), 7.98-8.03 (m, 2H), 8.15 (s, 1H), 8.20-8.21 (m, 1H), 8.72 (s, 1H), 9.40 (br s, 1H). MS (ESI) m/e (M+H + ) 471.0

Using general method D, Example A29 (0.25 g, 0.47 mmol) in DMSO (2 mL) and Example All (0.13 g, 0.52 mmol) were combined to yield 1 -(3-t-butyl-l -(I -(2,2,2- trifluoroacetyl)indolin-5-yl)-/H-pyrazol-5-yl)-3-(3-(8- methyl-7-oxo-6,7,8,8a-tetrahydropyrido[2,3-d]pyrimidin-

6-yl)phenyl)urea, which was deprotected with 7N NH 3 ZMeOH (2 mL) at room temperature for 2h. Water (10 mL) was added and the mixture was extracted with CH 2 C1 2 (3x20 mL). The organic extracts were dried (MgSCM, concentrated and purified by column chromatography to yield 1-(3-t-butyl-1-(indolin-5-yl)-/H-pyrazol-5-yl)-3-(3-(8-methy l-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.20 g, 79% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.22 (s, 1H), 9.16 (s, 1H), 9.11 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.83 (t, / = 1.6 Hz, 1H), 7.44 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.30 (m ,1H), 7.08 (brs, 1H), 6.96 (dd, J = 2.0, and 8.0 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.32 (s, 1H), 5.81 (brs, 1H), 3.71 (s, 3H), 3.49 (brt, J = 8.4 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H), 1.25 (s, 9H); LC-MS (EI) m/z: 535.2 (M+H + ). To a solution of this material (30 mg, 0.06 mmol) in EtOAc (1 mL) was added 3M HCl/EtOAc (21 DL). The solid was filtered and dried under vacuum to obtain 1-(3-t-butyl-1- (indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(8-methyl-7-oxo-7,8-dih ydropyrido[2,3-d]pyrimidin-6- yl)phenyl)urea (31 mg, 97 % yield) as the HCl salt. 1 H NMR (400 MHz, DMSO- 6 ): δ 9.32 (brs, 1H), 9.16 (s, 1H), 9.12 (s, 1H), 8.47 (brs, 1H), 8.17 (s, 1H), 7.83 (t, J = 1.6 Hz, 1H), 7.45 (m, 1H), 7.37 (brs, 1H), 7.36 (t, / = 8.0 Hz, 1H), 7.29 (m, 1H), 7.28 (brs, 1H), 7.08 (brs, 1H), 6.37 (s, 1H), 3.71 (s, 3H), 3.65 (m, 2H), 3.14 (m, 2H), 1.27 (s, 9H); LC-MS (EI) m/z: 535.2 (M+H + ).

Using the same procedure as for Example 108, Example 196 (170 mg, 0.32 mmol) and methanesulfonyl chloride (73 mg, 0.64 mmol) were combined to yield 1-(3-t-butyl- 1-(1-(methylsulfonyl)indolin-5-yl)-7H-pyrazol-5-yl)-3-(3- (8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)urea (60 mg, 31 % yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-4): δ 9.18 (brs, 1H), 9.16 (s, 1H), 9.12 (s, 1H), 8.41 (brs, 1H), 8.17 (s, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.46 (m, 1H), 7.42 (d, J = 1.2 Hz, 1H), 7.36 (m, 4H), 7.30 (dt, J = 1.6, and 7.6 Hz, 1H), 6.38 (s, 1H), 4.02 (t, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.20 (t, J = 8.4 Hz, 2H), 1.27 (s, 9H); LC-MS (EI) m/z: 613.3 (M + H + ).

Using general method D, Example A35 (0.12 g, 0.4 mmol) and 1- Aminonaphthalene (0.034 g, 0.23 mmol) were combined to yield 1- (3-t-butyl-1-(2-oxo-l,2,3,4-tetrahydroquinolin-6-yI)-lH-pyra zol-5- yl)-3-(naphthalen-1-yl)urea (36 mg, 19% yield, 2 steps). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.3 (s, 1H), 9.04 (s, 1H), 8.76 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.54 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.32 (dd, / = 2.4, and 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 2.98 (t, / = 6.8 Hz, 1H), 1.28 (s, 9H); MS (EI) m/z: 454.2 (M+H + ).

Using general method D, Example A38 (0.20 g, 0.54 mmol) and (S)-aminoindane (0.035 g, 0.26 mmol) were combined to yield 1- (3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-6-yl)-lH-pyrazol -5-yl)- 3-((S)-2,3-dihydro-lH-inden-1-yl)urea HC1 salt (82 mg, 53% yield, 2 steps). 1 H NMR (400 MHz, DMSOd 6 ): δ 9.51 (brs, 2H), 8.32 (m, 1H), 7.23 (m, 5H), 7.07 (m, 1H), 6.47 (brs, 1H), 6.23 (s, 1H), 5.09 (m, 1H), 4.30 (m, 2H), 3.37 (m, 2H), 3.07 (brt, J = 4.8 Hz, 2H), 2.90 (m, 1H), 2.76 (m, 1H), 2.38 (m, 1H), 1.71 (m, 1H), 1.27 (s, 9H); MS (EI) m/z: 430.2 (M+H + ).

Using the same procedure as for Example 108, Example 145 (0.14 g, 0.3 mmol) was transformed 1-(3-t-butyl-1-(2-(methylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-6-yl)-lH-pyrazol-5-yl)-3-(2,4- difluorophenyl)urea (60 mg, 40% yield). 1 H NMR (400 MHz, DMSO-^ 6 ): δ 8.88 (brs, 1H), 8.77 (s, 1H), 8.04 (m, 1H), 7.31 (m, 4H), 7.02 (m, 1H), 6.38 (s, 1H), 4.43 (s, 2H), 3.46 (t, / - 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H), 1.25 (s, 9H); LC-MS

(EI) m/z: 504.2 (M+H + ).

To a stirred suspension of Example 106 (20 mg, 0.045 mmol) and Et 3 N (6.8 mg, 0.068 mmol) in CH 2 Cl 2 (2.0 ml) was added triflic anhydride (14 mg, 0.051 mmol) at -78 °C which was stirred for 30 min. The reaction was quenched with saturated NaHCO 3 and allowed to warm to RT. The mixture was diluted with EtOAc and the organic layer was washed with NH 4 C1, NaHCO 3 , brine, and dried (MgSO 4 ), and concentrated under reduced pressure to obtain 1-(3-t-butyl-1-(1-(trifluoromethylsulfonyl)indolin-5-yl)-lH- pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea as a pale yellow solid (20 mg, 100 % yield). 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.22 (s, 1H), 8.74 (brs, 1H), 8.04 (dd, J = 4.4, and 5.6 Hz, 1H), 7.54 (brs, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.42 (s,1H), 7.32 (d, J = 1.6 Hz, 1H), 6.39 (s, 1H), 4.30 (t, / = 8.4 Hz, 2H), 3.33 (s, 2H), 3.32 (t, J = 8.4 Hz, 2H), 1.27 (s, 9H); LC-MS (EI) m/z: 576.2 (M+H + ).

A solution of Example A57 (415 mg, 1.23 mmol) in THF (4 mL) of THF was cooled to -78 °C and treated with sodium bis(trimethylsilylamide) (1.0M in THF, 2.6 mL, 2.6 mmol). The reaction mixture was stirred for 30 min at -78 °C. Methyl iodide (0.090 mL, 1.47 mmol) was added and the reaction mixture was allowed to slowly warm to 0 °C over 90 min. The reaction was partitioned between saturated aqueous NH 4 Cl (10 mL) and EtOAc

(30 mL). The organic layer was washed with H 2 O (10 mL) and brine (10 mL). The combined aqueous washes were extracted with ether (10 mL). All organics were combined, dried (Na 2 SO 4 ) and purified via column chromatography to yield ethyl 2-(4-(5-amino-3-t-butyl-lH- pyrazol-1-yl)phenyl)propanoate (99 mg, 26% yield). MS (ESI) m/z: 316.3 (M+η + ).

Using general method A, the material from the previous step (97 mg, 0.31 mmol) and 2,3-dichlorophenyl isocyanate (0.061 mL, 0.46 mmol) were combined to yield ethyl 2-(4-(3- t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-lH-pyrazol-1-yl)phe nyl)propanoate (89 mg, 57% yield) as a foam. MS (ESI) m/z: 503.3 (M+η + ).

Using general method E, the material from the previous step (84 mg, 0.17 mmol) was saponified to yield 2-(4-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-lH-pyrazol- 1- yl)phenyl)propanoic acid (67 mg, 84% yield). 1 H NMR (400 MHz, DMSO-^ 6 ): δ 12.42 (brs, 1H), 9.32 (s, 1H), 8.81 (s, 1H), 8.09 (m, 1H), 7.49-7.43 (m, 4H), 7.35-7.29 (m, 2H), 6.39 (s, 1H), 3.77 (q, J = 7.2 Hz, 1H), 1.41 (d, / = 7.2 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 475.2

(M+H + ).

A solution of Example 202 (51 mg, 0.11 mmol) in DMF (1.5 mL) was treated with ammonia (0.5M in dioxane, 1.5 mL, 0.75 mmol). PyBOP (80 mg, 0.15 mmol) was added and the resultant solution was stirred overnight at RT. Water (10 mL) was added and the precipitate was filtered and further purified via column chromatography to yield 1-(1-(4-(l-amino-1-oxopropan-2- yl)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(2,3-dichlorophenyl) urea (42 mg, 83% yield). 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.31 (s, 1H), 8.82 (s, 1H), 8.10 (m, 1H), 7.50-7.43 (m, 5H), 7.35-7.29 (m, 2H), 6.88 (s, 1H), 6.39 (s, 1H), 3.66 (q, / = 7.2 Hz, 1H), 1.36 (d, J = 7.2 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 474.0 (M+H + ).

To a solution of 3-hydroxy phenethylamine hydrochloride (0.500 g, 2.88 mmol) in ethanol (10 mL) was added ethyl glyoxylate (50% in toluene, 1.18 g, 5.76 mmol) and the mixture was heated at 80 °C for 2h. The solution was cooled to RT and triethylamine (0.874 g, 4.32 mmol) and Boc anhydride (0.943 g, 4.32 mmol) were added and the resulting solution was stirred at RT for Ih. Evaporation of the solvent and column chromatography yielded 2-t-butyl 1-ethyl 6-hydroxy-3,4-dihydroisoquinoline-l,2(lH)-dicarboxylate (720 mg, 78% yield) as a colorless foam. 1 H NMR (400 MHz, CDCl 3 ): δ 7.35 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 5.49 (s, 0.4H), 5.33 (s, 0.6H), 4.95 (brs, 0.6H), 4.93 (brs, 0.4H), 4.17-4.10 (m, 2H), 3.77-3.69 (m, 2H), 2.93-2.75 (m, 2H), 1.49 (s, 4H), 1.47 (s, 5H), 1.28-1.21 (m, 3H); MS (ESI) m/z: 344.3 (M+Na + ).

To a solution of the material from the previous step (0.770 g, 2.240 mmol) in CH 2 CI 2 (10 mL) was added triethylamine (0.401 mL, 0.291 g, 2.88 mmol) and triflic chloride (0.306 mL, 0.485 g, 2.88 mmol) and the resulting solution was stirred at RT for 3h. Water was added (50 mL) and the mixture was extracted with CH 2 Cl 2 (3x50 mL), dried (MgSO 4 ) and concentrated to yield 2-t-butyl 1-ethyl 6-(trifluoromethylsulfonyloxy)-3,4- dihydroisoquinoline-l,2(lH)-dicarboxylate (1.05 g, 97% yield) of the crude product as a colorless oil which was used without further purification. 1 H NMR (400 MHz, CDCl 3 ): δ 7.61 (d, J = 8.8 Hz, 0.4H), 7.60 (d, J = 8.8 Hz, 0.6H), 7.13 (d, J = 8.4 Hz, 1H), 5.62 (s, 0.4H), 5.44 (s, 0.6H), 4.18 (q, J = 7.0 Hz, 2H), 3.96-3.83 (m, 1H), 3.73-3.64 (m, 1H), 3.15-3.09 (m, 1H),

2.96-2.89 (m, 2H), 1.53 (s, 4H), 1.47 (s, 5H), 1.29-1.23 (m, 3H); MS (ESI) m/z: 476.0 (M+Na + ).

To a degassed solution of the material from the previous step (1.05 g, 2.32 mmol), bis(pinacolato)diboron (0.882 g, 3.47 mmol), and potassium acetate (0.682 g, 6.95 mmol) in DMF (10 mL) was added PdCl 2 (dppf) (0.095 g, 0.116 mmol) and the resulting mixture was stirred at 80 °C for 3h. Water was added (100 mL) and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ), concentrated and purified via column chromatography to yield 2-t-butyl 1-ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroi soquinoline- l,2(lH)-dicarboxylate (935 mg, 94% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.65 (d, 1H, J = 7.6 Hz), 7.61 (s, 0.6H), 7.60 (s, 0.4H), 7.50 (t, J = 8.8 Hz, 1H), 5.58 (s, 0.4H), 5.42 (s, 0.6H), 4.14 (q, J = 7.2 Hz, 2H), 3.79-3.73 (m, 2H), 2.98-2.84 (m, 2H), 1.49 (s, 4H), 1.47 (s, 5H), 1.34 (s, 12H), 1.20 (t, J = 7.6 Hz, 3H); MS (ESI) m/z: 454.2 (M+Na + ).

To a solution of the material from the previous step (0.900 g, 2.09 mmol) in acetone/water 4: 1 was added sodium periodate (1.34 g, 6.26 mmol) and the resulting slurry was stirred at RT for 30 min. 2N HCl was added (2.09 mL, 4.17 mmol) and the resulting mixture was stirred at RT overnight. Water was added (100 mL) and the mixture was extracted with EtOAc (3x100 mL), dried (MgSO 4 ) and concentrated to yield 2-(t- butoxycarbonyl)-1-(ethoxycarbonyl)-l,2,3,4-tetrahydroisoquin olin-6-ylboronic acid (670 mg, 92% yield) as a brown solid which was used without further purification. MS (ESI) m/z: 372.3 (M+Na + ).

To a solution of Example A31 (0.075 g, 0.229 mmol), Example A57 (0.100 g, 0.286 mmol) and pyridine (0.054 g, 0.688 mmol) in CH 2 Cl 2 (5 mL) was added copper(II)-acetate (0.062 g, 0.688 mmol) and the resulting green solution was stirred at RT until all starting material was consummed. Water was added (100 mL) and the mixture was extracted with CH 2 Cl 2 (3x50 mL), dried

(MgSO 4 ), concentrated and purified via column chromatography to yield 2-t-butyl 1-ethyl 6- (3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-lH-pyrazol-1-yl) -3,4-dihydroisoquinoline- l,2(lH)-dicarboxylate (85 mg, 59% yield) as a colorless foam. 1 H NMR (400 MHz, CDCl 3 ): δ 8.62 (brs, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.19 (brs, 1H), 7.65 (d, J = 8.4 Hz, 0.5H), 7.61 (d, J = 8.4 Hz, 0.5H), 7.49-7.44 (m, 2H), 7.31 (t, J = 8.2 Hz, 1H), 7.24 (dd, J = 7.6, and 1.6 Hz, 1H), 6.49 (s, 1H), 5.58 (s, 0.5H), 5.51 (s, 0.5H), 4.21-4.14 (m, 2H), 3.88-3.78 (m, 1H), 3.75- 3.63 (m, 1H), 2.99-2.90 (m, 2H), 1.48 (s, 4H), 1.46 (s, 5H), 1.32 (s, 9H), 1.26-1.21 (m, 3H);

MS (ESI) m/z: 630.2 (M+H + ).

A solution of Example A58 (0.080 g, 0.130 mmol) in 3N hydrochloric acid in methanol (10.0 mL) was stirred at RT for Ih. The solvent was evaporated and the residue was dissolved in 8N methylamine in ethanol (3 mL) and the solution was stirred at 50 °C overnight. The solvent was evaporated and the residue was purified by reverse phase chromatography and coevaporated with THF/4N HCl to yield 1-(3-t-butyl-1-(1-(methylcarbamoyl)-l,2,3,4- tetrahydroisoquinolin-6-yl)-lH-pyrazol-5-yl)-3-(2,3-dichIoro phenyl)urea (43 mg, 59% yield) of as a colorless solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.03 (t, J = 5.0 Hz, 1H), 7.64-7.58 (m, 3H), 7.28-7.27 (m, 2H), 6.60 (s, 1H), 5.23 (s, 1H), 3.88-3.81 (m, 1H), 3.56-3.50 (m, 1H), 3.30-3.15 (m, 2H), 2.90 (s, 3H), 1.39 (s, 9H); MS (ESI) m/z: 515.0 (M+H + ).

Using general method E, Example A58 (0.280 g, 0.444 mmol) was saponified to yield 2-(t-butoxycarbonyl)-6-(3-t-butyl-5-(3-(2,3- dichloropheny l)ureido)- 1 H-pyrazol - 1 -yl)- 1 ,2,3 ,4- tetrahydroisoquinoline-3-carboxylic acid (234 mg, 88% yield) as an off-white foam. MS (ESI) m/z: 602.2 (M+η + ). A solution of this material (0.065 g, 0.11 mmol) was stirred in 4N hydrogen chloride in dioxane (5 mL) for Ih. Evaporation of the solvent and purification via reverse phase chromatography and co-evaporation with HCl/ethanol (2x100 mL) yielded (25 mg, 43% yield) of the desired product as its hydrochloride. 1 H NMR (400 MHz, CD 3 OD): 5 8.05 (t, J = 5.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.52 (d, / = 8.4 Hz, 1H), 7.27- 7.26 (m, 2H), 6.69 (s, 1H), 4.62 (d, / = 16.4 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.50 (dd, / = 11.2, and 4.8 Hz, 1H), 3.59-3.56 (m, 1H), 3.38-3.30 (m, 1H), 1.40 (s, 9H), urea, acid and amine protons not visible; MS (ESI) m/z: 502.0 (M+H + ).

General Experimental for Examples :206-213

Example A3 and the appropriate aniline were combined as indicated.

To a solution of Example 207 (0.092 g, 0.22 mmol) in dry ethanol (2 mL) was at -78 °C added acetyl chloride (1.1 g, 14 mmol) and the resulting solution was kept at RT overnight. The solvent was evaporated and to the residue was added 7N ammonia in methanol (2 mL) and the mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse-phase chromatography, which was followed by an additional basic extraction and reacidification with HCl to yield 1-(3-t-butyl-1-(3-carbamimidoylphenyl)-lH- pyrazol-5-yl)-3-(2,4,5-trifluorophenyl)urea (45 mg, 43% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.05 (t, J = 1.6 Hz, 1H), 8.02-7.92 (m, 3H), 7.83 (t, J = 8.0 Hz, 1H), 7.23 (dt, J = 10.8, and 7.2 Hz, 1H), 6.60 (s, 1H), 1.39 (s, 9H), amidine and urea protons not visible; MS (ESI) m/z: 431.0 (M+H + ).

Dry urea (3.0 g) was added to a solution of NaOMe (0.1 mol, in 50 mL of MeOH) at RT, stirred for 30 min, after which diethyl oxalate (7.0 g) was slowly added. The mixture was stirred for Ih, cone. HCl (10 mL) was added and the solution stirred for 10 min. After filtration, the residue was washed twice with a small quantity of MeOH, and the combined filtrates were concentrated to yield imidazolidine-2,4,5-trione as a white solid which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ): δll.8 (s, 2 H).

To a solution of NaOMe (0.15 mol, in 60 mL of MeOH) was added 7.2 g of sulfamide at RT. The resulting mixture was stirred for 30 min, after which dimethyl oxalate (11.0 g) was added. The suspension was heated at reflux forlβh, cooled, filtered, the precipitate washed with MeOH, and dried under vacuum to yield l,2,5-thiadiazolidine-3,4-dione 1,1-dioxide as the disodium salt (12.2 g). 13 C-NMR (300 MHz, D 2 O): δ 173 (s, 2 C).

Using general method A, Example Al (143 mg, 0.5 mmol) and 1- fluoro-2-isocyanato-benzene (67 mg, 0.5 mmol) were combined to afford ethyl 3-{ 3-t-butyl-5-[3-(2-fluorophenyl)ureido]-7H-pyrazol-1- yl}benzoate (40 mg, 19% yield).

Using general method B, Example Al (143 mg, 0.5 mmol) and 2,3-difluorophenylamine (67 mg, 0.5 mmol) were combined to afford ethyl 3-{3-t-butyl-5-[3-(2,3-difluorophenyl)ureido]-1H- pyrazol-1-yl}benzoate (50 mg, 23% yield).

Using general method A, Example Al (500 mg, 1.74 mmol) and 5-isocyanato-benzo[l,3]dioxole (290 mg, 1.8 mmol) were combined to afford ethyl 3-{5-[3-(benzo[d][l,3]dioxo-5- yl)ureido]-3-t-butyl-7H-pyrazol-1-yl}benzoate (320 mg, 41% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 8.73 (s, 1 H), 8.34 (s, 1 H), 8.03 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 7.09 (s, 1 H), 6.76 (d, / = 8.1 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 1 H), 6.32 (s, 1 H), 5.92 (s, 2 H), 4.29 (q, J = 6.9 Hz, 2 H), 1.28 (s, 9 H), 1.26 (t, J = 6.9 Hz, 3 H); MS (ESI) m/z: 451 (M+H + ).

Using general method A, Example Al (10.7 g, 70.0 mmol) and 4- nitrophenyl 4-chlorophenylcarbamate (10 g, 34.8 mmol) were combined to yield ethyl 3-{3-t-butyl-5-[3-(4- chlorophenyl)ureido]-lH-pyrazol-1-yl }benzoate (8.0 g, 52% yield). 1 H NMR (DMSO- d 6 ): δ 9.11 (s, 1H), 8.47 (s, 1H), 8.06 (m, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 8.0, 7.6 Hz, 1H), 7.43 (d, / = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.34 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 1.27 (s, 9H), 1.25 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 441 (M + +H).

Using General method C, Example 215 (35 mg, 0.083 mmol) was reduced to afford l-{ 3-t-butyl-1-[3-(hydroxymethyl)phenyl]-1H- pyrazol-5-yl}-3-(2- fluorophenyl)urea (20 mg, 63% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.90 (br s, 1 H), 8.81 (s, 1 H), 8.08 (t, J = 6.3 Hz, 1 H), 7.48-6.98 (m, 7 H), 6.36 (s, 1 H), 5.30 (t, J = 5.7 Hz, 1 H), 4.55 (d, J = 5.7 Hz, 1 H), 1.22 (s, 9 H); MS (ESI) m/z: 383

(M+H + ).

Using General method C, Example 216 (45 mg, 0.10 mmol) was reduced to afford l-{3-t-butyl-1-[3-(hydroxymethyl)phenyl]-1H- pyrazol-5-yl }-3-(2,3- difluorophenyl)urea (30 mg, 75% yield). 1 H- NMR (300 MHz, DMSO-d 6 ): δ 9.08 (s, 1 H), 8.85 (s, 1 H), 7.88 (t, J = 7.5 Hz, 1 H), 7.48-7.42 (m, 2 H), 7.33 (d, J =7.5 Hz, 2 H), 7.13-6.95 (m, 2 H), 6.36 (s, 1 H), 4.55 (s, 1 H), 1.24 (s, 9 H); MS

(ESI) m/z: 401 (M+H + ).

Using General method C, Example 217 (100 mg, 0.22 mmol) was reduced to afford 1-(benzo[d][l,3]dioxol-5-yl)-3-(3-t-butyl-1-(3- (hydroxymethyl)phenyl)- 7H-pyrazol-5-yl)urea (50 mg, 56% yield). 1 H NMR (300 MHz, CD 3 OD): δ 7.52-7.47 (m, 4 H), 7.02 (s, 1 H), 6.65-6.69 (m, 2 H), 6.41 (s, 1 H), 5.89 (s, 2 H), 4.69 (s, 2 H), 1.33 (s, 9 H); MS (ESI) m/z: 409 (M+H + ).

To a solution of CuI (1 mol%), 1,10-phenanthroline (10 mol%), Cs 2 CO 3 (9.8 g, 30 mmol) and DMF (20 mL) was added t-butyl carbazate (3.4 g, 25 mmol), 3-iodobenzyl alcohol (5.0 g, 21 mmol). The reaction mixture was heated at 80 °C for 2h. The reaction mixture was filtered through a pad of silica gel and the filtrate was evaporated under reduced pressure to obtain crude product, l-Boc-1-(3-carbinol)phenylhydrazine as yellow oil. The product was used for the next reaction without further purification.

To a solution of l-Boc-1-(3-carbinol)phenylhydrazine (2.0 g, 8.4 mmol) in absolute ethanol (30 mL) at RT was added cone. HCl (3.5 mL, 42 mmol). The reaction mixture was stirred at 60 °C for 30 min. Pivaloylacetonitrile (1.3 g, 10 mmol) was added into the reaction mixture, which was heated at 90 °C for 3h. The solvent was evaporated under reduced pressure and the residue was dissolved in water and lyophilized to obtain the crude product [3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]methanol as the HC1 salt. The product was used for the next step without further purification. 1 H-NMR (DMSO-d 6 ): δ 7.4-7.6 (m, 4H), 5.62 (br s, 1H), 4.59 (s, 2H), 1.29 (s, 9H).

To a solution of [3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]rnethanol hydrochloride salt (2.0 g, 7.1 mmol) in DMF (20 mL) was added imidazole (2.7 g, 39 mmol) and TBSCl (2.1 g, 14 mmol), which was stirred at RT for 8h. The reaction mixture was quenched with water and extracted with EtOAc (3x). Organic extracts were washed with NaHCO 3 , H 2 O and 10 % LiCl solution. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to yield 3-t-butyl-1-(3-[(f-butylmethylsilyloxy)methyl]phenyl }-7H-pyrazol-5-amine in 36% yield (for three steps): 1 H-NMR (CDC1 3 ): δ 7.3-7.6 (m, 4H), 5.54 (s, 1H), 4.80 (s, 2H), 1.34 (s, 9H), 0.97 (s, 9H), 0.13 (s, 6H); MS (EI) m/z: 360 (M+H + ).

To a solution of Example A61 (100 mg, 0.18 mmol) in THF (2 mL) was added pyridine (45 mL, 0.56 mmol) and 3-chlorophenyl isocyanate (43 mg, 0.18 mmol). The reaction mixture was stirred at RT for 20 min, heated until all solids were dissolved, and stirred at RT for 4h. The reaction mixture was concentrated under reduced pressure to yield 1 -(3-t-butyl- 1 - { 3-[(r- butyldimethylsilyloxy)methyl]phenyl }-7H-pyrazol-5-yl)-3-(3-chlorophenyl)urea (62 mg, 43% yield).

To a solution of 1-(3-t-butyl-1-{3-[(r-butyldimethylsilyloxy)methyl]phenyl}- IH-

pyrazol-5-yl)-3-(3-chlorophenyl)urea (120 mg, 0.12 mmol) in THF (2 mL) was added TBAF (1.0 M, 0.13 mL, 0.13 mmol). The reaction mixture was stirred at RT for 2.5h. The solvent was removed under reduced pressure. EtOAc was added into the residue followed by IN- HCl (5 drops). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to yield 1-(3-t-butyl-1-(3- hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-chlorophenyl)ure a as a white powder (34 mg, 71% yield). 1 H-NMR (CDCl 3 ): δ 8.11 (s, 1H), 7.34 (t, J = 2.0 Hz, 1H), 7.05-7.25 (m, 7H), 6.99 (dt, J = 1.3, and 7.8 Hz, 1H), 6.39 (s, 1H), 4.39 (s, 2H), 1.33 (s, 9H); MS (EI) m/z: 399 (M+H + ).

Using the same procedure as for Example 222, Example A61 (100 mg, 0.28 mmol) and 3-bromophenyl isocyanate (55 mg, 0.28 mmol) were combined to yield l-{3-t-butyl-1-[3- (hydroxymethyl)phenyl]-7H-pyrazol-5-yl}-3-(3-bromophenyl)ure a as a white powder (19 mg, 15% yield). 1 H-NMR (CDC1 3 ): δ 8.17

(s, 1H), 7.47 (t, J = 1.8 Hz, 1H), 7.34 (s, 1H), 7.00-7.25 (m, 7H), 6.39 (s, 1H), 4.37 (s, 2H), 1.32 (s, 9H); MS (EI) m/z: 443 and 445 (M + and M + +2H + ).

To a stirred solution of Example 218 (1.60 g, 3.63 mmol) in THF (200 mL) was added LiAlH 4 powder (413 mg, 10.9 mmol) at -10 °C under N 2 . The mixture was stirred for 2h and excess LiAlH 4 was quenched by adding ice. The solution was acidified to pH = 7 with dilute HCl. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200 + 100 mL). The filtrate was concentrated to yield l-{ 3-M)utyl-1-[3- hydroxymethyl)phenyl]-lH-pyrazol-5-yl }-3-(4- chlorophenyl)urea (1.40 g, 97% yield). 1 H NMR (DMSO- d 6 ): δ 9.11 (s, 1H), 8.47 (s, 1H), 7.47-7.27 (m, 8H), 6.35 (s, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 399 (M+H + ).

A solution of Example 224 (800 mg, 2.0 mmol) and SOCl 2 (0.30 mL, 4 mmol) in CHCl 3 (30 mL) was refluxed gently for 3h. The solvent was evaporated in vacuo and the residue was taken up to in CH 2 C1 2 (2x20 mL). After removal of the solvent, l-{3-t-butyl- l-[3-(chloromethyl)phenyl]-1H-pyrazol-5-yl }-3-(4- chlorophenyl)urea (812 mg, 97% yield) was obtained as white powder. η NMR (DMSO- d 6 ): δ 9.57 (s, 1η), 8.75 (s, 1η), 7.63 (s, 1η), 7.50-7.26 (m, 7η), 6.35 (s, 1H), 4.83 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 417

To a mixture of Example A62 (100 mg, 0.24 mmol) in DMF (2 mL) was added Example A60 (91.0 mg, 0.48 mmol) at RT, which was stirred overnight at RT. The reaction solution was concentrated and the residue purified via column chromatography to yield l-{5-t-butyl-2-[3-(l,l,3,4-tetraoxo-1λ 6 -

[l,2,5]thiadiazolidin-2-ylmethyl)phenyl]-2H-pyrazol-3-yl }-3-(4- chlorophenyl)urea (40 mg, 31% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.96 (s, 1 H), 8.45 (s, 1 H), 7.53 (s, 1 H), 7.25-7.46 (m, 7 H), 6.35 (s, 1 H), 4.69 (S, 2 H), 1.25 (s, 9 H).

Using General method E, Example A2 (80 mg, 0.17 mmol) was saponified to afford 3-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-1H-pyrazol-1-yl}benzoic acid (60 mg, 79% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.46 (br s, 1 H), 8.82 (br s, 1 H), 8.05 (br s, 1 H), 7.98 (t, J =4.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 8.7 Hz, 1 H), 7.63 (t, / = 7.8 Hz, 1 H), 7.27 (d, J = 4.5 Hz, 2 H), 6.37 (s, 1 H), 1.26 (s, 9 H)

Using the same procedure as for Example 41, Example 116 (0.11 g, 0.28 mmol) was reduced to afford l-{ l-[3- (aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl }-3-(3-chloro- phenyl)urea as an off-white HCl salt (77.2 mg, 64% yield). 1 H NMR (DMSO-d 6 ): δ 10.11 (s, 1H), 8.91 (s, 1H), 8.43 (br s, 3H),

7.72 (s, 1H), 7.68 (s, 1H), 7.56-7.55 (m, 2H), 7.48-7.46 (m, 1H), 7.31-7.25 (m, 2H), 7.02- 6.99 (m, 1H), 6.42 (s, 1H), 4.16-4.12 (m, 2H), 1.30 (s, 9H); MS (ESI) m/z: 398.3 (M+H + ), 400.2 (M+2+H + ).

To a solution of Example 1 (150 mg, 0.34 mmoL), Example A59 (43 mg, 3.7 mmol) and PPh 3 (98 mg, 3.7 mmoL) in anhydrous THF (1 mL) was slowly added a solution of DEAD (74 μL, 3.7 mmoL) in THF(I mL). The reaction mixture was allowed to stir for 3h and then quenched with H 2 O, extracted with CH 2 C1 2 (3x25 mL), dried (MgSO 4 ), filtered, concentrated and purified by column chromatography to yield 1-(3-t-butyl-1-(3-((2,4,5- trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(2 ,3-dichlorophenyl)urea (60 mg, 33.4%). 1 H NMR (300 MHz, DMSO-tfe): 12.05 (s, 1H), 9.24 (s, 1H), 8.70 (s, 1H), 8.04 (m, 1H), 7.35-7.46 (m, 4H), 7.25-7.27 (m, 2H), 6.37 (s, 1H), 4.68 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 529 (M+H + )

To a solution of Example 1 (300 mg, 0.7 mmol) in anhydrous DMF (6 mL) was added SOCl 2 (165 mg, 0.1 mL, 1.4 mmol) at 0 DC. The solution was heated at reflux for 4h and concentrated to yield 1 -(3-t-butyl- 1 -(3-(chloromethyl)phenyl)- 1 H-pyrazol-5-yl)-3- (2,3-dichlorophenyl)urea (150 mg, 43% yield), which was used without further purification. MS (ESI) m/z: 451 (M+H + ).

To a solution of the material from the previous reaction (150 mg, 0.33 mmol) in anhydrous DMF (10 mL) was added l,2,5-thiadiazolidine-3,4-dione 1,1 -dioxide disodium salt (136 mg, 0.70 mmol) and KI (17 mg, 0.1 mmol). The mixture was stirred at 40 °C overnight. After filtration, the solution was concentrated to give the crude product, which was purified by reverse phase chromatography to afford l-{5-ϊ-butyl-2-[3-(4- methylene-l,l,3-trioxo-[l,2,5]thiadiazolidin-2-ylmethyl)-phe nyl]-2H-pyrazol-3-yl}-3-(2,3- dichlorophenyl)-urea (18mg, 5%). 1 H NMR (DMSO-^): 9.28 (s, 1 H), 8.73 (s, 1 H), 8.04 (t, J = 3.3 Hz, 1 H), 7.52 (s, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.35 (q, J = 7.8 Hz, 2 H), 7.27 (t, J = 3.3 Hz, 2 H), 6.36 (s, 1 H), 4.70 (s, 2 H), 4.65 (s, 1 H), 1.24 (s, 9 H). MS (ESI) m/z: 565 (M+H + ).

Using General method A, Example A4 (70 mg, 0.29 mmol) and 4- fluorophenylisocyanate (39 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3- methoxyphenyl)-lH-pyrazol-5-yl)-3-(4- fluorophenyl)urea as a white powder (38 mg, 35% Yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.59 (brs, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.8-7.1 (m, 8H), 6.77 (dd, J = 1.8 and 8.7 Hz, 1H), 6.30 (s, 1H), 3.66 (s, 3H) 1 1.27 (s, 9H); MS (EI) m/z: 383 (M+H + ).

Using General method A, Example A4 (70 mg, 0.29 mmol) and 3- chloropheπylisocyanate (44 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3- methoxyphenyl)-lH-pyrazol-5-yl)-3-(3- chlorophenyl)urea (83 mg, 73% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.30 (s, 1H), 7.38 (s, 1H), 7.20 (t, J = 1.8 Hz, 1H), 7.07 (m, 2H), 6.95 (dt, J = 1.2, and 7.8 Hz, 2H), 6.82 (t, J = 2.1 Hz, 1H), 6.78 (s, 1H), 7.72 (dd, 7 = 2.1, and 8.7 Hz, 1H), 6.28 (s, 1H), 3.56 (s, 3H), 1.21 (s, 9H);

MS (EI) m/z: 399 (M+H + ).

Using General method A, Example A4 (70 mg, 0.29 mmol) and 3-bromophenylisocyanate (57 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3- methoxyphenyl)-lH-pyrazol-5-yl)-3-(3- bromophenyl)urea as a white solid (107 mg, 85% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.08 (brs, 1H), 7.38 (s, 1H), 7.23 (s, 1H). 7.0-7.2 (m, 4H), 7.8-7.9 (m, 2H), 6.75 (dd, J = 2.4 and 8.4 Hz, 1H), 6.32 (s, 1H), 3.59 (s, 3H), 1.24 (s, 9H); MS (EI) m/z: 443 and 445 (M + and M+2H + ).

Using General method A, Example A4 (70 mg, 0.29 mmol) and 2,4-dichlorophenyl isocyanate (54 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3-methoxyphenyl)-1H-pyrazol- 5-yl)-3-(2,4-dichlorophenyl)urea (76 mg, 61% yield). 1 H NMR (CDCl 3 ): δ 7.96 (d, J = 9.0 Hz), 7.67 (s, 1H), 7.65 (s, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 2.4, and 9.0

Hz, 1H), 6.9 - 7.0 (m, 2H), 6.78 (dd, J = 2.4, and 8.7 Hz, 1H), 6.33 (s, 1H), 3.70 (s, 3H), 1.32

(s, 9H); MS (EI) m/z: 433 (M + H + ).

Using General method A, Example A4 (86 mg, 0.35 mmol) and 5-isocyanatobenzo[d][l,3]dioxole (69 mg, 0.43 mmol) were combined to afford 1-(benzo[d][l,3]dioxo-5-yl)-3-(3-t-butyl-1- (3-methoxyphenyl)-lH-pyrazol-5-yl)urea as a pale yellow solid (98 mg, 68 % yield). 1 H NMR (400 MHz, DMSO-de): δ 8.94 (s, 1H), 8.92 (brs, 1H), 8.31 (s, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.0-7.2

(m, 3H), 6.98 (dd, / = 1.8, and 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 2.0, and 8.4 Hz, 1H), 6.35 (s, 1H), 5.96 (s, 2H), 3.80 (s, 3H), 1.28 (s, 9H); MS (EI) m/z: 409 (M+H + ).

To a solution of Example A4 (123 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) in anhydrous THF (5 mL) was added l-fluoro-2- isocyanato-benzene (69 mg, 0.5 mmol) at 0 °C. This resulted mixture was stirred at RT for 3h, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified by preparative TLC to afford l-[3-t-butyl- 1-(3-methoxy-phenyl)-lH-pyrazol-5-yl]-3- (2-fluorophenyl)urea. 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.92 (s, 1 H), 8.80 (s, 1 H), 8.06 (t, / = 7.5 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H), 7.17-6.96 (m, 6 H), 6.35 (s, 1 H), 3.75 (s, 3 H), 1.22 (s, 9 H); MS (ESI) m/z: 383(M+H + ).

Using General method B, Example A4 (123 mg, 0.5 mmol) and 2,3-difluoro-phenylamine (65 mg, 0.5 mmol) were combined to afford l-[3-t-butyl-1-(3-methoxy-phenyl)-1H-pyrazol-5-yl]-3-(2,3- difluorophenyl)urea. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.11 (s, 1 H), 8.84 (s, 1 H), 7.87 (t, J = 7.8 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.09-6.94 (m, 5 H), 6.36 (s, 1 H), 3.76 (s, 3 H), 1.23 (s, 9 H); MS (ESI) m/z: 401(M+H + ).

A mixture of (4-methoxy-phenyl)-hydrazine (17.4 g, 0.1 mol) and 4,4- dimethyl-3- oxo-pentanenitrile (13.8 g, 0.11 mol) in ethanol (500 mL) and cone. HCl (50 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography to give 3-t- butyl-1-(4-methoxyphenyl)-lH-pyrazol-5-amine (20 g, 82% yield). 1 H- NMR (300 MHz, DMSO- d 6 ): δ 7.38 (d, J = 9.0 Hz, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 5.32 (s, 1 H), 4.99 (br s, 2 H), 3.75 (s, 3 H), 1.17 (s, 9 H); MS (ESI) m/z: 246

(M+H + ).

Using General method A, Example A63 (123 mg,0.5 mmol) and 1- fluoro- 2-isocyanato-benzene (69 mg, 0.5 mmol) were combined to afford l-[3-t-butyl-1-(4- methoxyphenyl)-lH-pyrazol-5-yl]-3-(2- fluorophenyl)urea. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.01 (s, 1 H),

8.89 (s, 1 H), 8.09 (t, J = 7.8 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 2 H), 7.09-7.21 (m, 2 H), 7.05 (d, J = 8.7 Hz, 2 H), 6.97 (t, / = 8.7 Hz, 1 H), 6.32 (s, 1 H), 3.79 (s, 3 H), 1.23 (s, 9 H); MS (ESI) m/z: 383 (M+H + ).

Using General method A, Example A63 (123 mg,0.5 mmol) and l-isocyanato-3-trifluoromethyl-benzene (93 mg, 0.5 mmol) were combined to afford l-[3-t-butyl-1-(4-methoxyphenyl)-lH- pyrazol-5-yl]-3-(3-trifluoromethylphenyl)urea (65 mg, 30% yield). 1 H NMR (300 MHz, DMSO-J 5 ): δ 9.38 (s, 1 H), 8.40 (s, 1 H), 7.94 (br s, 1 H), 7.45 (d, / = 4.8 Hz, 2 H), 7.38 (d, J = 9.0

Hz, 2 H), 7.27 (m, 1 H), 7.03 (d, J = 9.0 Hz, 2 H), 6.32 (s, 1 H), 3.78 (s, 3 H), 1.24 (s, 9 H);

MS (ESI) m/z: 433 (M+H + ).

Using General method A, Example A63 (123 mg,0.5 mmol) and l-bromo-3-isocyanato-benzene (98 mg, 0.5 mmol) were combined to afford 1-(3-bromophenyl)-3-[3-t-butyl-1-(4-methoxyphenyl)- lH-pyrazol-5-yl]urea (65 mg, 29% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.18 (s, 1H), 8.34 (s, 1H), 7.80 (br s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 5.1 Hz, 2H), 7.12 (m, 1H), 7.03 (d, / = 9.0 Hz, 2H), 6.31 (s, 1H), 3.78 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 443 (M+H + ).

Using General method A, Example A63 (123 mg,0.5 mmol) and l-chloro-3-isocyanato-benzene (76 mg, 0.5 mmol) were combined to afford l-[3-t-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-3-(3- chlorophenyl)urea (65 mg, 33% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.17 (s, 1 H), 8.34 (s, 1 H), 7.65 (t, J = 2.1 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 2 H), 7.22 (m, 1 H), 7.15 (m, 1 H), 6.31 (s, 1

H), 3.78 (s, 3 H), 1.24 (s, 9 H); MS (ESI) m/z: 399 (M+H + ).

Using General method B, Example A63 (123 mg, 0.5 mmol) and

1-fluoro- 2,3-difluorophenylamine (65 mg, 0.5 mmol) were combined to afford l-[3-t-butyl-1-(4-methoxyphenyl)-1H-pyrazol-

5-yl]-3-(2,3-difluorophenyl)urea (65 mg, 32% yield). 1 H-NMR

(300 MHz, DMSO-4): δ 9.08 (s, 1 H), 8.77 (s, 1 H), 7.90 (t, J =

7.2 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 2 H), 7.13-6.95 (m, 4 H), 6.33 (s,

1 H), 3.79 (s, 3 H), 1.23 (s, 9 H); MS (ESI) m/z: 401 (M+H + ).

Ethyl 4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from ethyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al, J. Med. Chem., 45, 2994 (2002).

Using General method B, Example A64 (287 mg, 1.0 mmol), and 2,3-difluorophenylamine (134 mg, 1.0 mmol) were combined to afford ethyl 4-{3-t-butyl-5-[3-(2,3-difluorophenyl)ureido]-7H- pyrazol-1-yl}benzoate (250 mg, 57% yield).

Using the same procedure as for Example A18, Example A64 (1 g, 3.09 mmol) and l,2-dichloro-3-isocyanato-benzene (0.7 g, 3.71 mmol) were combined to afford ethyl 4-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-7H-pyrazol-1-yl}benzoate (0.7 g, 48% yield). 1 H-NMR (300 MHz, DMSOd 6 ): δ 9.20 (br s, 1 H), 8.77 (br s, 1 H), 8.04 (m, 1 H), 7.44 (br s, 4 H), 7.29-7.26 (m, 2 H),

6.36 (s, I H), 4.31 (q, J = 7.2 Hz, 2 H), 1.27 (s, 9 H), 1.26 (t, 7 =7.2 Hz, 3 H).

Using General method E, Example 243 (80 mg, 0.17 mmol) was saponified to afford 4-{ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]- 1H-pyrazol-1-yl} benzoic acid (60 mg, 79 % yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.39 (br s, 1 H), 8.78 (br s, 1 H), 8.07-8.02 (m, 3 H), 7.68 (d, J =8.4 Hz, 2 H), 7.29 (d, J = 7.8 Hz, 1 H), 6.41 (s, I H), 1.21 (s, 9 H)

To a solution of Example 1 (100 mg, 0.23 mmol) and Et 3 N (50 mg 0.5 mmol) in anhydrous CH 2 Cl 2 (10 mL), was add acetyl chloride (22 mg, 0.28 mmol) at 0 °C. The mixture was stirred at RT for 3h and then poured into H 2 O. The mixture was extracted with CH 2 Cl 2 (3x50 mL). The combined organic layers were washed with brine, dried (Na 2 Sθ 4 ), filtered, concentrated and purified via reverse phase chromatography to afford 3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1- yl)benzyl acetate (58 mg, 53 % yield). 1 H NMR (DMSOd 6 ): 9.25 (s, 1 H), 8.73 (s, 1 H), 8.00 (m, 1 H), 7.48-7.41 (m, 3 H), 7.36 (m, 1 H), 7.26-7.22 (m, 2 H), 6.33 (s, 1 H), 5.09 (s, 2 H), 1.98 (s, 3 H), 1.22 (s, 9 H). MS (ESI) m/z: 475 (M+H + ).

To a solution of Example A5 (1.0 g, 3.32 mmol) and triethylamine (606 mg, 6.0 mmol) in THF (50 mL) was added 5-isocyanato- benzo[l,3]dioxole (570 mg, 3.5 mmol) in THF (5.0 mL) at 0 °C. The mixture was stirred at RT for 3h, and then poured into water (100 mL). The mixture was extracted with CH 2 Cl 2 (3x). The combined organic extracts were washed with brine, dried

(Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford ethyl 2-(3- {5-[3-(benzo[d][l,3]dioxol-5-yl)ureido]-3^butyl-7H-pyrazol-1 -yl}phenyl)- acetate (950 mg, 62% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.84 (s, 1 H), 8.28 (s, 1 H), 7.48-7.34 (m, 3 H), 7.27 (d, J = 8.4 Hz, 1 H), 7.11 (s, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.31 (s, 1 H), 5.92 (s, 2 H), 4.04 (q, J = 7.2 Hz, 2 H), 3.73 (s, 2 H), 1.23 (s, 9 H), 1.15 (t, J = 7.8 Hz, 3 H); MS (ESI) m/z: 465 (M+H + ).

A suspension of Example A5 (575 mg, 1.70 mmol) in THF (10 mL) was cooled in a dry ice/acetone bath under Ar and treated with KHMDS (0.5 M in toluene, 6.0 mL, 3 mmol). The resultant red-brown-colored reaction mixture was stirred 15 min at -78 °C and was treated with methyl iodide (0.22 mL, 3.5 mmol) and stirred 30 min at -78 °C, then allowed to warm to RT and quenched with saturated aqueous NH4CI (15 mL). The reaction mixture was partitioned between EtOAc (40 mL) and H 2 O (15 mL). The organic layer was washed with H 2 O, 5% Na 2 S 2 O 3 , brine, dried (Na 2 Sθ4), filtered, concentrated and purified via column chromatography to yield 323 mg of a mixture of ethyl 2-(3-(5-amino-3-t-butyl-1H-pyrazol-1- yl)phenyl)propanoate and ethyl 2-(3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl)-2- methylpropanoate (approx 2.5: 1 ratio).

Using general method A, this mixture was combined with 2,3-dichlorophenyl isocyanate (0.15 mL, 1.14 mmol) to yield ethyl 2-(3-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)-2-methylpropa noate [MS (ESI) m/z: 517.0 (M+H + )] and ethyl 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol- 1- yl)phenyl)propanoate (200 mg, MS (ESI) m/z: 503.0 (M+H + ), which were separable by column chromatography. The latter compound was saponified using general method E to yield 2-(3-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol- 1-yl)phenyl)propanoic acid (61.5 mg, 72% yield) as a colorless crystalline solid. 1 H NMR (400 MHz, DMSO-de): δ

12.43 (s, 1 H), 9.24 (s, 1 H), 8.75 (s, 1 H), 8.07 (m, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.45-7.39 (m, 2 H), 7.35-7.29 (m, 3 H), 6.39 (s, 1 H), 3.79 (q, J = 7.2 Hz, 1 H), 1.39 (d, J = 7.2 Hz, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: 475.0 (M+H*).

Using general method I, Example 248 (38 mg, 0.08 mmol) and NH 3 (0.5 M in dioxane, 0.48 mL, 0.24 mmol) were combined and the product crystallized from Et 2 O to yield 1-(1-(3-(l-amino-1- oxopropan-2-yl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (13 mg, 34% yield). 1 H NMR (400 MHz, DMSO-Ci 6 ): δ 9.25 (s, 1 H), 8.75 (s, 1 H), 8.09 (m, 1 H), 7.49-7.43 (m, 3 H), 7.39-7.33 (m, 2 H), 7.32-7.27 (m, 2 H), 6.87 (br s, 1 H), 6.39 (s, 1 H), 3.66 (q, J = 7.2 Hz, 1 H), 1.34 (d, J = 7.2 Hz, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: 474.2 (M+H + ).

Using general method C, Example 247 (930 mg, 2.0 mmol) iwas reduced to afford 1-(benzo[d][l,3]dioxol-5-yl)-3-{3-t-butyl-1-[3- (2-hydroxyethyl)phenyl]-lH-pyrazol-5-yl }urea (800 mg, 95% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.86 (s, 1 H), 8.26 (s, 1 H), 7.39-7.30 (m, 4 H), 7.11 (s, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 1 H), 6.31 (s, 1 H), 5.92 (s, 2 H), 4.64 (t, J =

5.4 Hz, 1 H), 3.60 (q, J = 6.9 Hz, 2 H), 2.76 (t, J = 7.2 Hz, 2 H), 1.23 (s, 9 H), 1.05 (t, / = 7.2

Hz, 3 H); MS (ESI) m/z: 423(M-HH + ).

To a solution of Example 250 (750 mg, 1.78 mmol) in THF (50 mL) was added dropwise SOCl 2 (1.0 mL, 14 mmol) at 0 °C. The mixture was heated to reflux for 3h, then concentrated under reduced pressure to yield 1-(benzo[d][l,3]dioxol-5-yl)-3-{3-r- butyl-1-[3-(2- chloroethyl)phenyl]-1H-pyrazol-5-yl }urea (680 mg, 87% yield), which was used for the next reaction without further purification. MS (ESI) m/z: 441 (M+η + ).

To a solution of Example 251 (680 mg, 1.5 mmol) in DMF (15 ITiL) was added NaN 3 powder (130 mg, 2.0 mmol), which was stirred at RT overnight. The mixture was poured into ice-water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford l-{ l-[3-(2- azidoethyl)phenyl]-3-t-butyl-7H-pyrazol-5-yl }-3-(benzo[d][l,3]dioxol- 5-yl)urea (450 mg,

67% yield). MS (ESI) m/z: 448 (M+η + ).

A mixture of Example 252 (200 mg, 0.45 mmol) and Pd/C (40 mg, 20 %) in methanol (20 mL) was stirred at RT under 20 psi of H 2 for 3h, and then filtered. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt. The mixture of TFA salt in MeCN / H 2 O (50 mL) was basified to pH = 10.0 with a aqueous solution of 1.0 N Na 2 CO 3 . After lyophylization, the residue was dissolved in THF and filtered. The filtrate was adjusted to pH = 6.0 with 1.0 N HCl/MeOH (2.0 mL), then concentrated to yield l-{ l-[3-(2-aminoethyl)phenyl]-3-t-butyl- 1H-pyrazol-5-yl}-3-(benzo[d][l,3]dioxol-5-yl)urea as the hydrochloride salt (80 mg, 40% yield). 1 H NMR (300 MHz, DMSO-4): δ 9.37 (s, 1 H), 8.65 (s, 1 H), 7.92 (br s, 3 H), 7.52- 7.47 (m, 3 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.02 (s, 1 H), 6.65-6.69 (m, 2 H), 6.31 (s, 1 H), 5.92 (s, 2 H), 3.13-3.07 (m, 2 H), 2.96-2.88 (m, 2 H), 1.24 (s, 9 H); MS (ESI) m/z: 422 (M+H + ).

To a stirring solution of Example A17 (0.180 g, 0.51 mmol) in dry CH 2 Cl 2 (5 ml) at RT was added 4-chlorophenyl isocyanate (82 mg, 0.53 mmol). The resulting mixture was stirred at RT overnight. More 4-chlorophenyl isocyanate was added (40 mg, 0.26 mmol) and stirring was continued. After 2h, the reaction was concentrated to dryness and purified by flash chromatography to yield pure 1-(3-t-butyl-1-{ 3-[2-(2,2,2-trifluoroacetamido)ethyl]- phenyl }-1H-pyrazol-5-yl)-3- (4-chlorophenyl)urea as an orange foam (0.134 g, 52% yield). 1 H NMR (CDC1 3 ): δ 8.14 (br s, 1H), 7.39-7.20 (m, 8H), 7.03 (br s, 1H), 6.57 (s, 1H), 3.77 (m, 2H), 2.88 (m, 2H), 1.35 (s, 9H); MS (ESI) m/z: 508.3 (M+H + ).

To a stirring solution of Example 254 (0.134 g, 0.264 mmol) in MeOH (10 ml) and H 2 O (0.6 ml) at RT was added potassium carbonate (0.182 g, 1.32 mmol). The resulting suspension was stirred at 60-65 °C for 2h, then cooled to RT and the volatiles evaporated. The residue was carefully dissolved in IM HCl to pH 1-2 and extracted with Et 2 O (2x). The aqueous was then basified

(pH 13-14) with 3M NaOH and extracted with CH 2 Cl 2 (4x). The combined CH 2 Cl 2 extracts were washed with brine (Ix), dried (Na 2 SO 4 ), filtered, and concentrated to provided l-{ l-[3- (2-aminoethyl)phenyl]-3-t-butyl-7H-pyrazol-5-yl }- 3-(4-chlorophenyl)urea as a foam (70.6 mg, 65% yield). 1 H NMR (CDCl 3 ): δ 8.64 (br s, 1H), 7.33-7.00 (m, 8H), 6.39 (s, 1H), 2.65 (m, 4H), 1.31 (s, 9H); MS (ESI) m/z: 412.3 (M-I-H + ).

Using General method A, Example A15 (50 mg, 0.14 mmol) and 3-chlorophenyl isocyanate (0.034 ml, 0.28 mmol) were combined to afford 1-(3-t-butyl-1-{3-[2-(2,2,2- trifluoroacetamido)ethyl]phenyl }-lH-pyrazol-5-yl)-3-(3- chlorophenyl)urea (32.2 mg, 45% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.18 (s, 1H), 7.51-7.48 (m, 2H), 7.43 (s, 1H), 7.37- 7.34 (m, 3H), 7.20-7.14 (m, 2H), 7.08-7.05 (m, 1H), 7.02- 6.99 (m, 1H), 6.58 (s, 1H), 3.78 (q, J = 6.4 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 1.36 (s, 9H); MS (ESI) m/z: 508.3 (100, M-I-H + ), 510.2 (37, M+2H + ).

Using the same procedure as for Example 39, Example 122 (32.2 mg, 0.063 mmol) was deprotected to afford l-{ l-[3-(2- aminoethyl)phenyl]-3-?-butyI-7H-pyrazol-5-yl }-3- (3- chlorophenyl)urea (19.1 mg, 73% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.29 (brs, 1H), 7.46 (s, 1H), 7.43-7.29 (m, 1H), 7.23- 7.19 (m, 2H), 7.16-7.10 (m, 3H), 7.01-6.97 (m, 2H), 6.41 (s, 1H),

2.94 (brs, 2H), 2.71 (brs, 2H), 1.34 (s, 9H); MS (ESI) m/z: 412.3 (100, M+H + ), 414.2 (36,

M+2).

To a solution of 1-(3-t-butyl-1-(3-(2-(methylamino)-2- oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (0.071 g, 0.15 mmol) in THF (2 raL) was added a solution of IM BH 3 -THF (1 mL, 1 mmol) at 0° C under Ar. After stirring the mixture at 60° C for 24h, it was cooled to 0° C, and 3M HCl was added slowly. The mixture was heated to 60° C for 30 min, cooled to 0° C, and basified with 20% NaOH solution. The product was extracted with CHCl 3 (3x25 mL). The combined organic extracts were washed with H 2 O (1x30 mL), brine, dried (Na 2 SO 4 ) and concentrated. The resultant residue was dissolved in CH 2 Cl 2 (2 mL) and 3M HC1/ EtOAc solution (1 mL) was added and stirred for 10 min to yield (0.025 g, 36%) 1- (3-t-butyl-1-(3-(2-(methylamino)ethyl)phenyl)-1H-pyrazol-5-y l)-3-(2,3-dichlorophenyl)urea as a solid. 1 H NMR (300 MHz, DMSO-^ 6 ): D 9.52 (s, 1H), 8.92 (s, 1H), 8.70-8.66 (brs, 2H), 8.05 (dd, J = 6.0 Hz, 4.0 Hz, 1H), 1.51-1.42 (m, 3H), 7.34-7.28 (m, 3H), 6.39 (s, 1H), 3.24- 3.17 (m, 2H), 3.02-2.98 (m, 2H), 2.58-2.55 (m, 3H), 1.28 (s, 9H). MS (ESI) m/z: 460.2 (M+H + ).

Using the same procedure as for Example 258, Example 441 (0.083 g, 0.16 mmol) was reacted with IM BH 3 -THF (ImL, 1 mmol) to afford (0.071 g, 88%) 1 -(3-t-buty 1- 1 -(3-(2- (isopropylamino)ethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea as a solid. 1 H NMR (300 MHz, DMSO-^ 6 ): D 9.70 (s, 1H), 9.03 (s, 1H), 8.93 (brs, 1H), 8.02 (dd, J = 6.0 Hz, 4.0 Hz, 1H), 7.51-7.42 (m, 3H), 7.33-7.28 (m, 3H), 6.38 (s, 1H), 3.03-3.17 (m, 3H), 3.07-3.02 (m, 2H), 1.28 (s, 9H), 1.23 (d, / = 6.8 Hz, 6H); MS (ESI) m/z: 488.2 (M+H + )

To a solution of Example A35 (100 mg, 0.23 mmol) in CH 3 OH (3 mL) was added NH 2 ORHCl (61 mg, 0.58 mmol) and I- PR2NET (0.073 mL, 0.28 mmol), then the solution was stirred overnight at RT. After the solvent was removed, the residue was purified by prep-HPLC to give 4-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]pyrazol-1-yl}-N-hydroxybenzamidine (75 mg, 71 % yield) as a white power. 1 H NMR (300 MHz, DMSO-4): δ 9.33 (s, 1H), 8.75 (s, 1H), 7.99 (m, 1H), 7.84-7.81 (d, J = 9.0 Hz, 2H), 7.76-7.73 (d, J = 9.0 Hz, 2H), 7.27-7.24 (d, J = 6.9 Hz, 2H), 6.40 (s, 1 H), 1.26 (s, 9H); MS (ESI) m/z: 461 (M+H + ).

Using General method B, Example Al 8 (300 mg, 1 mmol) and 2,3-difluorophenylamine (129 mg, 1.0 mmol) were combined to afford ethyl 2-(4-(3-t-butyl-5-(3-(2,3-difluorophenyl)ureido)-1H- pyrazol-1-yl)phenyl)acetate (220 mg, 48% yield).

Using General method C, Example 261 (100 mg, 0.21 mmol) was transformed to 1-(3-t-butyl-1-(4-(2-hydroxyethyl)phenyl)-1H- pyrazol-5-yl)-3-(2,3-difluoro- phenyl)urea (55 mg, 63% yield). 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.10 (br s, 1 H), 8.85 (s, 1 H), 7.89 (m, 1 H), 7.36 (br s, 4 H), 7.11-6.98 (m, 2 H), 6.35 (s, 1 H), 4.66 (t, J = 5.1 Hz, 1 H), 3.62 (q, / = 6.9 Hz, 2 H), 2.76 (t, J = 7.2 Hz, 2

H), 1.23 (s, 9 H); MS (ESI) m/z: 415 (M+H + ).

To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH 2 Cl 2 (200 mL) was added dropwise (triphenyl-λ5-phosphanylidene)-acetic acid ethyl ester (34.8 g, 0.1 mol) in CH 2 Cl 2 (100 mL) at 0 °C. After the addition was complete, the resulting mixture was stirred for Ih. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3- (3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 % yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 8.23 (dd, J = 0.8, and 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 16.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H).

A mixture of 3-(3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6 mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi of H 2 at RT for 2h, then filtered through celite. After removal the solvent, 14 g of 3-(3-aminophenyl)propionic acid ethyl ester was obtained. 1 H NMR (400 MHz, CDC1 3 ): δ 7.11 (t, J = 5.6 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13 (q, J =7.2 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H); MS (ESI): m/z: 194 (M+H + ).

To a solution of 3-(3-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in cone. HCl (200 mL) was added aqueous (10 mL) Of NaNO 2 (5 g, 72.5 mmol) at 0 °C and the

resulting mixture was stirred for Ih. A solution of SnCl 2 .2H 2 O (33 g, 145 mmol) in cone. HCl (150 mL) was then added at 0 °C. The reaction solution was stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-(3- hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H + ).

A mixture of 3-(3-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(3-(3-t-butyl-5-amino-7H-pyrazol-1- yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1 H NMR (300 MHz, DMSOd 6 ); δ 7.50-7.42 (m, 4H), 5.63 (s, 1H), 5.14 (s, 2H), 4.04 (q, J = 6.9 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J = 7.5 Hz, 3H); MS (ESI) m/z: 316 (M+H + ).

Using General method A, Example A65 (101 mg, 1.0 mmol) and 1- fluoro-2-isocyanato-benzene (137 mg, 1.0 mmol) were combined to afford 3-(3-{3-t-butyl-5-[3-(2-fluorophenyl)-ureido]-1H-pyrazol-1- yl }phenyl)propionic acid ethyl ester (240 mg, 53% yield), which was used with further purification.

Using General method A, Example A65 (300 mg, 1.0 mmol) and l,2-dichloro-3-isocyanato-benzene (187 mg, 1.0 mmol) were combined to afford 3-(3-{ 3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-1H-pyrazol-1-yl }phenyl)propionic acid ethyl ester (210 mg, 42 % yield), which was used without further purification 1 H NMR (DMSOd 6 ): δ 9.20 (s, 1H), 8.76 (s, 1H), 8.05 (m, 1 H), 1 Al-1.26 (m, 6 H), 6.38 (s, 1 H), 4.04 (q, J = 7.2 Hz, 2 H), 2.93 (t, J = 7.5 Hz, 2 H), 2.65 (t, J = 7.5 Hz, 2 H), 1.28 (s, 9 H), 1.15 (t, / = 7.2 Hz, 3 H); MS (ESI) m/z: 503 (M+H + ).

Using General method E, Example 263 (100 mg, 0.221 mmol) was saponified to afford 3-(3-{3-t-butyl-5-[3-(2-fluorophenyl)ureido]- 1H-pyrazol-1-yl }- phenyl)propionic acid (80 mg, 85% yield). 1 H NMR (300 MHz, DMSO-^ 5 ): δ 8.90 (br s, 1 H), 8.81 (s, 1 H), 7.08 (t, J = 7.5 Hz, 1 H), 7.42 (t, / = 7.5 Hz, 1 H), 7.35 (s, 1 H), 7.28 (t, / = 6.9 Hz, 1 H), 7.28 (m, 1 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.98 (m, 1 H),

6.37 (s, 1 H), 2.87 (t, J = 7.5 Hz, 2 H), 2.55 (t, J = 7.5 Hz, 2 H), 1.24 (s, 9 H); MS (ESI) m/z:

425 (M+H + ).

To a suspension of 2-(3-bromo-phenyl)-5-?-butyl-2H-pyrazol-3-ylamine (5.8g, 20 mmol), Pd(OAc) 2 (450 mg, 2 mmol), PPh 3 (1.Og, 4 mmol), and K 2 CO 3 (5.5g, 40 mmol) in DMF (50 mL) was added 2-methyl- acrylic acid ethyl ester (2.8g, 25 mmol) at RT under N 2 . The mixture was stirred at 80 °C overnight, concentrated under reduced pressure, and purified by column chromatography to afford (£)-3-[3-(5-amino-3- r-butyl-7H-pyrazol-1- yl)phenyl]-2-methylacrylic acid (3.2 g). MS (ESI) m/z: 328 (M+η + )

A mixture of (E)-3-(3-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)-2-methyl acrylic acid ethyl ester (3.0 g, 9.14 mmol) and Pd/C (0.3 g) in methanol (50 mL) was stirred at RT under 40 psi of H 2 for 2h. The reaction mixture was filtered and the filtrate was concentrated to afford ethyl 3-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]-2-methylprop anoate (2.5 g, 83% yield). MS (ESI) m/z: 330 (M+η + ).

Using General method A, Example A66 (200 mg, 0.61 mmol) and l,2-dichloro-3-isocyanatobenzene (187 mg, 1.0 mmol) were combined to yield 180 ethyl 3-(3-{ 3-M>utyl-5-[3-(2,3- dichlorophenyl)ureido]-7H-pyrazol-1-yl }phenyl)-2- methylpropanoate (180 mg, 57% yield). MS (ESI) m/z: 517 (M+η + ).

Using General method E, Example 266 (100 mg, 0.19 mmol) was saponified to afford 3-(3-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-7H-pyrazol-1-yl }- phenyl)-2- methylpropanoic acid (60 mg, 65% yield). 1 H-NMR (DMSO-d 6 ): δ 9.20 (s, 1 H), 8.72 (s, 1 H), 8.03 (m, 1 H), 7.43-7.19 (m, 6 H), 6.34 (s, 1 H), 2.95 (m, 1 H), 2.69-2.62 (m, 2 H), 1.24 (s, 9 H),

1.01 (d, J = 6.3 Hz, 3 H); MS (ESI) m/z: 489 (M+H + ).

To a stirred solution of Example Al (19.5 g, 68.0 mmol) in THF (200 mL) was added LiAIH 4 powder (5.30 g, 0.136 mol) at -10 °C under N 2 . The mixture was stirred for 2 h at RT and excess LiA1H 4 was destroyed by slow addition of ice. The reaction mixture was acidified to pH = 7 with diluted HCl, the solution concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic extracts were concentrated to yield [3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-methanol (16.35 g, 98%) as a white powder. 1 H NMR (DMSO-d6): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, 1 H), 6.41 (s, 1H), 4.60 (s, 2 H), 1.28 (s, 9 H); MS (ESI) m/z: 415 (M+H + ).

A solution of Example A67 (13.8 g, 56mmol) and SOC1 2 (8.27 mL, 0.11 mol) in THF (200 mL) was refluxed for 3 h and concentrated under reduced pressure to yield 5-f-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol- 3-ylamine (14.5 g, 98%) as a white powder which was used without further purification. 1 H NMR (DMSO-d6), 57.62 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.31 (d, J = 7.2 Hz,l H), 5.38 (s, 1 H), 5.23 (br s, 2 H), 4.80 (s, 2H), 1.19 (s, 9 H). MS (ESI) m/z: 264 (M+H + ).

To a suspension of NaH (26 mg, 0.67 mmol) in DMSO (2 mL) was added powder l-methyl-[l,2,4]triazolidine-3,5-dione (77 mg, 0.67 mmol) at RT under N 2 atmosphere. The resulting mixture was stirred for 30 min and then added to a solution of Example A68 (100 mg, 0.33 mmol) and Et 3 N (1 mL) in DMSO (2 mL). After stirring for 3 h, the reaction mixture was quenched with methanol, concentrated and purified by column chromatography to afford 90 mg of 4-[3-(5-amino-3-t-butyl-pyrazol-1- yl)-benzyl]-1-methyl-[l,2,4]triazolidine- 3,5-dione.

To a suspension of Example A69 (90 mg, 0.26 mmol) and triethylamine (0.5 mL) in fresh THF (10 mL) was added a solution of l,2-dichloro-3- isocyanato-benzene (95 mg, 0.5 mmol) in THF (2 mL) dropwise through syringe at 0 °C under N 2 atmosphere. The mixture was allowed to rise to RT and stirred overnight. The reaction mixture was quenched with ice-cold aqueous HCl (1 mol/L) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified column chromatography to afford 80 mg of l-{5-t-butyl-2-[3-(l-methyl-3,5- dioxo- [l,2,4]triazolidin-4-ylmethyl)-phenyl]-2H-pyrazol-3-yl }-3-(2,3-dichloro-phenyl)-urea. 1 H- NMR (DMSO-d 6 ), δll.30 (s, 1 H), 9.27 (s, 1 H), 8.70 (s, 1 H), 8.04 (m, 1 H), 7.50-7.46 (m, 3 H), 7.28-7.26 (m, 3 H), 6.37 (s, 1 H), 4.74 (s, 2 H), 2.96(s, 3 H), 1.25 (s, 9 H).

To a solution of aniline (2.51 g, 27 mmol) dissolved in glacial acetic acid (14 mL) and water (28 mL) was slowly added a solution of potassium cyanate (4.4 g, 54 mmol) dissolved in water (35 mL). The mixture stirred for 2h at RT, filtered, washed with water and dried under reduced pressure to yield phenylurea as a white solid (1.85 g, 50% yield). 1 H NMR (DMSO- (I 6 ): δ 8.47 (s, 1H), 7.38 (dd, J = 8.4 Hz, 0.9 Hz, 2H), 7.2 (t, J = 7.6 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 5.81 (brs, 2H); MS (ESI) m/z: 137 (M+H + ).

A suspension of Example A19 (0.4 g, 3 mmol) in ether (20 mL) was added oxalylchloride (0.8 g, 6 mmol) and refluxed for 3h. Solvent was removed under reduced pressure and solid was dried to yield l-phenylimidazolidine-2,4,5-trione (0.51 g, 89% yield), which was used without purification. 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.53-7.38 (m, 5H); MS (ESI) m/z: 191 (M+H + ).

To a solution of triphenyl phosphine (0.23 g, 0.88 mmol) in THF (5 mL) at -20 °C were added di-r-butyl azadicarboxylate (DBAD) (0.2 g, 0.88 mmol), a solution of Example 224 (0.175 g, 0.44 mmol) in THF (5 mL) and Example A70 (0.1 g, 0.53 mmol). The resulting clear yellow solution was heated at 60 °C for 8h, followed by the further addition of one equivalent of triphenyl phosphine and DBAD and additional heating at 60 °C overnight. One additional equivalent of triphenyl phosphine and DBAD were added and reaction mixture was heated at 60 °C for 3h. The reaction mixture was concentrated and purified via column chromatography to yield 1-(3-t-butyl-1-(3-[(2,4,5- trioxo-3-phenylimidazolidin-1-yl)methyl]phenyl }-lH-pyrazol-5-yl)-3-(4-chlorophenyl)urea as a white solid (70mg, 28% yield). 1 H NMR (400 MHz, DMSO-de): δ 9.02 (s, 1H), 8.45 (s, 1H), 7.53 - 7.28 (m, 12H), 6.39 (s, 1H), 4.87 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 571 (M+H + ).

To a solution of Example Al (0.57 g, 2 mmol) in THF were added pyridine (0.31 g, 4 mmol) 4-fluoro phenyl isocyanate (0.27 g, 2 mmol) and reaction mixture was stirred at RT for 2Oh. Then solvent was removed under reduced pressure, and the residue was solidified by stirring with hexane to yield of ethyl 3-{ 3-t-butyl-5- [3-(4-fluorophenyl)ureido)-/H- pyrazol-1-yl }benzoate as a white solid (0.78g, 92% yield) 1 H NMR (400 MHz, DMSO-4): D 9.02 (s, 1H), 8.44 (s, 1H), 8.08 (t, J = 1.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 8 Hz, 1.6 Hz, 1H), 7.67 (t, J = 8 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 6.37 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.30 - 1.28 (m, 12H); MS (ESI) m/z: 425 (M+H + ).

To a solution of Example 270 (0.78 g, 1.8 mmol) in THF (20 mL) was added LAH (5.5 mL of IM solution in THF) at 0 °C. The mixture was warmed to RT, stirred for Ih, quenched with ice at 0 °C and concentrated under reduced pressure. The residue was acidified with IM HCl and product was extracted with EtOAc (2x50 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to yield l-{3-t-butyl-1-[3- (hydroxymethyl)phenyl]-7H-pyrazol-5-yl }-3-(4-fluorophenyl)urea as a white solid (0.66g,

94% yield) 1 H NMR (DMSO-d 6 ): δ 9.20 (s, 1H), 8.48 (s, 1H), 7.48 - 7.36 (m, 6H), 7.10 (t, J = 8.8 Hz, 2H), 6.37 (s, 1H), 4.58 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 383 (M+H + ).

To a solution of Example 271 (0.45 g, 1.2 mmol) in chloroform (20 mL) was added thionyl chloride (0.28 g, 2.4 mmol) and mixture was stirred for 2h at 65 °C. Water was added and organic layer separated. The aqueous layer was extracted with CH 2 C1 2 (1x50 mL) and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to yield l-{3-t-butyl-1-[3-(chloromethyl)phenyl]-7H-pyrazol-5- yl}-3-(4-fluorophenyl)urea as a solid (0.43g, 96% yield). 1 H NMR (CDCl 3 ): δ 7.52 (s, 1H), 7.39-7.34 (m, 3H), 7.23 - 7.19 (m, 2H), 6.97 - 6.95 (m, 3H), 6.41 (s, 1H), 4.57 (s, 2H), 1.36 (s, 9H); MS (ESI) m/z: 401 (M+H + ).

A solution of Example A70 (80 mg, 0.45 mmol), DMF (4 mL) and NaH (5 mg, 0.22 mmol) under Ar at 0 °C was stirred for 30 min. Example A71 (90 mg, 0.22 mmol) was added and the mixture was warmed to RT, stirred for 6h, quenched with water (20 mL) and extracted with ethyl acetate (2x25 mL). The combined organic extracts were washed with water, brine, dried (Na 2 SO 4 ), concentrated under reduced pressure and purified via column chromatography to yield 1-(3-t-butyl-1-{3-[(3,5-dioxo-1-phenyl- l,2,4-triazolidin-4-yl)methyl]phenyl}-1H- pyrazol-5-yl)-3-(4- fluorophenyl)urea as a white solid (65 mg, 53% yield) 1 H NMR (DMSO-d 6 ): δ 8.96 (s, 1H), 8.44 (s, 1H), 7.49-7.33 (m, 9H), 7.24 (s, 1H), 7.12-7.08 (m, 3H), 6.35 (s, 1H), 4.64 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 542 (M+H + ).

Using the same procedure as for Example A71, Example 1 (0.61 g, 1.4 mmol) was transformed to yield 1-(3-t-butyl-1-(3- (chloromethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea as a solid (0.6g, 94% yield). 1 H NMR (CDCl 3 ): δ 8.12 - 8.09 (m, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.47 - 7.36 (m, 3H), 7.19 - 7.17 (m, 2H), 6.95 (br s, 1H), 6.44 (s, 1H),

4.58 (s, 2H), 1.38 (s, 9H); MS (ESI) m/z: 451 (M+H + ).

A solution of Example A70 (70 mg, 0.4 mmol), DMF (5 mL) and NaH (5 mg, 0.2 mmol) under Ar at 0 °C was stirred for 30 min, after which Example A72 (90 mg, 0.2 mmol) was added. The mixture was warmed to RT, stirred for 6h, quench with water (20 mL) and extracted with EtOAc (2x). The combined organic extracts were washed with water, brine, dried (Na 2 SC^), concentrated under reduced pressure and purified via column chromatography to yield 1-(3-t-butyl-1-{3-[(3,5-dioxo-1-phenyl- 1 ,2,4-triazolidin-4- y l)methyl]phenyl } - lH-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea as a white solid (85 mg, 72% yield). 1 H NMR (DMSOd 6 ): δ 9.29 (s, 1H), 8.73 (s, 1H), 8.07 (dd, J = 6.4 Hz, 3.2 Hz, 1H), 7.50 - 7.44 (m,4H), 7.37 - 7.25 (m, 5H), 7.12 - 7.10 (m, 1H), 6.38 (s, 1H), 4.64 (s, 2H), 1.28 (m, 9H); MS (ESI) m/z: 592 (M+H + ).

General Experimental for Examples 274-277

A solution of Example A20 and the appropriate isocyanate (general method A) or the appropriate aniline (general method D) were combined to yield the indicated compound.

Using General method E, Example Al (318 mg, 0.982 mmol) was saponified to yield (277 mg, >100% yield)3-(5-amino-3-t-butyl- lH-pyrazol-1-yl)benzoic acid as a foam.

Using general method J, this crude material (277 mg, 0.983 mmol) and hydrazine hydrate (0.18 mL, 3.69 mmol) were combined to yield 3-(5-amino-3-t-butyl-lH-pyrazol-1-yl)benzohydrazide (100 mg, 37% yield). MS (ESI) m/z: 274.2 (M+η + ). This material (30 mg, 0.11 mmol) in THF (2 mL) was treated with CDI (30 mg, 0.19 mmol) and the reaction mixture was stirred at RT. After 30 min, another portion of CDI (30 mg, 0.19 mmol) was added. After another 30 min, the reaction was quenched with satd. NaHCO 3 (5 mL) and extracted with EtOAc (2x15 mL). The organics were washed with 5% citric acid (2x10 mL), H 2 O (10 mL), brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated to yield 5-(3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl)-l,3,4-oxadia zol-2(3H)-one (50 mg, > 100% yield) as a film. MS (ESI) m/z: 300.3 (M+H + ).

Using General method A, this crude material (50 mg, 0.11 mmol theory) and 2,3- dichlorophenyl isocyanate (0.060 mL, 0.45 mmol) were combined to yield 1-(3-t-butyl-1-(3- (5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazol-5 -yl)-3-(2,3- dichlorophenyl)urea (40mg, 74% yield over 2 steps). 1 H NMR (400 MHz, DMSO-ύfe): δ 12.69 (br s, 1 H), 9.30 (s, 1 H), 8.76 (s, 1 H), 8.00 (m, 1 H), 7.92 (t, J = 1.7 Hz, 1 H), 7.82- 7.66 (m, 3 H), 7.32-7.29 (m, 2 H), 6.42 (s, 1 H), 1.30 (s, 9 H). MS (ESI) m/z: 487.3.0

(M+H + ).

Pivalamidine hydrochloride (5.00 g, 37 mmol) dissolved in methanol (80 mL) was treated with NaOMe (2.0 g, 37 mmol) and stirred at RT for 15 min. To this was added dimethyl 2- (methoxymethylene)malonate (6.4 g, 37 mmol) and the solution stirred at RT overnight. The solution was heated at reflux for Ih, then cooled to RT and concentrated. The oily mass was dissolved in H 2 O (125 mL) and the pH adjusted to ~3 (wet litmus) with AcOH. The precipitated solids were collected by filtration, washed with H 2 O (50 mL) and dried to yield methyl 2-t-butyl-4- hydroxypyrimidine-5-carboxylate (3.50 g, 45%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.29 (s, 9 H), 2.97 (s, 3H), 8.47 (s, 1H).

To ice cold (0-5 °C) POCl 3 (35 mL) was added dropwise Et 3 N (0.4 mL), followed by methyl 2-t-butyl-4-hydroxypyrimidine-5-carboxylate (3.45 g, 16.4 mmol). The mixture was then warmed to 40 °C and stirred under Ar for Ih, then concentrated and diluted with CHCl 3 (100 mL) and poured carefully onto ice (~300 g) and stirred at RT until the ice all melted. The organic phase was separated, washed with NaHCO 3 (100 mL), H 2 O (100 mL), dried (Na 2 SO 4 ), concentrated and dried to yield methyl 2-t-butyl-4-chloropyrimidine-5-carboxylate (3.28 g, 87% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.35 (s, 9 H), 3.90 (s, 3H), 9.14 (s, 1H).

In a mixture of satd. NaHCO 3 : PhMe: EtOH (1:2: 1) (12 mL) was dissolved the material from the previous reaction (3.25 g, 14.2 mmol), phenylboronic acid (3.5 g, 28.4 mmol) and Pd(PPh 3 ) 4 (328 mg). The mixture was stirred at 75 °C, under Ar overnight, then diluted with EtOAc (60 mL) and H 2 O (60 mL) and the mixture filtered through Celite ® and the organic phase separated. The organic phase was washed with 5% citric acid (50 mL), brine (50 mL) dried (Na 2 SO 4 ), concentrated to an oil and purified by column chromatography to yield methyl 2-t-butyl-4-phenylpyrimidine-5-carboxylate (1.26 g, 33% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.29 (s, 9 H), 3.61 (s, 3H), 7.40-7.42 (m, 3H), 7.51-7.53 (m, 2H), 8.66 (s, 1H).

Using general method E, the material from the previous reaction (1.26 g, 4.70 mmol) was saponified to yield 2-t-butyl-4-phenylpyrimidine-5-carboxylic acid (1.10 g, 92% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.40 (s, 9 H), 7.50-7.52 (m, 3H), 7.67- 7.69(m, 2H), 9.02 (s, 1H). 2-t-butyl-4-phenylpyrimidine-5-carboxylic acid (1.10 g, 4.29 mmol) was combined in t-BuOH (11 mL) with DPPA (1.18 g, 4.29 mmol) and Et 3 N (0.434 g,

4.29 mmol). The mixture was heated at reflux, stirred overnight, then cooled to RT and diluted with EtOAc (75 mL) and H 2 O (75 raL). The organic phase was separated, washed with brine, dried (Na 2 SO,;) and concentrated. The resultant solid was treated with EtOAc (5 mL) and sonicated for 5 min then filtered free of solids and evaporated to a small volume and the solution purified by column chromatography to yield t-butyl 2-t-butyl-4-phenylpyrimidin- 5-ylcarbamate (1.2 g, 85% yield) as a white foam. LC-MS (EI) m/z: 328.3 (M+H + ). This material (1.02 g, 3.0 mmol) was dissolved in CH 2 Cl 2 (10 mL) and treated with 3N HCl/EtOAc (10 mL), stirred at RT and subsequently treated with additional 3N HCl/EtOAc (5 mL) and then concentrated to yield 2-t-butyl-4-phenylpyrimidin-5-amine hydrochloride as a yellow solid (0.724g, 88%). LC-MS (EI) m/z: 228.2 (M+H + ). Using general method A, this material (120 mg, 0.455 mmol) and l,2-dichloro-3-isocyanatobenzene (94 mg, 0.500 mmol) were combined to yield 1-(2-t-butyl-4-phenylpyrimidin-5-yl)-3-(2,3- dichlorophenyl)urea (45 mg, 24% yield). 1 H NMR (400 MHz, DMSO-d<5): δ 1.39 (s, 9H), 7.29-7.34 (m, 2H), 7.53-7.59 (m, 3H), 7.77-7.79 (m, 2H), 8.06-8.08 (m, 1H), 8.20 (s, 1H), 8.98-9.02 (m, 2H); LC-MS (EI) m/z: 417.0 (M+H + ).

Using general method A, 2-t-butyl-4-phenylpyrimidin-5- amine hydrochloride (100 mg, 0.379 mmol, available from Example 279) and 1-(3-isocyanatophenoxy)benzene (88 mg, 0.417 mmol) were combined to yield 1-(2-t-butyl-4- phenylpyrimidin-5-yl)-3-(3-phenoxyphenyl)urea (42 mg, 25% yield). 1 H NMR (DMSO-J6): δ 1.38 (s, 9H), 6.61-

6.63 (m, 1H), 7.01-7.56 (m, HH), 7.73-7.75 (m, 2H), 8.10 (s, 1H), 9.02 (s, 1H), 9.19 (s, 1H).

LC-MS (EI) m/z: 439.3 (M + H + ).

Using general method D, 2-t-butyl-4-phenylpyrimidin-5- amine hydrochloride (150 mg, 0.569 mmol, available from Example 279) and 3-(pyridin-3-yloxy)benzenamine (128 mg, 0.683 mmol) were combined to yield 1-(2-t-butyl-4- phenylpyrimidin-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (133 mg, 51% yield). 1 H NMR (DMSO-λ6) δ 1.38 (s, 9H), 6.73-6.76 (m, 1H), 6.89-7.05 (m, 1H), 7.14-7.16 (m, 1H), 7.32-7.38 (m, 2H), 7.51-7.56 (m, 3H), 7.74-7.79 (m, 4H), 8.38 (s, 1H), 8.53-8.62 (m, 2H), 9.00 (s, 1H), 9.56 (s, 1H). LC-MS (EI) m/z: 440.2 (M + H +).

Using general method A, Example A21 (133 mg, 0.5 mmoL) and isocyanatobenzene (60 mg, 0.5 mmol) were combined to afford l-[3- f-butyl-1-(quinoIin-6-yl)-1H-pyrazol-5-yl]-3-phenylurea (90 mg, 47% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.99 (s, 1 H), 8.97 (d, J = 4.5 Hz, 1 H), 8.58 (s, 1 H), 8.56 (d, / = 8.4 Hz, 1 H), 8.19 (s, 1 H), 8.16 (d, J = 8.7 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.67 (m, 1 H), 7.35 (d, / = 7.8 Hz, 2 H), 7.21 (t, J = 7.8 Hz, 2H), 6.92 (t, J = 7.8 Hz, 1 H), 6.42 (s, 1 H), 1.28 (s, 9 H).

General Experimental for Examples 283-285

A solution of Example A21 and the appropriate isocyanate or aniline was converted to the target compound using the general method indicated.

Using general method A, Example A23 (169 mg, 0.5 mmol) and isocyanatobenzene (60 mg, 0.5 mmol) were combined to afford ethyl 3-[3-t-butyl-5-(3-phenylurido)-1H-pyrazol-1-yl]-1-naphthoate (110 mg, 48% yield). 1 H NMR (300 MHz, DMSO-tfc): δ 8.96 (s, 1 H), 8.73 (d, J = 8.1 Hz, 1 H), 8.53 (s, 1 H), 8.33 (s, 1 H), 8.23 (s, 1 H), 8.10 (d, J = 8.1 Hz, 1 H), 7.62-7.71 (m, 2 H), 7.35 (d, / = 7.5 Hz, 2 H), 7.21 (t, / = 7.5 Hz, 2 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.41 (s, 1 H),

4.37 (q, J = 7.2 Hz, 2 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.29 (s, 9 H).

Using general method E, Example 58 (100 mg, 0.20 mmol) is saponified to afford 3-{ 3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido]-lH-pyrazol-1-yl}-1- naphthoic acid (60 mg, 60% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.37 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.76 (s, 1H), 8.30 (m, 1H), 8.10 (m, 1H), 8.00 (t, J = 4.8 Hz, 1H), 57.67 (m, 1H), 7.28 (d, J = 4.8 Hz, 1H),

6.45 (s, 1H), 1.30 (s, 9H); MS (EI) m/z: 497.1 (M+H + ).

Using general method A, Example A23 (200 mg, 0.593 mmol) and 4-cyclohexylisocyanate (256 mg, 1.78 mmol) were combined to afford ethyl 3-(3-t-butyl-5-(3-cyclohexylureido)-1H-pyrazol-1-yl)- 1-naphthoate (15 mg, 5.5% yield). 1 H NMR (400 MHz, DMSO- d 6 ): δ 1.05-1.30 (m, 5H), 1.29 (s, 9H), 1.36-1.41 (m, 3H), 1.47-1.73 (m, 5H), 3.32-3.38 (m, 1H), 4.40-4.46 (m, 2H), 6.32 (s, 1H), 6.40- 6.42 (m, 1H), 7.67-7.71 (m, 2H), 8.09-8.27 (m, 4H), 8.74-8.76 (m, 1H); LC-MS (EI) m/z: 462.7 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 2,4-difluoroaniline (30 mg, 0.234 mmol) were combined to yield ethyl 3-(3-t-butyl-5-(3-(2,4-difluorophenyl)ureido)-1H- pyrazol-1-yl)-1-naphthoate (89 mg, 77% yield). 1 H NMR (400 MHz, DMSOd 6 ): δ 1.25-1.31 (m, 3H), 1.29 (s, 9H), 4.39-4.47 (m, 2H), 6.45 (s, 1H), 7.02-7.03 (m, 1H), 7.28-7.29 (m, 1H), 7.68-7.73 (m, 2H), 7.99-8.01 (m, 1H), 8.13-8.15 (m, 1H), 8.24 (s, br, 1H), 8.36 (s, 1H), 8.76-8.78 (m, 1H), 8.84 (s, 1H), 8.91 (s, 1H); LC-MS (EI) m/z: 493.2

(M+H + ).

Using general method C, Example 286 (100 mg, 0.22 mmol) was reduced to afford 1 -[3-t-butyl- 1 -(4- (hydroxymethyl)naphthalen-2- yl)-lH-pyrazol-5-yl]-3-phenylurea (50 mg, 55% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.99 (s, 1 H), 8.49 (s, 1 H), 8.06 (m, 1 H), 8.01 (m, 1 H), 7.92 (s, 1 H), 7.69 (s, 1 H), 7.54-7.60 (m, 2 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.21 (t, J = 7.8 Hz, 2 H), 6.92 (t, J = 7.5 Hz, 1 H), 6.41 (s, 1 H), 5.01 (s, 2 H), 1.28 (s, 9 H).

Using General method D, Example A24 (120 mg, 0.234 mmol) and 2-fluoroaniline (26 mg, 0.234 mmol) were combined to yield ethyl 3-(3-t-butyl-5-(3-(2-fluorophenyl)ureido)-lH-pyrazol-1-yl)-1 - naphthoate (104 mg, 93% yield). Using General method C, ethyl 3-(3-t-butyl-5-(3-(2-fluorophenyl)ureido)- 1 H-pyrazol- 1 -yl)- 1 - naphthoate (104 mg, 0.22 mmol) was reduced to afford 1-(3-t- butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-lH-pyrazol-5-yl)- 3- (2-fluorophenyl)urea (32 mg, 34% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.30 (s, 9H), 5.04 (s, 2H), 6.46 (s, 1H), 6.98-7.02 (m, 1H), 7.09-7.22 (m, 2H), 7.61 (s, br, 2H), 7.71 (s, 1H), 7.95 (s, 1H), 8.03-8.14 (m, 3H), 8.92-8.95 (m, 2H); LC-MS (EI) m/z: 433.2 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and cyclohexylamine (23 mg, 0.234 mmol) were combined to afford 65 mg (60%), ethyl 3-(3-t-butyl-5-(3-cyclohexylureido)-1H-pyrazol-1- yl)-1-naphthoate, used as is. Using general method C, this ester (65 mg, 0.14 mmol) was reduced to give 1-(3-t-butyl-1-(4- (hydroxymethyl)naphthalen-2-yl)-lH-pyrazol-5-yl)-3- cyclohexylurea (34 mg, 58% yield) as a foam,. 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.07-1.98 (m, 10H), 1.29 (s, 9H), 3.34-3.39 (m, 1H), 5.02 (brs, 2H), 5.47 (s, br, 1H), 6.32 (brs, 1H), 6.46-6.47 (m, 1H), 7.60-7.68 (m, 3H), 7.86 (brs, 1H), 8.00-8.08 (m, 3H); LC-MS (EI) m/z: 421.2 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 4-fluoroaniline (26 mg, 0.234 mmol) to afford 89 mg (80%), ethyl 3-(3-t-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol-1-yl)- 1-naphthoate. Using general method C, this ester (89 mg, 0.19 mmol) was reduced to give 1-(3-t-butyl-1-(4- (hydroxymethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3- cyclohexylurea (59 mg, 73% yield). 1 H NMR (400 MHz, DMSO-d 6 ); δ 1.31 (s, 9H), 5.04 (s, 2H), 6.43 (s, 1H), 7.06-7.11 (m, 2H), 7.38-7.41 (m, 2H), 7.57-7.62 (m, 2H), 7.73 (s, br, 1H), 7.98 (s, 1H), 8.02-8.10 (m, 2H), 8.62 (s, 1H), 9.24 (s, 1H). LC-MS (EI) m/z: 433.3 (M+H + ).

Using general method D, Example A24 (120 mg, 0.234 mmol) and 2,3-difluoroaniline (30 mg, 0.234 mmol) were combined to give 82 mg (71%), ethyl 3-(3-t-butyl-5-(3-(2,3- difluorophenyl)ureido)- 1H-pyrazol- 1 -y I)- 1 -naphthoate. Using general method C, this ester (82 mg, 0.17 mmol) was reduced give 1-(3-t-butyl-1-(4-(hydroxymethyl)naphthalen-2-yl)-lH-pyrazol -5- yl)-3-cyclohexylurea (51 mg, 68% yield) an off white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 1.31 (s, 9H), 5.04-5.05 (m, 2H), 5.50 (m, 1H), 6.46 (s, 1H), 7.02-7.14 (m, 2H), 7.60-7.62 (m, 2H), 7.59-7.62 (m, 2H), 7.71 (s, 1H), 7.91-7.96 (m, 2H), 8.03-8.11 (m, 2H), 8.98 (s, 1H), 9.11 (s, 1H). LC-MS (EI) m/z: 451.2 (M+H + ).

To a solution of Example A23 (400 mg, 1.25 mmol) and triethylamine (303 mg, 3.0 mmol) in THF (10.0 mL) was added isocyanato-benzeπe (250 mg, 1.5 mmol) in THF (2.0 mL) at 0 °C. The mixture was stirred at RT overnight then poured into water (50 mL). The mixture was extracted with CH 2 Cl 2 (3x100 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to afford l-[1-(4-(azidomethyl)naphthalen-2-yl)-3-t-butyl-lH-pyrazol-5 -yl]-3-phenylurea (320 mg, 58% yield). MS (ESI) m/z: 440 (M+η + ).

A mixture of Example A73 (300 mg, 0.68 mmol) and Pd/C (60 mg, 20 %) in methanol (20 mL) was stirred at RT under 20 psi of H 2 for 3h and then filtered. The filtrate was concentrated to yield the crude product, which was purified by preparative HPLC to afford the TFA salt. The mixture of TFA salt in MeCN / H 2 O (50 mL) was basified to pH = 10 with IN Na 2 CO 3 . After lyophylization, the residue was dissolved in THF and filtered. The filtrate was adjusted to pH = 6 with IN HCl / MeOH (2.0 mL) and then concentrated to l-[1-(4-(aminomethyl)naphthalen-2-yl)-3-t-butyl-lH-pyrazol- 5-yl]-3-phenylurea (180 mg, 64% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 8.96 (s, 1H), 8.58 (brs, 1H), 8.16 (s, 2H), 8.09 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.64 (s, 2H), 7.38 (d, J = 5.7 Hz, 2H), 7.21 (t, J = 5.4 Hz, 2H), 6.91 (t, J = 5.4 Hz, 1H), 6.44 (s, 1H), 4.61 (s, 2H), 1.29 (s, 9H); MS (ESI) m/z: 414 (M+H + ).

To a solution of Example 70 (0.12 g, 0.24 mmol) in water (5 mL) was added glacial acetic acid (43 mg, 0.71 mmol). Potaasium cyanate (58 mg, 0.71 mmol) was added into the reaction mixture over a period of 30 min. The reaction mixture was stirred at room temperature overnight. The mixture was kept in refrigerator. The solid was filtered, washed with water and acetic acid (1:1) mixture. The solid was dissolved in CH 3 CN:H 2 O (1:1 4 mL) and lyophilized to obtain the diurea solid (105 mg, 86% yield) as an off-white. 1 H NMR (400 MHz, DMSO-^ 6 ): δ 9.43 (s, 1H), 9.17 (brs, 1H), 8.20 (m, 1H), 8.05 (m, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.87 (m, 1H), 7.61 (m, 1H), 7.10 (m, 1H), 6.61 (t, J = 5.6 Hz, 1H), 6.48 (s, 1H), 4.73

(d, J = 5.6 Hz, 2H), 1.31 (s, 9H); LC-MS (EI) m/z: 511.2 (M+H + ).

Using the same procedure as for Example 296, Example 71 (0.10 g, 0.21 mmol) and potaasium cyanate (51 mg, 0.63 mmol) were combined to afford the diurea (78 mg, 73% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.12 (s, 1H), 8.98 (brs, 1H), 8.18 (m, 2H), 8.05 (m, 1H), 7.96 (d, / = 1.6 Hz, 1H), 7.61 (m, 3H), 6.59 (t, J = 5.6 Hz, 1H), 6.47 (s, 1H), 4.73 (d, J = 5.6 Hz, 2H), 1.31 (s, 9H); LC-MS (EI) m/z: 511.2 (M-HH + ).

Using general method A, Example A27 (400 mg, 1.1 mmol) 1- chloro-4-isocyanatobenzene (260 mg, 1.7 mmol) were combined to afford (3-{ 3-t-butyl-5-[3-(4-chlorophenyl)ureido]pyrazol-1- yl }naphthalen-1-yl)acetic acid ethyl ester (154 mg, 30 % yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.10 (s, 1H), 8.51 (s, 1H), 8.00-7.93 (m, 3H), 7.60-7.55 (m, 3H), 7.37 (d, / =

9.0 Hz, 2H), 7.28 (d, / = 9.0 Hz, 2H), 6.40 (s, 1H), 4.19 (s, 2H), 4.07 (q, J = 7.2 Hz, 2H),

1.26 (s, 9H), 1.13 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 505 (M+H + ).

Using general method A, Example A27 (1 g, 2.8 mmol) and isocyanatobenzene (407 mg, 3.4 mmol) were combined to afford {3- [3-t-butyl-5-(3-phenylureido)pyrazol-1-yl]naphthalen-1-yl } acetic acid methyl ester (790 mg, 62 % yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.97 (s, 1H), 8.49 (s, 1H), 8.02-7.94 (m, 3H), 7.62 (s, 1H), 7.60-7.56 (m, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.22

(t, J = 8.1 Hz, 2H), 6.95 (t, J = 7.5 Hz, 1H), 6.41 (s, 1H), 4.23 (s, 2H), 3.57 (s, 3H), 1.27 (s,

9H); MS (ESI) m/z: 457 (M+H + ).

Using general method E, Example 298 (100 mg, 0.2 mmol) was saponified to afford (3-{ 3-t-butyl-5-[3-(4- chlorophenyl)ureido]pyrazol-1-yl }naphthalen-1-yl)acetic acid (85 mg, 90% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.28 (s, 1H), 9.18 (s, 1H), 8.64 (s, 1H), 7.97 (brs,

2H), 7.60-7.54 (m, 2H), 7.45-7.36 (m, 3H), 7.29-7.23 (m, 3H), 6.39 (s, 1H), 4.10 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 511(M+H + ).

Using general method E, Example 299 (250 mg, 0.54 mmol) was saponified to afford { 3-[3-t-butyl-5-(3-phenylureido)pyrazol-1- yl]naphthalen-1-yl } acetic acid (180 mg, 87 % yield) as a white solid. 1 H NMR (300 MHz, DMSO-^ 6 ): δ 8.00-7.94 (m, 3H), 7.58-7.56 (m, 3H), 7.33 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.1 Hz, 2H), 6.91 (t, J = 6.6 Hz, 1H), 6.40 (s, 1H), 4.10 (s, 2H), 1.26 (s, 9 H); MS (ESI) m/z:

443(M+H + ).

Using general method C, Example 298 (350 mg, 0.7 mmol) was reduced to afford l-{5-t-butyl-2-[4-(2-hydroxyethyl)naphthalen- 2-yl]-2H-pyrazol-3-yl }-3-(4-chlorophenyl)urea (268 mg, 83%yield) as a white solid. 1 H-NMR (300 MHz, DMSOd 6 ): δ 9.17 (s, 1H), 8.53 (s, 1H), 8.12 (m, 1H), 7.96 (m, 1H), 7.89 (s, 1H), 7.55 (m, 2H), 7.51 (s, 1H), 7.31 (dd, J = 9.0 Hz, 9.0 Hz,

4H), 6.39 (s, 1H), 3.71 (t, J = 6.9 Hz, 2H), 3.23 (t, J = 6.9 Hz, 2H), 1.27(s, 1H); MS (ESI) m/z: 463 (M+H + ).

Using general method C, Example 76 (70 mg, 0.13 mmol) was reduced to afford l-{5-t-butyl-2-[4-(2-hydroxyethyl) naphthalen-2-yl]-2H-pyrazol-3-yl }-3-(2,3-dichlorophenyl) urea (57mg, 86% yield) as a white solid. 1 H NMR (300 MHz, OMSO-d 6 ): δ 9.29 (s, 1H), 8.77 (s, 1H), 8.12 (m, 1H), 8.13-7.95 (m, 2H), 7.90 (s, 1H), 7.56-7.52 (m, 3H), 7.28-7.26 (m, 2H),

6.41 (s, 1H), 3.73 (t, J = 6.9 Hz, 2H), 3.24 (t, J = 6.9 Hz, 2H), 1.27(s, 9H); MS (ESI) m/z:

497 (M+H + ).

To a mixture of Example 102 (120 mg, 0.26 mmol) and K 2 CO 3 (0.1 g, 0.7 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (500 mg). The resulting mixture was heated to reflux for 3h. After removal of the solvent, the residue was purified by preparative HPLC to give l-[5-t-butyl-2-(3- hydroxyiminoindan-5-yl)-2H-pyrazol-3-yl]-3-(2,3-dichloro phenyl)urea (75 mg, 61 % yield). 1 H NMR (300 MHz, MeOD-4): δ 8.04 (d, J = 5.4 Hz, 1H), 7.73 (s, 1H), 7.52-7.43 (m, 2H), 7.22-7.20 (m, 2H), 6.48 (s, 1H), 3.20-3.12 (m, 2H), 2.97 (m, 2H), 1.33 (s, 9H); MS (ESI) m/z: 473 (M+H + ).

In a 1: 1: 1 mix of EtOH:H2O:dioxane (6 mL) was placed ethyl 6- (3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1 - yl)-2,3-dihydro-1H-indene-1-carboxylate (520 mg, 0.986 mmol) and lithium hydroxide (71 mg, 2.96 mmol). The solution warmed to 4OC and stirred, ON. LC shows complete reaction. The solution cooled to RT and diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with brine and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol -1-yl)-2,3-dihydro-1H- indene-1-carboxylic acid as a foam, 474 mg (96%), used as is. In DMF (5 mL) was placed 6- (3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)- 1H-pyrazol- 1 -yl)-2,3-dihydro- 1H-indene- 1 - carboxylic acid (474 mg, 0.949 mmol), HOBt (196 mg, 1.09 mmol) and EDAC (218 mg, 1.42 mmol). The mixture was stirred at RT for 1 hr and then treated with a solution of 0.5N ammonia in dioxane (7.59 mL, 3.80 mmol). The mixture was stirred at RT, ON. LC shows complete reaction. The mixture was diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The solvents evaporated at reduced pressure to give a foam, dried on high vacuum line at RT for 2 hrs. The foam was then purified by Biotage chromatography (Sl-25 column, 65-95% Ethyl acetate/Hex). Fractions 10-19 were combined and evaporated at reduced pressure to give 1-(1-(3-carbamoyl-2,3-dihydro-1H- inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichloroph enyl)urea as a white solid. The solid was dried on the high vacuum line at 65C in the abderhalden for 3 hrs, 210 mg (44%). I H NMR (DMSO - UO) 1 59 1 73 ^ 6H) ! 95^ 99 (m> 2R)j 2 .23-2.33 (m, 2H), 2.88-3.06 (m, 3H), 3.90-4.04 (m, 1H), 6.31 (s, 1H), 6.98 (s, 1H), 7.26-7.42 (m, 5H), 7.63 (br s, 1H), 8.07-8.09

(m, 1H), 8.77 (s, 1H), 9.21 (s, 1H). LC-MS (EI) m/z: 500.0 (M+H + ).

Using general method D, Example A78 (70 mg, 0.20 mmol,) and l-fluoro-3-isocyanatobenzene (27 mg, 0.20 mmol) were combined to yield 1-(3-t-butyl-1-(indolin-5-yl)-lH-pyrazol-5-yl)-3-(3- fluorophenyl)urea HCl salt (47 mg, 60% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.53 (s, 1H), 8.66 (s, 1H), 7.49 (s, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 7.27 (m, 2H), 7.06 (dd, J = 1.2, and 8.0 Hz, 1H), 6.78 (dt, J = 2.4, and 8.8 Hz, 1H), 6.37 (s, 1H), 3.70 (t, J = 8.4 Hz, 2H), 3.20 (t, / = 8.4

Hz, 2H), 1.28 (s, 9H); LC-MS (EI) m/z: 490.2 (M+H + ).

Using general method D, A78 (85 mg, 0.24 mmol,) and 2,3- difluorobenzenamine (90 mg, 0.68 mmol) were combined to yield 1-(3-t-butyl-1-(indolin-5-yl)-lH-pyrazol-5-yl)-3-(2,3- difluorophenyl)urea HCl salt (80mg, 74% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.20 (s, 1H), 9.03 (brs, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.48 (brs, 1H), 7.36 (m, 1H), 7.26 (m,1H), 7.13 (m, 1H),

7.02 (m, 1H), 6.39 (d, J = 1.6 Hz, 1H), 3.70 (t, J = 6.4 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H), 1.28 (s, 9H); LC-MS (EI) m/z: 412.3 (M+H + ).

Using the same method as for Example 108, Example 307(80 mg, 0.20 mmol,) and triflic anhydride (70 mg, 0.2 mmol) were combined to yield 1-(3-t-butyl-1-(l-

(trifluoromethylsulfonyl)indolin-5-yl)-lH-pyrazol-5-yl)-3-(2 ,3- dichlorophenyl)urea (50 mg, 43 % yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.08 (brs, 1H), 8.89 (brs, 1H), 7.90 (dt, J = 1.6, and 7.6 Hz, 1H), 7.53 (brs, 1H), 7.43 (d, J = 2.0

Hz, 1H), 7.13 (m, 1H), 7.04 (m, 1H), 6.39 (s, 1H), 4.32 (t, J = 8.8 Hz, 2H), 3.32 (s, 2H), 3.31

(t, J = 8.4 Hz, 2H), 1.27 (s, 9H); LC-MS (EI) m/z: 544.2 (M+H + ).

General Experimental for Examples 309-314

A solution of Example A35 and the appropriate isocyanate (general method A) or the appropriate anline (general method D) were combined to yield the indicated compound.

General Experimental for Examples 315-326

A solution of Example A35 and the appropriate isocyanate (general method A) or the appropriate aniline (general method D) were combined to yield the indicated compound.

To a solution of amide compound (Example 310, 0.3 Ig, 0.8 mmol) in THF (10 mL) was added a solution of Lithium Aluminum Hydride (8 mL of IM soln, 8 mmol) at RT and stirred for 16h at 65 0 C under Ar. The mixture was cooled to 0 0 C, to this were added 0.3 mL of water, 0.3 mL of 3M NaOH and 0.3 mL water sequentially. The resultant suspension was stirred at RT for 6h, filtered over celite, celite was washed with EtOAC (3x5 mL). The combined filtrate was concentrated to afford residue, which was stirred with 1 mL of HCl in ethyl acetate for 30 min. The resultant solid was filtered and washed with ether, dried under vacuum to yield 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-7-yl)-lH-pyraz ol-5-yl)-3- cyclohexylurea (80 mg, 27% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.57 (brs, 2H), 8.27 (s, 1H), 7.40-7.32 (m, 3H), 6.73 (brs, 1H), 6.25 (s, 1H), 4.35-4.31 (m, 2H), 3.39- 3.37 (m, 3H), 3.04 (t, J = 6.4 Hz, 2H), 1.74-1.51 (m, 6H), 1.25 (s, 9H), 1.19-1.07 (s, 4H). MS (ESI) m/z: 393.3 (M+H + ).

Using the same methof as for Example 108, Example 144 (70 mg, 0.15 mmol) and methanesulfonyl chloride (34 mg, 0.30 mmol) were combined to yield 1-(3-t-butyl-1-(2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-yl)-lH-pyrazol-5-yl)-3-(2,3- difluorophenyl)urea (60 mg, 80% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.11 (brs, 1H), 8.87 (s, 1H), 7.92 (m, 1H), 7.35 (m, 3H), 7.13 (m, 1H), 7.03 (m, 1H), 6.40 (s, 1H), 4.43 (s, 2H), 3.50 (t,

J = 6.0 Hz, 2H),3.00 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H), 1.27 (s, 9H); LC-MS (EI) m/z: 504.2

(M+H + ).

General Experimental for Examples 329-333

A solution of Example A5 and the appropriate isocyanate (general method A) or the appropriate aniline (general method D) were combined to yield the indicated compound.

Using general method D, Example A46 (0.55 mg, 1.8 mmol) and 2,3-difluoroaniline (27 mg, 0.21 mmol) were combined to yield 1- (3-t-butyl-1-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-y l)- lH-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea as a pale yellow powder (15 mg, 2% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.11 (s, 0.65H), 9.06 (s, 0.35H), 8.86 (s, 0.65H), 8.72 (s, 0.35H), 7.91 (m, 1H), 7.68 (t, J = 5.6 Hz, 0.65H), 7.61 (t, J = 5.6 Hz, O.35H), 7.38-7.02 (m, 4H), 6.39 (s, 0.35H), 6.38 (s, 0.65H), 3.89 (s, 0.70H), 3.87 (s, 1.30H), 3.52 (dd, J = 5.6, and 11.6 Hz, 1.30H), 3.41 (m, 0.70H), 3.07 (t, J = 6.0 Hz, 2H), 1.26 (s, 5.85H), 1.24 (s, 3.15H); MS (EI) m/z: 454.0 (M+H + ).

Using general method A, Example A46 (70 mg, 0.18 mmol) and 3-fluorophenyl isocyanate (25 mg, 0.18 mmol) were combined to yield 1-(3-t-butyl-1-(2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yl)- lH-pyrazol-5-yl)-3-(3-fluorophenyl)urea HCl salt. (0.21 g, 25% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.59 (brs, 1H), 9.09 (m, 1H), 9.04 (m, 1H), 8.63 (s, 1H), 7.45 (t, / = 2.0 Hz, 1H), 7.42 (m, 2H), 7.34 (m, 1H), 7.28 9m, 1H), 7.06 (dd, J = 1.6, and 8.0 Hz, 1H), 6.78 (dt, J = 2.4, and 8.4 Hz, 1H), 6.36 (d, J = 1.6 Hz, 1H), 3.20 (m, 4H), 3.15 (m, 4H), 1.27 (s, 9H); LC-MS (EI) m/z: 422.2 (M+H + ).

Using the same method as for Example 108, Example 166 (70 mg, 0.14 mmol) and methanesulfonyl chloride (19 mg, 0.17 mmol) were combined to yield 1 -(3-t-butyl- 1 -(3- (methylsulfonyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepin-7-yl)- lH-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white off solid (22 mg, 29% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.17 (dd, J = 2.0, and 7.2 Hz, 1H), 7.70 (s, 1H), 7.24 (m, 5H), 6.55

(bs, 1H), 6.46 (s, 1H), 3.47 (m, 4H), 3.07 (m, 4H), 2.82 (s, 3H), 1.40 (s, 9H); LC-MS (EI) m/z: 550.0 (M+H + ).

3-Aminophenylacetic acid (2.00 g, 13 mmol, 1.0 eq) was dissolved with sonication in IM HCl (40 ml, 40 mmol, 3.00 eq) and cooled thoroughly in an ice/salt bath until the internal temperature was -5-0 °C. A solution of NaNO 2 (0.98 g, 14 mmol, 1.07 eq) in H 2 O (3 ml) was added slowly such that the internal temperature did not exceed 0 °C. After 15 min the reaction was treated with a solution of SnC1 2 -2H 2 O (15 g, 66 mmol, 5.00 eq) in cone. HCl (15 ml). The reaction was stirred for 2h with warming to +15 °C. The yellow solution was filtered through a cotton plug (to remove particulates and a little dark sludge) into a solution of 3-oxo-3-(thiophen-3-yl)propanenitrile (2.4 g, 16 mmol, 1.2 eq) in EtOH (60 ml). The reaction was heated in a 75 °C oil bath overnight. The reaction was complete, consisting of a roughly 2: 1 mixture of desired ester and the corresponding acid. The reaction was cooled to RT and then concentrated to remove most of the EtOH. The aqueous residue was chilled in an ice bath and treated with 6M NaOH (ca. 55 ml) to pH 8. EtOAc (100 ml) was added and the mixture shaken to dissolve product. The suspension was vacuum filtered through paper to remove tin salts and the cake washed with EtOAc (50 ml). The layers of the clear filtrate were separated and the organic washed with brine (2x) and dried (MgSO 4 ). Filtration and evaporation gave 4.6 g of a dark oil. This was dissolved in EtOH (55 ml), treated with satd. HCl/EtOH (5-6 ml) and heated at 75 °C overnight. When the esterification was complete, the reaction was cooled to RT and concentrated to remove EtOH. The residue was treated with satd. NaHCO 3 and extracted with EtOAc (2x). The combined organics were washed with satd. NaHCO 3 (Ix), brine (Ix) and dried (MgSO 4 ). Filtration and evaporation gave 4.2 g of crude product as an oil. This was purified by flash chromatography, eluting with 13-50% EtOAc/hexanes. Fractions containing product were pooled and concentrated to yield ethyl 2-(3-(5-amino-3-(thiophen-3-yl)-1H-pyrazol-1- yl)phenyl)acetate (2.4 g, 55% yield). 1 H NMR (300 MHz, DMSO-d 6 ): 7.73-7.72 (m, 1H), 7.56-7.53 (m, 3H), 7.46-7.42 (m, 2H), 7.24-7.22 (m, 1H), 5.82 (s, 1H), 5.43 (bra, 2H), 4.11 (q, 2H, J = 7.2 Hz), 3.76 (s, 2H), 1.21 (t, 3H, J = 7.2 Hz); MS (ESI) m/z: 328.0 (M+H + ).

Using general method A, Example A4 (70 mg, 0.29 mmol) and 3,4-dichlorophenyl isocyanate (54 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3-methoxyphenyl)-1H- pyrazol-5-yl)-3-(3,4-dichlorophenyl)urea (38 mg, 31% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.13 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 0.6, and 3.3 Hz, 1H), 7.19 (s, 1H), 7.12 (t, J = 8.1 Hz, 1H), 6.96 (dd, J = 2.4, and 8.7 Hz, 1H), 6.7 - 6.9 (m, 3H), 6.37 (s, 1H), 3.62 (s, 3H), 1.24 (s, 9H); MS (EI) m/z: 433 (M + H + ).

Using general method A, Example A4 (70 mg, 0.29 mmol) and 4-nitrophenylisocyanate (47 mg, 0.29 mmol) were combined to afford 1-(3-t-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4- nitrophenyl)urea (62 mg, 53% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.54 (s, 1H), 8.08 (AB quartet, J = 9.0 Hz, 2H), 7.45

(AB quartet, J = 9.0 Hz, 2H), 7.38 (s, 1H), 7.11 (t, J = 8.1 Hz, 1H), 6.7 -6.9 (m, 3H), 6.45 (s, 1H), 3.61 (s, 3H), 1.26 (s, 9H); MS (EI) m/z: 410 (M + H + ).

Using general method A, Example A21 (133 mg, 0.5 mmoL) and l-chloro-4-isocyanatobenzene (90 mg, 0.6 mmoL) were combined to afford l-[3-t-butyl-1-(quinolin-6-yl)-lH-pyrazol-5-yl]-3-(4- chlorophenyl)urea (100 mg, 48% yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.12 (s, 1 H), 8.91 (d, / = 3.9 Hz, 1 H), 8.60 (s, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 8.12 (d, / = 8.7 Hz, 1 H), 8.10 (s, 1

H), 7.93 (d, J = 8.7 Hz, 1 H), 7.57 (m, 1 H), 7.38 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2

H), 6.41 (s, I H), 1.28 (s, 9 H).

Using general method A, Example A18 (5 g, 14.8 mmol) and 1,2- dichloro-3-isocyanatobenzene (2.8 g, 15.0 mmol) were combined to afford 2-(4-{ 3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-lH- pyrazol-1-yl }phenyl)acetic acid (2.1 g, 29% yield). 1 H NMR (DMSO-afe): δ 9.24 (s, 1 H), 8.77 (s, 1 H), 8.05 (m, 1 H), 7.47- 7.38 (m, 4 H), 7.30-7.28 (m, 2 H), 6.36 (s, 1H), 4.08 (q, J = 7.2

Hz, 2 H), 2.72 (s, 2 H), 1.25 (s, 9 H), 1.18 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 489 (M+H + ).

Using general method A, Example A34 (5 g, 14.8 mmol) and 1- isocyanatonaphthalene (2.5 g, 15.0 mmol) were combined to afford ethyl 2-(3-{3-t-butyl-5-[3-(naphthalen-1-yl)ureido]-lH- pyrazol-1-yl}phenyl)acetate (1.5 g, 22% yield). MS (ESI) m/z: 471 (M+η + ).

Using general method C, the previous compound (80 mg, 0.17 mmol) was reduced to afford l-{ 3-t-butyl-1-[3-(2-hydroxyethyl)phenyl]-lH-pyrazol-5-yl }-3-(naphthalen-1-yl)urea (50 mg, 69% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.00 (s, 1 H), 8.75 (s, 1 H), 8.00-7.87 (m, 3 H), 7.65-7.21 (m, 8 H), 6.38 (s, 1 H), 4.68 (m, 1 H), 3.65 (t, J = 7.2 Hz, 2 H), 2.79 (t, J = 6.9 Hz, 2 H), 1.26 (s, 9 H); MS (ESI) m/z: 429 (M+H + ).

Using general method A, Example A5 (5 g, 14.8 mmol) and 1- chloro-4-isocyanato-benzene (2.2 g, 15.0 mmol) were combined to afford ethyl 2-(3-{3-t-butyl-5-[3-(4-chlorophenyl)ureido]-lH- pyrazol-1-yl}phenyl)acetate (2.7 g, 40% yield). 1 H NMR (DMSO-d 6 ): δ 9.10 (s, 1 H), 8.39 (s, 1 H), 7.46-7.37 (m, 5 H), 7.28-7.25 (m, 3 H), 6.34 (s, 1 H), 4.04 (q, J = 7.2 Hz, 2 H), 3.72 (s, 2 H), 1.25 (s, 9 H), 1.14 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 455 (M+H + ).

Using general method C, the previous compound (100 mg, 0.22 mmol) was reduced to afford l-{ 3-t-butyl-1-[3-(2-hydroxyethyl)phenyl]-lH-pyrazol-5-yl}-3-(4 -chlorophenyl)- urea (65 mg, 72% yield). 1 H NMR (DMSO-d 6 ): δ 9.11 (s, 1 H), 8.36 (s, 1 H), 7.41-7.21 (m, 8 H), 6.33 (s, 1H), 3.61 (q, J = 7.2 Hz, 2 H), 2.76 (t, J = 6.9 Hz, 2 H), 1.24 (s, 9 H); MS (ESI) m/z: 413 (M+H + ).

Using general method C, Example 114 (87 mg, 0.22 mmol) was reduced to afford l-{ l-[3-(aminomethyl)phenyl]-3-t-butyl-lH- pyrazol-5-yl }-3-(4-chloro- phenyl)urea as the HCl salt (78 mg, 82% yield). 1 H NMR (DMSO-d 6 ): δ 9.96 (s, 1H), 8.85 (s, 1H), 8.42 (br s, 3H), 7.72 (s, 1H), 7.56-7.55 (m, 2H), 7.48-7.45 (m, 3H), 7.32-7.30 (m, 2H), 6.41 (s, 1H), 4.16-4.12 (m, 2H), 1.29 (s, 9H); MS (ESI) m/z: 398.3 (M+H + ), 400.2 (M+2+ H + ).

The previous compound (100.0 mg, 0.25 mmol) and CDI (45mg, 0.28 mmol) were

combined in DMF (2 rnL) and stirred at RT for 2h. Morpholine (0.028 mL) was added and the mixture was stiired overnight at RT. The mixture was concentrated and the residue was purified silica gel column chromatography to yield 1-(3-t-butyl-1-{ 3- [(morpholine-4- carboxamido)methyl]phenyl }-lH-pyrazol-5-yl)-3-(4-chlorophenyl)urea (25 mg, 20% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.18 (s, 1 H), 8.40 (s, 1 H), 7.25-7.45 (m, 8 H), 7.15 (t, J = 6.0 Hz, 1 H), 6.35 (s, 1 H), 4.29 (d, J = 5.4 Hz, 2 H), 3.49 (t, J = 4.8 Hz, 4 H), 3.25 (t, J = 4.8 Hz, 4 H), 1.25 (s, 9 H).

Using general method I, Example 373 (200 mg, 0.46 mmol) and piperidine-4-carboxylic acid ethyl ester (102 mg, 0.65 mmol) were combined to afford ethyl l-[2-(3-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-lH-pyrazol-1- yl }phenyl)acetyl]piperidine-4-carboxylate (125 mg, 45% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.21 (br s, 1 H), 8.74 (br s, 1

H), 8.03 (m, 1 H), 7.42-7.24 (m, 6 H), 6.35 (s, 1 H), 4.15 (m, 1 H), 4.01 (q, J= 7.2 Hz, 2 H), 3.88 (m, 1 H), 3.76 (q, J= 5.4 Hz, 2 H), 3.04 (m, 1 H), 2.71 (m, 1 H), 2.50 (m, 1 H), 1.78- 1.70 (m, 2 H), 1.47-1.30 (m, 2 H), 1.24 (s, 9 H), 1.12 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 600 (M+H + ).

Using general method E, Example 344 (75 mg, 0.13 mmol) was saponified to afford acid l-[2-(3-{ 3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-lH- pyrazol-1- yl }phenyl)acetyl]piperidine-4-carboxylic acid (50 mg, 67% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.22 (s, 1 H), 8.75 (s, 1 H), 8.03 (m, 1 H), 7.42-7.20 (m, 6 H), 6.35 (s, 1 H), 4.17 (m, 1

H), 3.86 (m, 1 H), 3.76 (s, 2 H), 3.56 (m, 1 H), 2.69 (m, 1 H), 2.60 (m, 1 H), 1.77-1.63 (m, 2 H), 1.44-1.25 (m, 2 H), 1.24 (s, 9 H); MS (ESI) m/z: 572 (M+H + ).

Using general method I, Example 383 (200 mg, 0.43 mmol) and piperidine-3-carboxylic acid ethyl ester (102 mg, 0.65 mmol) were combined to afford ethyl l-[2-(4-{ 3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido]-7H-pyrazol-1- yl}phenyl)acetyl]piperidine-3-carboxylate (120 mg, 47% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 8.60 (s, 1 H), 8.50 (s, 1 H), 8.12 (m, 1 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.25-7.15 (m, 4 H), 6.59 (s, 1 H), 4.35 (m, 1 H), 4.18-4.12 (m, 2 H), 3.88-3.52 (m, 5 H), 2.41 (m, 1H), 2.05-1.88 (m, 2 H), 1.78-1.62 (m, 2 H), 1.34 (s, 9 H), 1.25 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 600 (MH-H + ).

Using general method E, Example 346 (70 mg, 0.12 mmol) was saponified to afford l-[2-(4-{3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido] - lH-pyrazol- 1 -yl } - phenyl)acetyl]piperidine-3-carboxylic acid (50 mg, 73% yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.26 (s, 1H), 8.77 (s, 1H), 8.02 (m, 1H), 7.41 (d, J =8.4 Hz, 2H), 7.34-7.25 (m, 4H), 6.30 (s, 1H),

4.36 (m, 1H), 3.84 (m, 1H), 3.79-3.74 (m, 2H), 3.40 (m, 1H), 3.00 (m, 1H), 2.55 (m, 1H), 1.88-1.85 (m, 2H), 1.67-1.48 (m, 2H), 1.23 (s, 9H); MS (ESI) m/z: 572(M+H + ).

Using general method A, Example A34 (2.0 g, 6.2 mmol) and 1- isocyanatonaphthalene (1.27 g, 7.5 mmol) were combined to afford l-[3-t-butyl-1-(l-oxo-l,2,3,4-tetrahydroisoquinolin-7-yl)- lH-pyrazol-5-yl]-3-(naphthalen-1-yl)urea. 1 H NMR (300 MHz, CDCl 3 ): δ 8.59 (brs, 1H), 8.32 (brs, 1H), 8.02 (brs, 1H), 7.85-7.04 (m, 10H), 6.62 (s, 1H), 3.42 (m, 2H), 2.83 (m, 2H), 1.34 (s, 9H)

Using general method C, Example 348 (1.5 g, 3.3 mmol) was reduced to afford l-[3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-7- yl)-lH-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (1.0 g, 69% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.86-6.92 (m, 10H), 6.44 (s, 1H), 3.03 (t, J = 6 Hz, 2H), 2.70 (t, J = 6 Hz, 2H), 1.33 (s, 9H).

General Experimental for Examples

The specified intermediates and the appropriate isocyanate (general method A) or the appropriate aniline (general method D) were combined to yield the pyrazole urea ester which was saponified using General method E to yield the indicated compound.

General Experimental for Examples

The specified intermediates and the appropriate isocyanate (general method A) or the appropriate aniline (general method D) were combined to yield the pyrazole urea ester which was saponified using General method E to yield the indicated compound.

General Experimental for Examples

The specified example and the appropriate amine were coupled using the method indicated to produce the target amide. Alternatively, the specified example and the appropriate isocyanate were coupled to yield the target amide.

To a flask charged with THF (250 mL) was added dropwise n-butyl lithium (18.4 mL, 46 mmol) at -78 °C under a N 2 atmosphere. After addition the resulting solution was warmed to -50 °C and dry MeCN (1.86 g, 45 mmol) was added slowly. After Ih, the reaction was cooled to -78°C and was treated with thiophene-2-carboxylic acid ethyl ester (6.93 g, 44.5 mmol). After stirring for Ih the resulting mixture was warmed to RT and stirred for Ih. Water was added dropwise at 0 °C to quench the reaction and the solution was extracted with ethyl acetate (3x200 mL). The organic layers were combined, washed with brine, dried (Na 2 SO 4 ) and the solvent was evaporated under reduced pressure to give a solid residue, which was re- crystallized from CH 2 Cl 2 . After the solid was collected by filtration, they were redissolved in ethyl acetate (100 mL), and acidified with dilute hydrochloride (2N). The aqueous layer was extracted with ethyl acetate (3x200 mL) and the combined organic layers were washed with

brine, dried (Na 2 Sθ 4 ),filtered and concentrated to yield 3-oxo-3-thiophen-2-yl-propionitrile (4.7 g, yield= 70%) as a yellow solid, which was used directly in the next step without purification.

To a flask charged with KOtBu (4 g, 36 mmol) and ether (100 mL, dry) was added dropwise a mixture of 2-fluorobenzonitrile (2.1 g, 17.5 mmol) and MeCN (0.738 g, 18 mmol) at 0 °C. After addition the mixture was stirred at RT. for 2 days. Water was added and the reaction and extracted with ether (3x100 mL). The organic layers were combined, washed with brine and dried (Na 2 SCU). The solvent was evaporated under reduced pressure to afford a yellow oil, which was dissolved in CH 2 Cl 2 and the solution was acidified with 3M HCl. After stirring the solution at RT for 2 hours, the solution was extracted with dichloromethane (3x200 mL). The organic layers were combined, washed with brine and dried (Na 2 SO 4 ). After filtration, the filtrate was concentrated in vacuo to give 3-(2-fluoro- phenyl)-3-oxo-propionitrile (2 g, 70% yield) as a yellow solid.

1 H NMR (300 MHz, DMSO-d 6 ): 7.99-7.92 (m, 1 H), 7.70-7.58 (m, 1 H), 7.35-7.14 (m, 2 H), 4.09 (m, 2 H).

General Experimental for Examples

Using General method M, the following Examples were prepared from the appropriate aniline and 3-oxo-3-subsitituted-propanenitrile (General method L)

Using general method D, Example 499 (0.22 g, 0.47 mmol) and 2- amino thiazole (0.071 g, 0.7 mmol) were combined to afford ethyl 2-(3-(3-t-butyl-5-(3-(thiazol-2-yl)ureido)-1H-pyrazol-1- yl)phenyl)acetate (0.13, 64%) as a solid. 1 H NMR (400 MHz, Acetone-d 6 ): D 10.05 (s, 1H), 7.56 (s, 1H), 7.53-7.44 (m, 2H), 7.38-7.36 (m, 1H), 7.28 (d, J = 3.6 Hz, 1H), 7.06 (d, 7 = 3.6 Hz, 1H), 6.54 (s, 1H), 4.12 (q, 7 = 7.2 Hz, 2H), 3.75 (s, 2H), 1.34 (s, 9H), 1.21 (t, 7 = 7.2 Hz, 3H);

MS (ESI) m/z: 428.0 (M+H + ).

Using general method E, ethyl 2-(3-(3-t-butyl-5-(3-(thiazol-2- yl)ureido)-1H-pyrazol-1-yl)phenyl)acetate (0.12 g, 0.28 mmol) was saponified to afford 2-(3-(3-t-butyl-5-(3-(thiazol-2-yl)ureido)- 1H-pyrazol-1-yl)phenyl)acetic acid/ Example 512 (0.1 g, 93%) as a solid. 1 H NMR (400 MHz, DMSO- 6 ): 08.92 (s, 1H), 7.48 (t, 7 = 8.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.34-7.32 (m, 2H), 7.12 (d, 7 = 3.6 Hz, 1H), 6.44 (s, 1H), 3.68 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 400.2 (M+H + ).

Using general method D, Example A30 (53 mg, 0.15 mmol) and (S)- 1,2,3,4-tetrahydronaphthalen-l -amine (68 mg, 0.46 mmol) were combined, and the product deprotected using general method G to yield 1-(3-t-butyl-1-(indolin-6-yl)-lH-pyrazol-5-yl)-3-((S)- l,2,3,4-tetrahydronaphthalen-1-yl)urea (30 mg, 49% yield) as the HCl salt. 1 H NMR (400 MHz, CD 3 OD): δ 7.52 (m, 1H), 7.13 (m, 2H), 3.89 (t, J = 7.6 Hz, 2H), 3.37 (t, J = 7.6 Hz, 2H), 2.78 (m, 2H), 1.99 (m, 1H), 1.82 (m, 3H), 1.41 (s, 9H); LC-MS (EI) m/z: 526.2 (M+H + ).

Using general method A, Example A30 (70 mg, 0.20 mmol) and 1- naphthalylisocyanate (34 mg, 0.20 mmol) were combined and the resultant product deprotected using general method G to yield 1- (3-t-butyl- 1 -(indolin-6-yl)- lH-pyrazol-5-yl)-3-(naphthalen- 1 - yl)urea as the HCl salt (71 mg, 84% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.32 (s, 1H), 9.24 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H),

7.92 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.51 (m, 5H), 6.41 (s, 1H), 3.72 (t, J = 8.4 Hz, 2H), 3.19 (t, J = 8.4 Hz, 2H), 1.30 (s, 9H); LC-MS (EI) m/z: 426.2 (M+H + ).

Using general method A, Example A29 ((70 mg, 0.20 mmol) and 1-naphthalylisocyanate (34 mg, 0.20 mmol) were combined and the resultant product deprotected using general method G to yield 1 -(3-t-butyl- 1 -(indolin-5-yl)- lH-pyrazol-5-yl)-3-(naphthalen- 1 - yl)urea (33 mg, 39% yield) as the HC1 salt. 1 H NMR (400 MHz, DMSO-.4): δ 9.26 (s, 1H), 9.11 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.55 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (m, 1H), 6.41 (s, 1H), 3.72 (t, J = 8.0 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H), 1.30 (s, 9H); LC-MS (EI) m/z: 426.2 (M+H + ).

Using general method D, 2,3-dichloroaniline (0.31 g, 0.91 mmol) and 5-amino-3-(2-thienyl)pyrazole (0.15 g, 0.91 mmol, available commercially) were combined to yield 1-(2,3-dichlorophenyl)-3- (3-(thiophen-2-yl)-1H-pyrazol-5-yl)urea (0.31 g, 96% yield). LC-MS (EI) m/z: 353.0 (M + H + ).

Using the same procedure as for Example 115, Example A33 (37 mg, 0.14mmol) and the material from the previous reaction (50 mg, 0.14 mmol) were coupled and the resultant product deprotected using general method G to yield 1-(2,3-dichlorophenyl)-3-(1-(indolin-5-yl)-3-(thiophen-2-yI) -lH- pyrazol-5-yl)urea HC1 salt (10 mg, 15% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.32 (bs, 1H), 8.92 (s, 1H), 8.08 (dd, / = 3.2, and 6.4 Hz, 1H), 7.48 (dd, J = 0.8, and 4.8 Hz, 1H), 7.44 (dd, J = 0.8, and 3.2 Hz, 1H), 7.33 (m, 2H), 7.18 (m, 1H), 7.10 (dd, J = 3.6, and 4.8 Hz, 1H), 6.89 (m, 1H), 6.79 (s, 1H), 3.09 (t, J = 8.0 Hz, 2H); LC-MS (EI) m/z: 470.0 (M+H + ).

Using general method D, Example A30 was combined with (S)-I- aminoindan (0.200 g, 1.50 mmol) and the resulting product deprotected using general method G to yield 173 mg (90%) of 1- (3-t-butyl-1-(indolin-6-yl)-1H-pyrazol-5-yl)-3-((S)-2,3-dihy dro- 1H-inden-1-yl)urea hydrochloride as a white solid. 1 H-NMR (methanol-^): δ 7.59 (d, 1H, J = 7.6 Hz), 7.53 (s, 1H), 7.52 (d, 1H, J = 8.0 Hz), 7.23-7.16 (m, 4H), 6.48 (s, 1H), 5.17 (t, 1H, / = 7.6 Hz), 3.90 (t, 2H, J = 7.8 Hz), 3.37 (t, 2H, J = 8.0 Hz), 2.96 (ddd, 1H, J = 16.0, 8.8, 4.0 Hz), 2.83 (ddd, 1H, J = 16.4, 8.0, 8.0 Hz), 2.53-2.46 (m, 1H), 1.82-1.75 (m, 1H), 1.37 (s, 9H). LC-MS (EI) m/z: 416.2 (M + H +)•

A solution of -(2-fluorophenyI)-3-oxopropanenitrile (1.02 g, 6.25 mmol; general method L) and hydrazine hydrate (0.313 g, 6.25 mmol) in EtOH (10 mL) was heated at 70 °C for 2 h. The solvent was evaporated and the residue was purified by column chromatography to give 3-(2-fluorophenyl)-1H-pyrazol-5-amine as a yellow wax-like solid (400 mg, 36%yield). 1 H-NMR (CDCl 3 ): δ 7.64

(dt, 1H, J = 7.8, 1.6 Hz), 7.35-7.29 (m, 1H), 7.23-7.13 (m, 2H), 6.06 (s, 1H), 5.28 (s, br, 3H).

LC-MS (EI) m/z: 178.2 (M + H +).

A solution of 2,2,2-trichloroethyl 2,3-dichlorophenylcarbamate (0.286 g, 0.847 mmol; general method D), 3-(2-fluorophenyl)-1H-pyrazol-5-amine (0.150 g, 0.847 mmol) and I- PR2NET (0.219 g, 1.69 mmol) in DMF (1 mL) was stirred at 90 °C overnight. Water was added (30 mL) and the mixture was extracted with EtOAc (3 x 30 mL), dried (MgSO 4 ), filtered and concentrated to yield crude 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1H- pyrazol-5-yl)urea as an off-white solid (285 mg, 92% yield). 1 H-NMR (DMSO-d 6 ): δ 9.86 (s, 1H), 8.25 (d, 1H, J = 7.2 Hz), 7.81 (t, 1H, J = 7.2 Hz), 7.45-7.27 (m, 5H), 6.65 (s, br, 1H).5.67 (s, 1H), one urea proton not visible. LC-MS (EI) m/z: 365.0 367.0 (M + H +).

A mixture of 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl )urea (0.100 g, 0.274 mmol), Example A56 (0.191 g, 0.548 mmol), pyridine (0.065 g, 0.82 mmol), Cu(OAc) 2 (0.075 g, 0.411 mmol) and CH 2 Cl 2 (5 mL) was stirred open to air, occasionally replacing evaporated solvent for 2d. Water was added (50 mL) and the mixture was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic extracts were dried (MgSO 4 ), concentrated, and purified by column chromatography to yield 2-t-butyl 3-ethyl 6-(5-(3-(2,3- dichlorophenyl)ureido)-3-(2-fluorophenyl)- 1 H-pyrazol- 1 -y l)-3 ,4-dihydroisoquinoline- 2,3(1H)-dicarboxylate as a yellow foam (139 mg, 76% yield). LC-MS (EI) m/z: 668.2 670.3 (M + H +).

To a solution of 2-t-butyl 3-ethyl 6-(5-(3-(2,3-dichlorophenyl)ureido)-3-(2- fluorophenyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (0.050 g, 0.075 mmol) in THF (2 mL) was added 6N HC1 (2 mL)and the solution was stirred at 50 °C overnight. The organic solvent was evaporated and the precipitate was collected to yield 6- (5-(3-(2,3-dichlorophenyl)ureido)-3-(2-fluorophenyl)-1H-pyra zol-1-yl)-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid hydrochloride as a white solid (15 mg, 35% yield). 1 H-NMR (acetone-d 6 ): δ 8.01-7.96 (m, 2H), 7.62-7.60 (m, 2H), 7.47 (d, 1H, J = 8.0 Hz), 7.42-7.37 (m, 1H), 7.27-7.19 (m, 4H), 6.92 (d, 1H, J = 3.6 Hz), 4.59 (d, 1H, J = 16.0 Hz), 4.50 (d, 1H, J = 16.0 Hz), 4.48 (dd, 1H, / = 11.4, 5.0 Hz), 3.61 (dd, 1H, J = 18.0, 5.2 Hz), urea, acid and amine protons not visible, one proton is buried under the methanol peak. LC- MS (EI) m/z: 540.0 542.0 (M + H +).

Using general method D, Example A29 (0.15 g, 0.28 mmol) was combined with 2,4-difluoroaniline (O.llg, 0.85 mmol) to yield 1- (3-t-butyl-1-(1-(2,2,2-trifluoroacetyl)indolin-5-yl)-1H-pyra zol-5- yl)-3-(2,4-difluorophenyl)urea. Using general method G, this product was deprOtoected and the resulting product transformed as in Example 109 to yield 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin- 5-yl)-1H-pyrazol-5-yl)-3-(2,4-difluorophenyl)urea (32 mg, 23%). 1 H-NMR (acetone-ds): δ 8.23-8.16 (m, 3H), 7.42 (s, br, 1H), 7.39 (d, 1H, J = 8.4 Hz), 7.35 (dd, 1H, J = 8.4, 2.0 Hz), 7.05 (ddd, 1H, J = 11.6, 8.4, 2.8 Hz), 6.45 (s, 1H), 4.06 (t, 2H, / = 8.4 Hz), 3.22 (t, 2H, / = 8.4 Hz), 3.02 (s, 3H), 1.31 (s, 9H).

Using the same approach as described for Example 520, Example A29 and 2,3-difluoroaniline were combined, deprotected and transformed to yield 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5- yl)-1H-pyrazol-5-yl)-3-(2,3-difluorophenyl)urea (30 mg, 22%). 1 H-NMR (acetone-d 6 ): δ 8.41 (s, br 1H), 8.27 (s, br, 1H), 8.06 (t, 1H, / = 7.8 Hz), 7.42 (s, 1H), 7.40 (d, 1H, J = 7.2 Hz), 7.35 (dd, 1H, J = 8.8, 2.0 Hz), 7.16-7.09 (m, 1H), 6.97-6.90 (m, 1H), 6.47 (s, 1H), 4.07 (t, 2H, J = 8.4

Hz), 3.23 (t, 2H, J = 8.8 Hz), 3.02 (s, 3H), 1.31 (s, 9H).

Using the same approach as described for Example 520, Example A29 and 3,5-difluoroaniline were combined, deprotected and transformed to yield 1-(3-t-butyl-1-(1-(methylsulfonyl)indolin-5- yl)-1H-pyrazol-5-yl)-3-(3,5-difluorophenyl)urea (35 mg, 25%). 1 H-NMR (acetone-d 6 ): δ 7.46 (s, 1H), 7.42 (d, 1H, J = 8.8 Hz), 7.39 (d, 1H, J = 8.4 Hz), 7.25-7.20 (m, 2H), 6.63-6.57 (m, 1H), 4.06 (t, 2H, J = 8.6 Hz), 3.24 (t, 2H, J = 8.6 Hz), 3.03 (s, 3H), 1.36 (s, 9H), urea and pyrazole protons not visible.

Using general method A, Example A30 (0.40 g, 1,14 mmol) was combined with 2,3-dichloropheyl isocyanate (0.21 gl.14 mmol) and the resulting product deprotected according to general method G to yield 1 -(3-t-butyl- 1 -(indolin-6-yl)- 1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (0.23 g, 42%). This product was transformed 1 -(I -( 1 -acetylindolin-ό-yO-S-t-butyl- 1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (103 mg, 70%). 1 H-NMR (acetone-cfc): δ 8.61 (s, br, 1H), 8.30 (s, 1H), 8.27 (dd, 1H, 7 = 8.0, 1.2 Hz), 8.21 (s, br, 1H), 7.30 (d, 1H, J = 8.4 Hz), 7.29 (s, 1H), 7.28 (d, 1H, J = 8.0 Hz), 7.22 (dd, 1H, J = 8.0, 1.2 Hz), 7.12 (d, 1H, J = 8.0, 2.0 Hz), 6.47 (s, 1H), 4.22 (t, 2H, 7 = 8.8 Hz), 3.25 (t, 1H, 7 = 8.6 Hz), 2.16 (s, 3H), 1.31 (s, 9H).

Using general method A, Example A34 (0.20 g, 0.675 mmol) and 2,3-dichlorophenyl isocyanate (0.127 g, 0.675 mmol) were combined to yield 1-(3-cyclopentyl-1-(2-oxo- 1,2,3,4- tetrahydroquinolin-6-yl)-lH-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea (195 mg, 60% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- 6 ): δ 10.3 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 8.06 (dd, J = 3.6, and 6.8 Hz, 1H), 7.32 (m, 3H), 7.26 (dd, 7 = 2.8, and 8.4 Hz, 1H), 6.97 (d, 7 = 8.4 Hz, 2H), 6.30

(s, 1H), 3.00 (m, 1H), 2.95 (t, 7 = 8.0 Hz, 2H), 2.48 (t, 7 = 8.0 Hz, 2H), 1.94 (m, 2H), 1.67

(m, 6H); LC-MS (EI) m/z: 484.0 (M+H + ).

To a solution of 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3- (thiophen-2-yl)-lH-pyrazol-5-amine (available from ethyl 3-(5- amino-3-(thiophen-2-yl)-lη-pyrazol-1-yl)benzoate using general method C followed by protection with TBSCl) (0.5 g, 1.3 mmol) in THF (3 mL) was added pyridine (0.10 g, 1.3 mmol) and 1,2,3- trifluoro-4-isocyanatobenzene (0.27 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 22 hours. Water was added and the solid was filtered, washed with H 2 O and dried under vacuum to obtain the crude product. To a solution of the crude product in THF was added TBAF (1.6 mL, 1.0 M). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. Ethyl acetate was added into the residue and then IN-HCl (5 drops) was added. The organic

layer was washed with water, dried (Na SO 4 ) and evaporated under reduced pressure to obtain the crude product. The crude was dissolved in methanol and the solid filtered and dried under vacuum to yield 1-(1-(3-(hydroxymethyl)phenyl)-3-(thiophen-2-yl)-lH-pyrazol- 5-yl)-3-(2,3,4-trifluorophenyl)urea (0.42 g, 73% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.13 (brs, 1H), 8.99 (s, 1H), 7.85 (m, 1H), 7.4-7.6 (m, 6H), 7.28 (m, 1H), 7.11 (dd, J = 3.6, and 4.8 Hz, 1H), 6.86 (s, 1H), 5.39 (t, J = 6.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H); MS (EI) m/z: 445.0 (M+H + ).

Using general method A, 1-(3-((t- butyldimethylsilyloxy)methyl)phenyl)-3-(2-fluorophenyl)-1H- pyrazol-5-amine (available from ethyl 3-(5-amino-3-(2- fluorophenyl)-1H-pyrazol-1-yl)benzoate using general method C, followed by protection with TBSCl) (0.4 g, 1.0 mmol) was combined with 2,3-dichlorophenyl isocyanate (0.32 g, 1.2 mmol) to yield 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1- (3-(hydroxymethyl)phenyl)-lH-pyrazol-5-yl)urea (0.28 g, 59% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.05 (s, 1H), 8.87 (s, 1H), 8.08 (m, 1H), 7.99 (dt, J = 2.0, and 8.0 Hz, 1H), 7.58 (m, 1H), 7.55 (d, J - 7.6 Hz, 1H), 7.50 (brd, J = 7.6 Hz, 1H), 7.45 (brd, J = 7.2 Hz, 1H), 7.41 (m, 1H), 7.32 (m, 3H), 6.91 (d, J = 4.4 Hz, 1H), 5.39 (t, J = 6.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H); MS (EI) m/z: 471.0 (M+H + ).

Using general method A, 1-(3-((t- butyldimethylsilyloxy)methyl)phenyl)-3-(2-fluorophenyl)-1H- pyrazol-5-amine ( available from ethyl 3-(5-amino-3-(2- fluorophenyl)-1H-pyrazol-1-yl)benzoate using general method C, followed by protection with TBSCl) (0.4 g, 1.0 mmol) was combined with 2,3,4-triflulorophenyl isocyanate (0.32 g, 1.2 mmol) to yield 1-(2,3,4-troflulorophenyl)-3-(3-(2-fluorophenyl)-1-(3-

(hydroxymethyl)phenyl)-lH-pyrazol-5-yl)urea (330 mg, 72% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.14 (brs, 1H), 9.01 (s, 1H), 7.98 (dt, J = 1.6, and 8.0 Hz, 1H), 7.86 (m, 1H), 7.2-7.6 (m, 8H), 6.96 (d, J = 4.0 Hz, 1H), 5.39 (t, J = 6.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H); MS (EI) m/z: 457.0 (M+H + ).

Using general method D, ethyl 4-(5-amino-3-t-butyl-1H-pyrazol- l-yl)benzoate (0.48 g, 0.87 mmol, available from Example 19) and (S)-(+)-aminoindane (0.11 ml, 0.87 mmol, 1.0 eq) were combined to yield (S)-ethyl 4-(3-t-butyl-5-(3-(2,3-dihydro-1H- inden-1-yl)ureido)-1H-pyrazol-1-yl)benzoate (0.243 g, 62% yield)as an off-white solid. 1 H NMR (CDCl 3 ): 58.11-8.08 (m, 2H), 7.66-7.64 (m, 2H), 7.23-7.22 (m, 2H), 7.19-7.15 (m, 1 H), 7.09-7.07 (m, 1H), 6.35 (s, 1H), 5.37-5.31 (m, 1H), 4.401-4.34 (m, 2H), 2.96-2.79 (m, 2H), 2.60-2.52 (m, 1H), 1.73-1.63 (m, 1H), 1.45-1.39 (m, 3H), 1.34 (s, 9H); MS (ESI) m/z: 447.3 (M+H + ).

This material was reduced using general method C to yield (S)-1-(3-t-butyl-1-(4- (hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dihydro-1H-in den-1-yl)urea (29.4 mg, 13% yield) as a white solid. 1 H NMR (DMSO-d 6 ): δ 8.07 (s, 1H), 7.43 (m, 4H), 7.24-7.19 (m, 4H), 6.95-6.93 (m, 1H), 6.33 (s, 1H), 5.12-5.06 (m, 2H), 4.56 (s, 2H), 2.93-2.86 (m, 1H), 2.82-2.74 (m, 1H), 2.43-2.36 (m, 1H), 1.76-1.67 (m, 1H), 1.27 (s, 9H); MS (ESI) m/z: 405.2 (M+H + ).

To a stirring solution of Example 349 (0.060 g, 0.14 mmol) and Et 3 N (0.023 ml, 0.16 mmol) in THF (1.4 ml) was added t-butyl bromoacetate (0.021 ml, 0.14 mmol). The resulting mixture was stirred at RT overnight. The completed reaction was diluted with EtOAc and washed with H 2 O (Ix), 5% citric acid (Ix), satd. NaHCO 3 (Ix), brine (Ix), dried (Na 2 SO 4 ), filtered, concentrated and purified via column chromatography to yield t- butyl 2-(7-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-y l)-3,4-dihydroisoquinolin- 2(1H)-yl)acetate (23.8 mg, 31% yield). 1 H NMR (CDCl 3 ): δ 7.89-7.82 (m, 2H), 7.73-7.72 (m, 1H), 7.68-7.66 (m, 1H), 7.46-7.38 (m, 2H), 7.34-7.31 (m, 1H), 7.08-7.03 (m, 2H), 6.97- 6.95 (m, 1H), 6.43 (s, 1H), 3.72 (brs, 2H), 3.31 (brs, 2H), 2.86 (brs, 2H), 2.78-2.77 (m, 2H), 1.50 (s, 9H), 1.33 (s, 9H); MS (ESI) m/z: 554.2 (M+H + ).

This material (0.0238 g, 0.0430 mmol) was dissolved in 100% formic acid (2 ml) and stirred at RT overnight. The completed reaction was concentrated to dryness. The residue was dissolved in IM HCl and extracted with EtOAc (2x). The combined organics were washed with IM HCl (Ix). The combined aqueous were diluted with iPrOH and concentrated (3x) until a foam resulted. This was dissolved in MeCWH 2 O frozen and lyopholized to yield 2-(7-(3-t-butyl-5-(3-(naphthaIen-1-yl)ureido)-1H-pyrazol-1-y l)-3,4-

dihydroisoquinolin-2(1H)-yl)acetic acid (17.5 mg, 76% yield) as an off-white solid as the HCl salt. 1 H NMR (DMSO-d 6 ): δ 9.51 (s, 1H), 9.44 (s, 1H), 8.27 (s, 1H), 7.95-7.90 (m, 2H), 7.63-7.61 (m, 1H), 7.56-7.51 (m, 4H), 7.46-7.38 (m, 2H), 7.23-7.10 (m, 1H), 6.38 (s, 1H), 4.59 (brs, 2H), 4.26 (brs, 2H), 3.47 (brs, 2H), 3.18 (brs, 2H), 1.29 (s, 9H); MS (ESI) m/z: 498.2 (M+H + ).

To a stirring solution of Example 349 (0.060 g, 0.14 mmol), glycolic acid (0.011 g, 0.15 mmol) and DCC (0.034 g, 0.16 mmol) in MeCN (1.5 ml) was added DMAP (0.0050 g, 0.041 mmol). The resulting mixture was stirred at RT for 30 min and then heated at 80-85 °C overnight. The completed reaction was cooled to RT and then cooled in ice to precipitate the DCU. The suspension was filtered and the filtrate concentrated and purified by reverse phase chromatography to yield of 1-(3-t-butyl-1- (2-(2-hydroxyacetyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-1H- pyrazol-5-yl)-3-(naphthalen-1- yl)urea (36.0 mg, 53% yield) as an off-white solid. 1 H NMR (DMSO-d 6, . mixture of rotamers): δ 9.05 (s, 1H), 8.83 and 8.79 (s, 1H), 8.03-8.01 (m, 1H), 7.96-7.91 (m, 2H), 7.66- 7.64 (m, 1H), 7.59-7.52 (m, 2H), 7.49-7.36 (m, 4H), 6.42 (s, 1H), 4.73 and 4.66 (s, 2H), 4.21 and 4.19 (s, 2H), 3.76-3.73 and 3.63-3.61 (m, 2H), 2.95-2.92 and 2.87-2.86 (m, 1H), 1.29 (s, 9H); MS (ESI) m/z: 498.2 (M+H + ).

Using general method K, Example 349(0.300 g, 0.683 mmol) and D-lactic acid, sodium salt (0.0841 g, 0.751 mmol) were combined to yield 1-(3-t-butyl-1-(2-((R)-2- hydroxypropanoyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-1H- pyrazol-5-yl)-3-(naphthalen-1-yl)urea (65.4 mg, 19% yield). 1 H NMR (DMSO-d 6 ; rotamers): δ 9.04 (s, 1H), 8.83 and 8.78 (s, 1H), 8.03-7.99 (m, 1H), 7.97-7.91 (m, 2H), 7.66-7.64 (m, 1H), 7.58-7.35 (m, 6H), 6.42 (s, 1H), 4.89-4.67 (m, 2H), 4.57-4.52 (m, 1H), 3.84-3.78 and 3.70-3.65 (m, 2H), 2.94-2.91 and 2.88-2.85 (m, 2H), 1.29 (s, 9H), 1.25-1.23 and 1.21-1.19 (m, 3H); MS (ESI) m/z: 512.3 (M-I-H + ).

Using general method D, Example A34 (0.280 g, 0.609 mmol) and (S)-(+)-aminoindane (0.0781 ml, 0.609 mmol, 1.00 eq) were combined to yield 1 -(3-t-butyl-l -(I -oxo- 1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-((S)-2,3- dihydro-1H-inden-1-yl)urea (151.0 mg, 56% yield) of as an off-white solid. 1 H NMR (CDCl 3 ): δ 8.08-8.02 (m, 2H), 7.64- 7.61 (m, 1H), 7.28-7.27 (m, 1H), 7.23-7.10 (m, 4H), 6/69 (brs, 1H), 6.39 (s, 1H), 5.82 (brs, 1H), 5.36-5.30 (m, 1H), 3.45-3.42 (m, 2H), 2.93-2.76 (m, 4H), 2.59-2.51 (m, 1H), 1.75-1.66 (m 1H), 1.33 (s, 9H); MS (ESI) m/z: 444.2 (M+H + ).

This material was reduced using general method C to yield 1 -(3-t-butyl-l -(1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-((S)-2,3-dihy dro-1H-inden-1-yl)urea (0.103 g, 81% yield) as an off-white solid as the HCl salt. 1 H NMR (DMSO-^ 6 ): δ 9.54 (brs, 2H), 8.36 (s, 1H), 7.41-7.32 (m, 4H), 7.25-7.14 (m, 3H), 6.32 (s, 1H), 6.06 (s, 1H), 5.12-5.06 (m, 1H), 4.32 (brs, 2H), 3.38 (brs, 2H), 3.06-3.02 (m, 2H), 2.93-2.86 (m, 1H), 2.82-2.74 (m, 1H), 2.44-2.33 (m, 1H), 1.77-1.57 (m, 1H), 1.27 (s, 9H); MS (ESI) m/z: 430.2 (M+H + ).

Te material from the previous reaction (0.0775 g, 0.166 mmol) and methanesulfonyl chloride (0.0386 ml, 0.499 mmol) were combined to yield 1 -(3-t-butyl-l -(2-(methylsulfonyl)- l,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-((S)- 2,3-dihydro-1H-inden-1-yl)urea (18.5 mg, 22% yield). 1 H NMR (CDCl 3 ): δ 7.31-7.28 (m, 2H), 7.22-7.11 (m, 5H), 6.69 (brs, 1H), 6.32 (s, 1H), 5.45 (brs, 1H), 5.29-5.23 (m, 1H), 4.42 (brs, 2H), 3.54-3.46 (m, 2H), 2.96- 2.77 (m, 3H), 2.81(s, 3H), 2.56-2.48 (m, 1H), 1.74-1.64 (m, 1H), 1.33 (s, 9H); MS (ESI) m/z: 508.3 (M+H + ).

Using general method D, Example A34 0.280 g, 0.609 mmol) and (S)-l,2,3,4-tetrahydro-naphthalen-1-amine were combined and the resultant lactam (440 mg, 88.4% yield, MS (ESI) m/z:458.3 (M+H + ) was reduced using general method C to yield 1-(3-t-butyl-1-(l,2,3,4-tetrahydroisoquinolin-7-yl)-1H- pyrazol-5-yl)-3-((S)-l,2,3,4-tetrahydronaphthalen-1-yl)urea (83.6 mg, 20% yield, MS (ESI) m/z: 444.2 (M+H + )). This material (0.160 g, 0.361 mmol) and methanesulfonyl chloride (0.0558 ml, 0.721 mmol) were combined to yield pure 1-(3-t-butyl-1-(2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquin olin-7- yl)-1H-pyrazol-5-yl)-3-((S)-l,2,3,4-tetrahydro-naphthalen-1- yl)urea (62.3 mg, 33% yield) as

a white solid. 1 H NMR (CDCl 3 ): δ 7.34-7.32 (m, 1H), 7.25-7.22 (m, 2H), 7.19-7.07 (m, 4H), 6.29 (s, 1H), 6.24 (brs, 1H), 5.18-5.15 (m, 1H), 5.04-4.99 (m, 1H), 4.49-4.42 (m, 2H), 3.58- 3.50 (m, 2H), 2.99-2.96 (m, 2H), 2.83 (s, 3H), 2.77-2.74 (m, 2H), 2.04-1.99 (m, 1H), 1.83- 1.71 (m, 3H), 1.33 (s, 9H); MS (ESI) m/z: 522.2 (M+H + ).

To a solution of ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H- pyrazol-1-yl)phenyl)acetate (0.244 g, 0.745 mmol) in THF (7.5 ml), thoroughly cooled to -78 °C, was added KHMDS in PhMe (1.79 ml, 0.894 mmol, 0.500 M). The resulting very dark mixture was stirred at -78 °C for Ih and then treated with MeI (0.056 ml, 0.894 mmol). The reaction was stirred with gradual warming to RT overnight. The completed reaction was quenched by addition of 3M HCl, diluted with EtOAc and the layers separated. The aqueous was extracted with EtOAc (2x) and the combined organics were washed with satd. NaHCO 3 (Ix), brine (Ix), dried (MgSO 4 ), filtered, and concentrated to yield ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propa noate (0.25 g) of crude which was used without further purification in the next reaction. MS (ESI) m/z: 342.3 (M+H + ).

Using general method A, this material was combined with 2,3-dichlorophenyl isocyanate (0.0967 ml, 0.732 mmol) and the resultant ester saponified using general method E to yield 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-2-yl)-1H- pyrazol-1- yl)phenyl propanoic acid (68.9 mg, 35% yield). 1 H NMR (DMSO-d 6 :acid): δ 9.47 (s, 1H), 8.89 (s, 1H), 8.12-8.09 (m, 1H), 7.58-7.47 (m, 6H), 7.34-7.31 (m, 2H), 7.13-7.01 (m, 1H), 6.87 (s, 1H), 3.81 (q, 1H, J = 6.8 Hz), 1.43 (d, 3H, J = 6.8 Hz); MS (ESI) m/z: 501.0 (M+H + ), 503.0 (M+2+H + ).

To a solution of 2-(4-(5-(3-(2,3-dichlorophenyl)ureido)-3- (thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)acetic acid (0.073 g, 0.15 mmol) in DMF (1 ml) were added PyBop (0.18 mmol) and MeOH (0.1 g, 0.45 mmol) and stirred for 4h at RT. The reaction mixture was poured into cold H 2 O and the product was extracted with EtOAc (3x20 ml). The combined organic extracts were washed with 3M HCl, brine, dried (Na 2 SO 4 ) and concentrated to

yield a crude product. To the crude product was added CH 2 Cl 2 (2 ml) and stirred for 10 min and the resultant solid was filtered and dried to afford pure methyl 2-(4-(5-(3-(2,3- dichlorophenyl)ureido)-3-(thiophen-3-yl)-7H-pyrazol-1-yl)phe nyl)acetate. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.40 (s, 1H), 8.87 (s, 1H), 8.10 (dd, / = 6.8 Hz, 2.4 Hz, 1H), 7.87-7.86 (m, 1H), 7.60 (dd, J = 4.8 Hz, 2.8 Hz, 1H), 7.57 (d, / = 8.0 Hz, 2H), 7.52-7.49 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.34-7.32 (m, 2H), 6.85 (s, 1H), 3.80 (s, 2H), 3.65 (s, 3H); MS (ESI) m/z: 501.0 (M+H + ).

Using the same general approach as for Example 524, ethyl 2-(3- (5-amino-3-(thiophen-3-yl)- 1 H-pyrazol- 1 -yl)phenyl)acetate

(0.2258 g, 0.450 mmol, 1.00 eq) was transformed to ethyl 2-(3- (5-amino-3-(thiophen-3-yl)- 1H-pyrazol- 1 -yl)phenyl)propanoate.

This, in turn, was combined with 2,3-dichlorophenyl isocyanate, according to general method A, to afford 2-(3-(5-(3-(2,3- dichloropheny l)ureido)-3-(thiophen-3-yl)- 1 H-pyrazol- 1 -yl)phenyl)propanoic acid. Using general method J, this product was combined with 0.5M NH 3 in dioxane (4.50 ml, 2.25 mmol, 5.00 eq). to afford 0.1731 g (77%) of pure 1-(1-(3-(l-amino-1-oxopropan-2- yl)phenyl)-3-(thiophen-3-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlor ophenyl)urea. 1 H NMR

(DMSO-d 6 ): δ 9.38 (s, 1H), 8.82 (s, 1H), 8.12-8.09 (m, 1H), 7.88-7.87 (m, 1H), 7.62-7.60 (m, 1H), 1.51-1.42 (m, 6H), 7.36-7.31 (m, 2H), 6.89 (brs, 1H), 6.86 (s, 1H), 3.69 (q,1H, J = 7.2 Hz), 1.36 (d, 3H, J = 7.2 Hz); MS (ESI) m/z: 500.0 (M+H + ), 502.0 (M+2+H + ).

Using the same general approach as for Example 524, ethyl 2-(3-

(5-amino-3-(thiophen-2-yl)- 1 H-pyrazol- 1 -yl)phenyl)acetate

(0.202 g, 0.403 mmol, 1.00 eq) was transformed to ethyl 2-(3-(5- amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propanoate.

This, in turn, was combined with 2,3-dichlorophenyl isocyanate, according to general method A, to afford 2-(3-(5-(3-(2,3- dichlorophenyl)ureido)-3-(thiophen-2-yl)-1H-pyrazol-1- yl)phenyl)propanoic acid. Using general method J, this product was combined with 0.5M NH 3 in dioxane (4.03 ml, 2.01 mmol, 5.00 eq) to afford 0.145 g (72%) of 1-(1-(3-(l-amino- l-oxopropan-2-yl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)- 3-(2,3-dichlorophenyl)urea. 1 H NMR (DMSO-d 6 ): δ 9.42 (s, 1H), 8.84 (s, 1H), 8.12 (m, 1H), 7.55-7.43 (m, 7H), 7.36-7.31 (m, 2H), 7.13-7.11 (m, 1H), 6.89 (brs, 1H), 6.87 (s, 1H), 3.69 (q, 1H, J = 7.2 Hz), 1.36 (d, 3H,

J = 7.2 Hz); MS (ESI) m/z: 500.0 (M+H + ), 502.0 (M+2+H + ).

3-(2-Fluorophenyl)-1-(3-iodophenyl)-1H-pyrazol-5-amine (0.500 g, 1.32 mmol, 1.00 eq), methacrylamide (0.281 g, 3.30 mmol, 2.50 eq), Pd(OAc) 2 (0.0118 g, 0.0527 mmol, 0.04 eq), Ph 3 P (0.0346 g, 0.132 mmol, 0.10 eq) and Et 3 N (0.919 ml, 6.59 mmol, 5.00 eq) were combined in DMF (3 ml) and heated at 80 °C overnight. The reaction was cooled to RT, diluted with H 2 O and extracted with EtOAc (2x). The combined organics were washed with 5% citric acid (2x), brine (Ix) and dried (MgSO 4 ). Filtration and evaporation gave crude product which was purified by flash chromatography to afford 0.4192 g (95%) of pure (E)-3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1- yl)phenyl)-2-methylacrylamide. MS (ESI) m/z: 337.2 (M+H + ).

(E)-3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl) -2-methylacrylamide (0.4192 g, 1.25 mmol, 1.00 eq) was hydrogenated (3.5 atm) over 10% Pd/C (0.0838 g, 0.0394 mmol, 0.0316 eq) in MeOH (5 ml) at RT for 36h. Filtration through Celite ® and evaporation yielded 0.245 g (58%) of crude 3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)- 2-methylpropanamide which was used as is in the next reaction. MS (ESI) m/z: 339.2 (M+H + ).

Using general method A, 3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)- 2-methylpropanamide (0.1225 g, 0.362 mmol, 1.00 eq) was combined with 2,3- dichlorophenyl isocyanate (0.102 g, 0.543 mmol, 1.50 eq) to yield 34.2 mg (18%) of pure 1- (1-(3-(3-amino-2-methyl-3-oxopropyl)phenyl)-3-(2-fluoropheny l)-1H-pyrazol-5-yl)-3-(2,3- dichlorophenyl)urea. 1 H NMR (DMSO-d 6 ): δ 9.40 (s, 1H), 8.89 (s, 1H), 8.11-8.08 (s, 1H), 8.02-7.98 (m, 1H), 7.53-7.39 (m, 4H), 7.36-7.26 (m, 6H), 6.92-6.91 (m, 1H), 6.76 (brs, 1H), 3.00-2.93 (m, 1H), 2.65-2.57 (m, 2H), 1.03-1.02 (m, 3H); MS (ESI) m/z: 526.0 (M+H + ), 528.0 (M+2+H + ).

Using general method J, Example 350 (81 mg, 0.2 mmol) and 0.5 M NH 3 in dioxane (1 mL) were combined to afford 1-(1-(3-(2- amino-2-oxoethyl)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-((S)-2 ,3- dihydro-lη-inden-1-yl)urea (25 mg, 31%) as white solid. 1 H NMR (400 MHz, DMSO-^ 6 ): □ 8.08 (s, 1H), 7.50 (s, 1H), 7.44-

7.19 (m, 8H), 6.91-6.89 (m, 2H), 6.33 (s, 1H), 5.09 (q, J = 7.6 Hz, 1H), 3.44 (s, 2H), 2.92- 2.73 (m, 2H), 2,44-2.36 (m, 1H), 1.76-1.66 (m, 1H), 1.27 (s, 9H); MS (ESI) m/z: 432.2 (M+H + ).

Example 506 (0.32 g, 1 mmol) was dissolved in 7N NH 3 /MeOH (10 mL) and the mixture was stirred for 24h at 50 0 C. Then solvent was removed under vacuum and the residue was purified by column chromatography to afford 2-(3-(5-amino-3-(thiophen-2-yl)-1H-pyrazol- l-yl)phenyl)acetamide (0.2 g, 67%) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ): 57.51-7.42 (m, 5H), 7.34 (dd, J = 3.2 Hz, 1.2 Hz, 1H),

7.24-7.22 (m, 1H), 7.08-7.06 (m, 1H), 6.93 (brs, 1H), 5.82 (s, 1H), 5.47 (s, 2H), 3.46 (s, 2H);

MS (ESI) m/z: 299.0 (M+H + ).

To a solution of phosgene (0.3 mL of 20% w/v solution in toluene) in MeCN (1 mL) was added a mixture of 3- (pyridin-3-yloxy)benzenamine (0.046 g, 0.25 mmol) and Et 3 N (0.066 g, 0.66 mmol) in MeCN (1 mL) at 0 0 C under Ar over a period of 10 min. After stirring for 30 min at RT, to the mixture was added a solution that contained 2-(3-(5- amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)acetamide (0.05 g, 0.16 mmol) and Et 3 N (0.06 g, 0.66 mmol) and stirred for 16h at RT. The solvents were removed to afford a residue which was purified by column chromatography to afford material that upon treatment with 3M HCl/EtOAc yielded 1-(1-(3-(2-amino-2-oxoethyl)phenyl)-3-(thiophen-2-yl)-1H-pyr azol- 5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (12 mg, 14%) urea as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 59.50 (s, 1H), 8.76 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 7.57- 7.68 (m, 2H), 7.57 (s, 1H), 7.51-7.32 (m, 8H), 7.16-7.09 (m, 2H), 6.95 (s, 1H), 6.82 (s, 1H), 6.75 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 3.49 (s, 2H); MS (ESI) m/z: 511.0 (M+H + ).

Using general method J, Example 351 (81 mg, 0.17 mmol) ethanolamine (13 mg, 0.22 mmol) were combined to afford 1- (2,3-dichlorophenyl)-3-( 1 -(3-(2-(2-hydroxyethylamino)-2- oxoethyl)phenyl)-3-phenyl-7H-pyrazol-5-yl)urea (55 mg, 62%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 5 9.41 (s,

1H), 8.86 (s, 1H), 8.15 (t, J = 5.6 Hz, 1H), 8.09 (dd, J = 6.8 Hz, 2.8 Hz, 1H), 7.86-7.84 (m, 2H), 7.56-7.31 (m, 9H), 6.95 (s, 1H), 3.54 (s, 2H), 3.39 (t, / = 6 Hz, 2H), 3.13-3.09 (m, 2H); MS (ESI) m/z: 524.0 (M+H + ).

To a solution of Example 213 (0.054 g, 0.137 mmol) in dry ethanol (2 mL) was at -78°C added acetyl chloride (1.1 g, 14 mmol) and the resulting solution was kept at room temperature overnight. The solvent was evaporated and to the residue was added 7N ammonia in methanol (2 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by reverse-phase chromatography (CV 12 mL, 20% acetonitrile in water to 50% acetonitrile in water, both solvents with 0.1% TFA, 20 CV). Basic extraction and reacidification with HC1 gave 21 mg (34%) of 1-(3-t-butyl-1-(3-carbamimidoylphenyl)-1H-pyrazol-5-yl)-3-(2 ,5- difluorophenyl)urea as a white solid. 1 H-NMR (methanol-d*): δ 8.09 (t, 1H, / = 1.8 Hz), 8.02-7.98 (m, 2H), 7.94-7.89 (m, 1H), 7.87 (t, 1H, J = 8.2 Hz), 7.15-7.09 (m, 1H), 6.79-6.71 (m, 1H), 1.41 (s, 9H), amidine, urea and pyrazolamine protons not visible. LC-MS (EI) m/z: 413.0 (M + H +).

Using the same method as Example A28, 5-nitroindoline (5.0 g, 152 mmol) was converted to l-[5-(2-amino-4-t-butylpyrrol-1-yl)-2,3- dihydroindol-1-yl]-2,2,2-trifluoroethanone (9.2 g, 40% yield, 3 steps) as a light-brown solid. 1 H NMR (300 MHz, DMSO d 6 ): δ 8.13-8.16 (m, 1 H), 7.57 (s, 1 H), 7.44-7.47 (m, 1 H), 5.61 (t, J = 7.8 Hz, 2 H), 4.34 (t, J = 7.8 Hz, 2 H), 3.28 (s, 1 H), 1.26 (s, 1 H). MS (ESI) m/z: 353.2 (M+H + ).

To a solution of (S)-l,2,3,4-Tetrahydroisoquinolone-3-carboxylic acid (5.00 g, 28.2 mmol) in sulfuric acid (20 mL) was at 0 °C dropwise added a solution of potassium nitrate (2.95 g, 29.2 mmol) in sulfuric acid (10 mL). When the addition was complete, the mixture was stirred for 5 min and the carefully diluted with water and neutralized with ammonium hydroxide (about 100 mL).The precipitate was filtered, washed with water and dried in vacuo to give (S)-7-nitro- 1,2,3,4-

tetrahydroisoquinoline-3-carboxylic acid (4.70 g, 75% yield) as a yellow solid. Acetyl chloride (20.0 mL, 22.1 g, 281 mmol) was added carefully to methanol (50 mL) at - 20 °C. The solution was allowed to reach room temperature and stirred for 10 min. (S)-7-nitro- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (4.70 g, 21.2 mmol) was then added and the resulting suspension was stirred at 50 °C for 5h. The solvent was evaporated and the residue was dried in vacuo to give (S)-methyl 7-nitro-l,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (5.77 g, 100% yield) as a crude form. (S)-methyl 7-nitro-l,2,3,4- tetrahydroisoquinoline-3-carboxylate hydrochloride (4.77 g, 17.5 mmol) was suspended in methylene chloride (50 mL). Triethylamine (2.93 mL, 2.12 g, 2.10 mmol) was added and then carefully trifluoroacetyl anhydride (2.92 mL, 4.41 g, 21.0 mmol). the mixture was stirred for 10 min. Water was added (100 mL) and the mixture was exctracted with methylene chloride (3x100 mL), dried over magnesium sulfate and concentrated. Column chromatography (CV 120 mL, 10% ethyl acetate hexanes to 30% ethyl acetate in hexanes, 20 (CV) gave the desired product, (S)-methyl 7-nitro-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquino line-3- carboxylate (2.70 g, 47% yield), and 1.28 g of coeluting byproduct mixture. Rf (ethyl acetate)

= 0.89. To a solution of (S)-methyl 7-nitro-2-(2,2,2-trifluoroacetyl)-l,2,3,4- tetrahydroisoquinoline-3-carboxylate (2.70 g, 8.13 mmol) in methanol (50 mL) was added palladium on charcoal (10%, 0.432 g, 0.406 mmol) and the resulting suspension was stirred in an atmosphere of hydrogen overnight. The mixture was filtered, charged with cone. HCl (1 mL) and concentrated to give (S)-methyl 7-amino-2-(2,2,2-trifluoroacetyl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxylate hydrochloride (2.60 g, 95% yield) as a grey solid. Rf

(ethyl acetate) = 0.82. Using general method M, (S)-methyl 7-amino-2-(2,2,2- trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-3-carboxylat e hydrochloride (2.60 g, 7.68 mmol) and pivaloylacetonitrile (0.961 g, 7.68 mmol) were combined to yield (3S)-methyl 7- (5-amino-3-t-butyl-lH-pyrazol-1-yl)-2-(2,2,2-trifluoroacetyl )-l,2,3,4-tetrahydroisoquinoline- 3-carboxylate which was used without purification.

Using General method D, Example A36 (0.500 g, 1.35 mmol) and cyclohexylamine (0.031 g, 0.242 mmol) to yield t-butyl 6-(3-t-butyl-

5-(3-cyclohexylureido)-lH-pyrazol-1-yl)-3,4-dihydroisoqui noline-

2(lH)-carboxylate (83 mg, 83% yield) as a white powder, which was deprotected using general method F to afford 1 -(3-t-butyl- 1 -( 1 ,2,3,4- tetrahydroisoquinolin-6-yl)-lH-pyrazol-5-yl)-3-cyclohexylure a (59

mg, 85% yield) as a colorless solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.51-7.46 (m, 3H), 6.62 (s, 1H), 4.48 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.55-3.50 (m, 1H), 3.23 (t, J = 6.0 Hz, 2H), 1.86-1.82 (m, 2H), 1.73-1.69 (m, 2H), 1.61-1.58 (m, 1H), 1.39 (s, 9H), 1.38-1.20 (m, 2H), 1.26-1,16 (m, 3H); LC-MS (EI) m/z: 396.3 (M+H*).

Using General method D, a solution of Example A79 (0.615 g, 7.68 mmol) and 2,3-difluoroaniline (0.032 g, 0.250 mmol) were combined to yield the crude product which was deprotected by ammonia in methanol (7N, 1 mL, 7 mmol) to afford the ammination and de-trifluoroacetylation product, 1-(3-t-butyl-1- ((3S)-3-carbamoyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)- 1H- pyrazol-5-yl)-3-(2,3-difluorophenyl)urea (20 mg, 24%, 2 steps) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.80 (t, 1H, / = 7.6 Hz), 7.56-7.51 (m, 3H), 7.11-7.06 (m, 1H), 6.98-6.91 (m, 1H), 6.58 (s, 1H), 4.56 (d, J = 15.2 Hz, 1H), 4.50 (d, , J = 15.2 Hz, 1H), 4.30 (dd, / = 11.2, and 5.0 Hz, 1H), 3.54 (dd, J = 17.2, 4.8 Hz, 1H), 1.28 (s, 9H); LC-MS (EI) m/z: 469.0 (M+H + ).

Using the same method as for Example 544, Example A79 (0.615 g, 7.68 mmol) and 2,4-difluoroaniline (0.032 g, 0.250 mmol) were combined to afford 1-(3-t-butyl-1-((3S)-3-carbamoyl- l,2,3,4-tetrahydroisoquinolin-7-yl)-lH-pyrazol-5-yl)-3-(2,4- difluorophenyl)urea (19 mg, 23% yield, 2 steps) as a green/white solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.93-7.87 (m, 1H), 7.56- 7.51 (m, 3H), 7.04-6.99 (m, 1H), 6.95-6.89 (m, 1H), 6.54 (s, 1H), 4.55 (d, J = 16.4 Hz, 1H), 4.50 (d, J = 15.6 Hz, 1H), 4.20 (dd, J = 11.6, and 5.2 Hz, 1H), 3.53 (dd, J = 17.2, and 4.8 Hz, 1H), 1.37 (s, 9H); LC-MS (EI) m/z: 469.2 (M+H + ).

Using the same method as for Example 544, Example A79 (0.615 g, 7.68 mmol) and 2,3-difluoroaniline (0.032 g, 0.250 mmol) were combined to yield the crude product which was treated with methylamine in ethanol (8N, 1 mL, 8 mmol) to afford the methylamminated and deprotected product, 1-(3-t-butyl-1-((3S)- 3-(methylcarbamoyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)- IH-

pyrazol-5-yl)-3-(2,3-difluorophenyl)urea (13 mg, 15% yield, 2 steps) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.79 (dt, J = 8.0, and 1.6 Hz, 1H), 7.56-7.49 (m, 3H), 7.12- 7.05 (m, 1H), 6.98-6.91 (m, 1H), 6.57 (s, 1H), 4.55 (d, J = 15.6 Hz, 1H), 4.50 (d, J = 16.0 Hz, 1H), 4.25 (dd, J = 11.6, and 5.2 Hz, 1H), 3.46 (dd, J = 19.6, and 5.2 Hz, 1H), 2.86 (s, 3H), 1.37 (s, 9H); LC-MS (EI) m/z: 483.3 (M+H + ).

Using the same method as for Example 544, Example A79 (0.615 g, 7.68 mmol) and 2,4,5-trifluoroaniline (0.050 g, 0.334 mmol) were combined to afford 1-(3-t-butyl-1-((3S)-3-carbamoyl- l,2,3,4-tetrahydroisoquinolin-7-yl)-lH-pyrazol-5-yl)-3-(2,4, 5- trifluorophenyl)urea (12 mg, 14% yield, 2 steps) as an off-white solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.06-7.98 (m, 1H), 7.54- 7.48 (m, 3H), 7.26-7.19 (m, 1H), 6.51 (s, 1H), 4.54 (d, J = 16.0

Hz, 1H), 4.28 (dd, J = 12.0, and 5.2 Hz, 1H), 4.49 (d, J = 16.4 Hz, 1H), 3.61-3.47 (m, 2H),

1.35 (s, 9H); LC-MS (EI) m/z: 487.3 (M+H + ).

To a suspension of alpha-methyl-DL-phenylalanine (2.00 g, 11.2 mmol) in cone. HCl (30 mL) was added formaldehyde (37%, 4.0 mL, 4.36 g, 4.81 mmol) and the resulting suspension was stirred at 60 °C for 48 h. The precipitated solid was collected and dried in vacuo to give 1.02 g (40%) of 3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride. 1 H NMR (400 MHz, CD 3 OD): δ 7.33-7.24 (m, 4H), 4.53 (d, J = 16.8 Hz, 1H), 4.42 (d, J = 16.0 Hz, 1H), 3.43 (d, / = 17.6 Hz, 1H), 3.18 (d, 7 = 17.2 Hz, 1H), 1.67 (s, 3H); LC-MS (EI) m/z: 192.0 (M+H + ). Using the same method as for VP-2851, 3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.01 g, 4.436 mmol) was converted to yield methyl 7-amino-3-methyl-2- (2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-3-car boxylate hydrochloride (600 mg, 38% yield, 2 steps) as a grey solid. 1 H NMR (400 MHz, CD 3 OD): δ 7.48 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.37 (dd, J = 8.0, 2.4 Hz, 1H), 4.83 (d, J = 15.2 Hz, 1H), 4.78 (d, J = 15.2 Hz, 1H), 3.63 (s, 3H), 3.27 (d, J = 14.8 Hz, 1H), 3.15 (d, J = 14.4 Hz, 1H), 1.51 (s, 3H); LC- MS (EI) m/z: 317.0 (M+H + ). Using general method M, methyl 7-amino-3-methyl-2-(2,2,2- trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-3-carboxylat e hydrochloride (0.600 g, 1.70 mmol) and pivaloylacetonitrile (0.21 g, 1.7 mmol) were combined to afford methyl 7-(5- amino-3-t-butyl- 1 H-pyrazol- 1 -yl)-3-methyl-2-(2,2,2-trifluoroacetyl)- 1 ,2,3,4-

tetrahydroisoquinoline-3-carboxylate (240 mg, 30% yield) as a yellow foam. LC-MS (EI) m/z: 439.0 (M+H + ).

Using general method A, Example A80 (0.070 g, 0.160 mmol) and 2,3-dichlorophenyl isocyanate (0.060 g, 0.319 mmol) were combined to yield methyl 7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-lH-pyrazol-1-yl)-3-methyl-2-(2,2,2- trifluoroacetyl)- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylate. LC-MS (EI) m/z: 626.0 (M+η + ). Using general method G, methyl 7-(3-t-butyl-5-(3-(2,3-dichloro-phenyl)ureido)-lH- pyrazol-1-yl)-3-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tet rahydroisoquinoline-3-carboxylate (0.100 g, 0.160 mmol) was deprotected to yield 7-(3-t-butyl-5-(3-(2,3- dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3-methyl-l,2,3,4-tet rahydroisoquinoline-3- carboxylic acid (60 mg, 68% yield) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.08-8.05 (t, J = 5.0 Hz, 1H), 7.62-7.55 (m, 3H), 7.28-7.25 (m, 2H), 6.76 (s, 1H), 4.68 (d, J = 16.8 Hz, 1H), 4.57 (d, J = 16.8 Hz, 1H), 3.58 (d, J = 17.6 Hz, 1H), 3.35 (d, / = 18.0 Hz, 1H), 1.68 (s, 3H), 1.40 (s, 9H); LC-MS (EI) m/z: 516.0 518.0 (M+H + ).

Using general method D, Example A80 and 2,4,5-trifluoroaniline (0.041 g, 0.28 mmol) were combined to yield methyl 7-(3-t-butyl- 5-(3-(2,5-difluorophenyl)ureido)-lH-pyrazol-1-yl)-1-methyl-2 - (2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-3-car boxylate which was deprocted using the general method G to afford 7-(3-t- butyl-5-(3-(2,4,5-trifluorophenyl)ureido)-lH-pyrazol-1-yl)-3 - methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (30 mg, 40% yield, 2 steps) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD): δ 8.11-8.04 (m, 1H), 7.60-7.54 (m, 3H), 7.27-7.20 (m, 1H), 6.68 (s, 1H), 4.66 (d, / = 16.8 Hz, 1H), 4.55 (d, J = 16.8 Hz, 1H), 3.56 (d, J = 17.6 Hz, 1H), 1.74 (s, 3H), 1.39 (s, 9H); LC-MS (EI) m/z: 502.2 (M+H + ).

Using the general method A, Example C (60 mg, 0.21 mmol) and 3- fluorophenyl isocyanate (29 mg, 0.21 mmol) were combined to afford 1-(3-t-butyl-1-(3-methoxyphenyl)-lH-pyrazol-5-yl)-3-(3- fluorophenyl)urea (49 mg, 60% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.2 -7.3 (m, 3H), 7.17 (brs, 1H), 6.95 -7.05 (m, 2H), 6.93 (dd, J = 1.6, and 8.2 Hz, 1H), 6.87 (dd, J = 1.8, and 7.6 Hz, 1H), 6.79 (dt, J = 1.9, and 8.8 Hz, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 3.77 (s, 3H), 1.35 (s, 9H);

MS (EI) m/z: 383 (M+H + ).

Using general method A, Example C (70 mg, 0.29 mmol) and 3- thienyl isocyanate (36 mg, 0.29 mmol) were combined to afford 1- (3-t-butyl-1-(3-methoxyphenyl)-lH-pyrazol-5-yl)-3-(thiophen- 3- yl)urea (45 mg, 43% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.05 - 7.3 (m, 4H), 6.8 -7.0 (m, 4H), 6.76 (s, 1H), 6.40 (s, 1H), 3.76 (s, 3H), 1.35 (s, 9H); MS (EI) m/z: 371 (M+H + ).

To a solution of m-aminobenzoic acid ethyl ester (200 g, 1.21 mmol) in cone. HCl (200 mL) was added an aqueous solution (250 mL) of NaNO 2 (102 g, 1.46 mmol) at 0 °C and the reaction mixture was stirred for Ih. A solution of SnCl 2 .2H 2 O (662 g, 2.92 mmol) in cone. HC1 (2 L) was then added at 0 °C. The reaction solution was stirred for 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate, which was used for the next reaction without further purification.

To a mixture of 3-hydrazinobenzoic acid ethyl ester (4.5 g, 25.0 mmol) and commercially available 3-oxo-3-phenylpropionitrile (5.5 g, 37.5 mmol) in ethanol (50 mL) was added cone. HCl (5 mL). The resulting mixture was heated to reflux for 3h. After removal of the solvent, the residue was washed with Et 2 O to afford ethyl 3-(5-amino-3- phenyl-lH-pyrazol-1-yl)benzoate (7 g, 2% yield, 2steps) which was used in the next reaction without further purification.

Using the same procedure as Example A81, 4-aminobenzoic acid ethyl ester (200 g, 1.21 mmol) and commercially available, 3-oxo-3- phenylpropanenitrile were combined to ethyl 4-(5-amino-3-phenyl-lH- pyrazol-1-yl)benzoate (7.4 g, 2% yield, 2 steps) which was used in the next reaction without further purification.

To a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) was added dropwise isobutyric acid ethyl ester (11.6 g, 0.1 mol) and anhydrous acetonitrile (50 g, 0.12 mol) in THF (100 mL) at 80 °C. The resulting mixture was refluxed overnight, then cooled to RT. After removal of the volatiles in vacuo, the residue was diluted in EtOAc and aqueous 10 % HCL. The combined organic extracts were dried (Na 2 SO 4 ), filtered, concentrated to yield 4- methyl-3-oxopentanenitrile (8.5 g), which was used for the next step reaction without further purification.

To a mixture of ethyl 3-hydrazinobenzoate (from Example A81, 3 g, 16.6 mmol) and 4-methyl-3-oxopentanenitrile (2.7 g, 24.9 mmol) in ethanol (50 mL) was added cone. HCl (5 mL). The resulting mixture was heated to reflux for 3h. After removal of the solvent, the residue was washed with Et 2 O to afford ethyl 3-(5-amino-3-isopropyl-lH-pyrazol-1- yl)benzoate (4 g), which was used in the next reaction without further purification.

Using the same method as Example A83, 4-hydrazinobenzoic acid ethyl ester (from Example A82, 3 g, 16.6 mmol) and 4-methyl-3- oxopentanenitrile (from Example A83, 2.7 g, 27.9 mmol) were combined to afford ethyl 4-(5-amino-3-isopropyl-7H-pyrazol-1-yl)benzoate (4 g, 88% yield), which was used to the next reaction without further purification.

Using the same procedure as for Example 1, A84 (1.37 g, 5.0 mmol) and l-chloro-4-isocyanatobenzene (0.9 g, 60 mol) were combined to afford ethyl 4-{5-[3-(4-chlorophenyl)ureido]-3- isopropyl-7H-pyrazol-1-yl }benzoate (1.3 g, 61% yield). Using the same procedure as for Example 2, ethyl 4-{5-[3-(4- chlorophenyl)ureido] -3-isopropyl- 1 H-pyrazol- 1 -y 1 } benzoate ( 100 mg, 0.23 mmol) was reduced to afford 1-(4-chlorophenyl)-3-{ l-[4-(hydroxymethyl)phenyl]- 3-isopropyl-lH-pyrazol-5-yl}urea (80 mg, 91% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.15 (brs, 1H), 8.70 (brs, 1H), 7.46-7.36 (m, 6H), 7.26 (d, / = 8.8 Hz, 2H), 6.25 (s, 1H), 5.28 (t, J = 6.0 Hz, 1H), 4.52 (d, J = 5.2 Hz, 2H), 2.85 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).

Using the same method as Example QQ, 4-hydrazinobenzoic acid ethyl ester (From Example A82, 3.0 g, 16.6 mmol) and commercially available 4,4,4-trifluoro-3-oxobutyronitrile (3.4 g, 24.9 mmol) were combined to afford ethyl 4-[5-amino-3-(trifluoromethyl)-lH-pyrazol-1-yl]benzoate (4.5 g, 91 % yield), which was used to the next reaction without further purification.

Using the same procedure as for Example 1, Example A85 (1.45 g, 5.0 mmol) and l-chloro-4-isocyanatobenzene (0.9 g, 6.0 mol) were combined to afford ethyl 4-{5-[3-(4-chlorophenyl)ureido]-3- (trifluoromethyl)-lH-pyrazol-1-yl}benzoate (0.85 g, 38% yield). Using the same procedure as for Example 2, ethyl 4-{5-[3-(4- chlorophenyl)ureido]-3-(trifluoromethyl)-lH-pyrazol-1- yl }benzoate (100 mg, 0.22 mmol) was reduced to afford 1-(4-chlorophenyl)-3-{ 3- (trifluoromethyl)-1-[4-(hydroxymethyl)phenyl]-lH-pyrazol-5-y l }urea (80 mg, 89% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.65 (s, 1H), 9.09 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, / = 8.8 Hz, 2H), 7.28 (d, / = 8.8 Hz, 2 H), 6.81 (s, 1H), 5.36 (t, J = 6.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H).

Using the same procedure as for Example 325, Example A62 (100 mg, 0.24 mmol), and Example A59 (29.0 mg, 0.24 mmol) were combined to affored l-{3-t-butyl-2-{3-[(2,4,5- trioxoimidazolidin- 1 -yl)methyl]phenyl } - 1 H-pyrazol-3-yl } -3-(4-chlorophenyl)urea (55 mg, 46% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.10 (s, 1H), 9.00 (s, 1H), 8.45 (s, 1H), 7.50-7.35 (m, 6H), 7.28 (d, 7 = 8.7 Hz, 2H), 6.37 (s, 1H), 4.70 (s, 2H), 1.27 (s, 9H).

A mixture of 1-phenylurazole (70 mg, 0.4 mmol), DMF (5 mL) and NaH (5 mg, 0.2 mmol) under Ar at 0 °C was stirred for 30 min. Example A62 (83 mg, 0.2 mmol) was added at 0 °C, reaction mixture was warmed to RT, stirred for 8h, quenched with water (25 mL), and extracted with EtOAc (2x25 mL). The combined organic extracts were washed with water and brine, dried (Na 2 SO 4 ), concentrated under reduced pressure and purified by column chromatography to yield 1-(3-t-butyl-1-{3-[(3,5-dioxo-1- phenyl-l,2,4-triazolidin-4- yl)methyl]phenyl }-lH-pyrazol-5-yl)-3-(4-chlorophenyl)urea as a white solid (85 mg, 77% yield). 1 H NMR (400 MHz, DMSO-d 6 ): □ 9.06 (s, 1H), 8.49 (s, 1H), 7.48-7.29 (m, 12H), 7.24 (s, 1H), 7.1-7.08 (m, 1H), 6.36 (s, 1H), 4.64 (s, 2H), 1.28 (s, 9H); MS (ESI) m/z: 558 (M+H + ).

To a mixture of 4-nitrophenol (10.0 g, 71.9 mmol), K 2 CO 3 (19.9 g, 143.9 mmol) and KI (2.6 g, 15.8 mmol) in acetonitrile was added chloromethylbenzene (10.0 g, 79.1 mmol) at RT. The resultant mixture was heated to reflux for 3h. After removal of the solvent, the residue was dissolved in EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to afford 4- benzyloxynitrobenzene (14.9 g, 90% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.20 (d, 7 =8.0 Hz, 2H), 7.43-7.37 (m, 5H), 7.03 (d, 7 =8.0 Hz, 2H), 5.17 (s, 2H).

" A mixture of 4-benzyloxynitrobenzene (13.0 g, 56.5 mmol) and Raney-Ni (15.0 g) in EtOH (50 mL) was stirred at RT under 30 psi of H 2 . The mixture was stirred at RT overnight, then filtered. The filtrate was concentrated to 4-benzyloxyphenylamine (10.5 g, 93% yield) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.43 (d, 7 =7.2 Hz, 2H), 7.38 (t, 7 =7.2 Hz,

1H), 7.32 (d, J =7.2 Hz, 2H), 6.83 (d, J =8.8 Hz, 2H), 6.65 (d, J =8.8 Hz, 2H), 5.00 (s, 2H), 2.94 (brs, 2H); MS(ESI) m/z: 200 (M+H + ).

Using the same method as Example 00, 4-benzyloxyphenylamine (10.0 g, 50.2 mmol) was converted to (4-benzyloxyphenyl)hydrazine hydrochloride (9.6 g, 76% yield) which was treated with commercially available 4,4-dimethyl-3-oxopentanenitrile (5.0 g, 40 mmol) to afford 3-t-butyl-1-(4-(benzyloxy)phenyl)- 1H-pyrazol-5-amine (8.2 g, 85% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.2 (brs, 3H), 7.49-7.45 (m, 4H), 7.39 (t, / =7.2 Hz, 1H), 7.34-7.29 (m, 2H), 7.19 (d, J =8.8 Hz, 2H), 5.62 (s, 1H), 5.19 (s, 2H), 1.26 (s, 9H); MS(ESI) m/z: 322 (M+H + ).

Using general method A, Example A86 (350 mg, 1.5 mmol) and 1- chloro-4-isocyanatobenzene (230 mg, 1.5 mmol) were combined to afford 1-(3-t-butyl-1-(4-hydroxyphenyl)-lH-pyrazol-5-yl)-3-(4- chlorophenyl)urea (120 mg, 20% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.82 (brs, 1H), 9.12 (s, 1H), 8.25 (s, 1H), 7.41 (d, J =9.0 Hz, 2H), 7.28 (d, J =9.0 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, 7 =8.7 Hz, 2H), 6.30 (s, 1H), 1.24 (s, 9H); MS (ESI) m/z: 385 (M+H + ).

The material from the previous reaction, 1-(3-t-butyl-1-(4-hydroxyphenyl)-1H- pyrazol-5-yl)-3-(4-chlorophenyl)urea (120 mg, 0.31 mmol) and chloroacetic acid ethyl ester (76.5 mg, 0.62 mmol) were combined to afford 1 -(3-t-buty 1- 1 -(4- (carbomethoxymethyl)oxyphenyl)-lH-pyrazol-5-yl)-3-(4-chlorop henyl-1-yl)urea (110 mg, 75% yield) as a white solid. 1 H NMR (300 MHz, DMSO-de): δ 9.09 (s, 1H), 8.31 (s, 1H), 7.40 (d, J =5.4 Hz, 2H), 7.34 (d, J =5.4 Hz, 2H), 7.27 (d, J =9.0 Hz, 2H), 7.04 (d, J =9.0 Hz, 2H), 6.30 (s, 1H), 4.81 (s, 2H), 4.16 (q, J =7.2 Hz, 2H), 1.24 (s, H), 1.20 (t, J =7.2 Hz, 3 H); MS (ESI) m/z: 471 (M+H + ).

Using the material from the previoius reaction, 1-(3-t-butyl-1-(4- (carbomethoxymethyl)oxyphenyl)-lH-pyrazol-5-yl)-3-(4-chlorop henyl-1-yl)urea (60 mg, 0.13 mmol) was saponified to afford 1-(3-t-butyl-1-(4-(carboxymethyl)oxyphenyl)-lH- pyrazol-5- yl)-3-(4-chlorophenyl-1-yl)urea (40 mg, 71% yield) as a white solid. 1 H NMR (300 MHz, DMSO-de): δ 9.14 (s, 1H), 8.35 (s, 1H), 7.40 (d, J =6.9 Hz, 2H), 7.37 (d, / =6.9 Hz, 2H), 7.27 (d, J =9.0 Hz, 2H), 7.02 (d, J =9.0 Hz, 2H), 6.30 (s, 1H), 4.71 (s, 2 H), 1.23 (s, 9H); MS (ESI) m/z: 443 (M+H + ).

Using general method I, Example 352 (88 mg, 0.18 mmol) N,N- dimethylamine hydrochloride (0.044 g, 0.54 mmol) were combined to yield 1-(2,3-dichlorophenyl)-3-(1-(3-(2- (dimethylamino)-2-oxoethyl)phenyl)-3-(thiazol-4-yl)-lH-pyraz ol- 5-yl)urea (46 mg, 51% yield) as a pale yellow colored solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.50 (s, 1H), 9.19 (s, 1H), 8.90 (s, 1H), 8.10 (dd, J = 7.2Hz, and 2.8 Hz, 1H), 8.06-8.01 (m, 2H),

7.54-7.47 (m, 3H), 7.39-7.31 (m, 3H), 6.91 (s, 1H), 3.51 (s, 2H), 2.56 (d, 7 = 4.4 Hz, 3H); MS

(ESI) m/z: 501.1 (M+H + ).

Using General method A, Example A17 (5 g, 0.014 mol) and 1- isocyanatonaphthalene (2.53 g, 0.015 mol) were combined to afford { 4-[3-t-butyl-5-(3-naphthalen- 1 -ylureido)pyrazol- 1 - yl] phenyl} acetic acid ethyl ester (0.6 g, 25 % yield) as a white solid. MS (ESI) m/z: 471(M-I-H + ). This compound was saponified using General method E to yield {4-[3-t-butyl-5-(3-naphthalen-1- ylureido)pyrazol-1-yl]phenyl }acetic acid (0.4 g, 99% yield) as a white solid. 1 H NMR (300 MHz, DMSOd 6 ): δ 9.05 (s, 1H), 8.84 (s, 1H), 8.00-7.40 (m, HH), 6.38 (s, 1H), 3.64 (s, 1H), 1.25 (s, 9H); MS (ESI) m/z: 443 (M+H + ).

To a solution of {4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol- l-yl]phenyl } acetic acid ethyl ester (150 mg, 0.32 mmol, intermediate in Example 559) in MeOH (2 mL) was added NH 3 /Me0H (10 mL) at RT. The mixture was stirred at that temperature overnight. After removal of the solvent, the crude product was purified by preparative HPLC to afford 2-{4-[3-t- butyl-5-(3-naphthalen-1-ylureido)pyrazol-1-yl]phenyl}acetami de (48 mg, 31% yield). 'H NMR (300 MHz, CD 3 OD): δ 7.87 (m, 2H), 7.76 (d, / = 5.4 Hz, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.53-7.42 (m, 7H), 6.57 (s, 1H), 3.64 (s, 2H), 1.36 (s, 9H); MS (ESI) m/z: 442 (M+H + ).

Using General method I, Example 385 (150 mg, 0.33 mmol) and Me 2 NH HC1 (80 mg, 0.398 mmol) were combined to afford 2-(4- {3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]pyrazol-1- yl }phenyl)N,N-dimethylacetamide (135 mg, 85% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.29 (s, 1H), 8.81 (s, 1H), 8.06 (q, J = 3.3 Hz 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 3.0 Hz, 2H), 6.37 (s, 1H), 3.74 (s, 2H), 3.03 (s, 3H),

2.83 (s, 3H), 1.25 (s, 9H); MS (ESI) m/z: 488 (M+lT).

Using General method I, Example 559 (250 mg, 0.56 mmol) and HNMe 2 HC1 salt (50 mg, 1.1 mmol) were combined to afford 2-{4- [3-t-butyl-5-(3-naphthalen- 1 -yl-ureido)pyrazol- 1 -yl]phenyl } -N,N- dimethylacetamide (46 mg, 17% yield). 1 H NMR (300 MHz, DMSOd 6 ): δ 9.06 (s, 1H), 8.83 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.90-7.87 (m, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.53-7.35 (m, 7H), 6.37 (s, 1H), 3.74 (s, 2H), 3.00 (s, 3H), 2.81 (s, 3H), 1.24 (s, 9H);

MS (ESI) m/z: 470 (M+H + ).

To an ice-cold bath solution of 4-fluorobenzoic acid (100 g, 0.714 mmol) in ethanol was dropwise added SOCl 2 (140 mL, 2.14 mol). After 30 min the ice bath was removed and the solution was heated to reflux overnight. The reaction was monitored with TLC and LC-MS until completion. After evaporation of the solvent, the mixture was diluted with the aqueous solution of K 2 CO 3 and EtOAc. The organic phase was collected and dried over sodium sulfate and concentrated to the product of ethyl 4-fluorobenzoate (119 g, 99% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.06 (d, J = 6.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 4.36 (q, J = 10.8 Hz, 2H), 1.39 (t, / = 7.5 Hz, 3H). Using general method L, ethyl 4-fluorobenzoate (119 g, 0.71 mol) and MeCN (75 mL) were combined to afford 3-(4-fluorophenyl)-3-oxopropionitrile (100 g, 86% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.98-7.94 (m, 2H), 7.22 (d, 7 = 6.6 Hz, 2H), 4.07 (s, 2H). Using general method M, (4-hydrazinophenyl)acetic acid ethyl ester (36 g, 0.217 mol) and 3- (4-fluorophenyl)-3-oxopropionitrile (38 g, 0.26 mol) were combined to yield {4-[5-amino-3-

(4-fluorophenyl)pyrazol-1-yl]phenyl} acetic acid ethyl ester (50 g, 68% yield). 1 H NMR (300 MHz, CDCl 3 ): δ 7.80 (s, 2H), 7.40 (m, 4H), 7.00 (m, 2H), 6.29 (s, 1H), 4.07 (q, J = 3.9 Hz, 2H), 3.53 (s, 2H), 1.23 (t, J = 3.9 Hz, 3H); MS (ESI) m/z: 340 (M+H + ).

Using General method A, Example A87 (8 g, 0.024 mol) 1,2- dichloro-3-isocyanatobenzene (3.7 mL, 0.028 mol) were combined to afford {4-[5-[3-(2,3-dichlorophenyl)ureido]-3-(4- fluorophenyl)pyrazol-1-yl]phenyl } acetic acid ethyl ester (5 g, 40% yield). MS (ESI) m/z: 527(M+H + ). Using General method E, {4-[5-[3-(2,3-dichlorophenyl)ureido]-3-(4- fluorophenyl)pyrazol-1-yl]phenyl } acetic acid ethyl ester (5 g, 9.5 mmol) was saponified to yield of {4-[5-[3-(2,3- dichlorophenyl)ureido]-3-(4-fluorophenyl)pyrazol-1-yl]phenyl }acetic acid (2.6 g, 55% yield).

1 H NMR (300 MHz, DMSO-d 6 ): δ 9.34 (s, 1H), 8.84 (s, 1H), 8.09-8.02 (m, 1H), 7.87-7.82

(m, 2H), 7.54 (d, J = 4.2 Hz, 2H), 7.42 (d, J = 4.2 Hz, 2H), 7.33-7.29 (m, 1H), 7.22 (t, J = 9.0

Hz, 2H), 6.82 (s, 1H), 3.66 (s, 2H); MS (ESI) m/z: 499 (M+H + ).

To a solution of 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H- pyrazol-1-yl)phenyl)acetic acid (200 mg, 0.43 mmol) in THF (10 mL) was added 2-amino-ethanol (260 mg, 4.3 mmol) and Et 3 N (0.5 mL), then this mixture was heated to 40 °C and stirred overnight. After removal of the solvent, this mixture was extracted with EtOAc and washed with IN HCl aqueous solution and the organic layer was dried over Na 2 SO 4 . After removal of the solvent, a crude product was obtained, which was purified by preparative HPLC to afford 2-{ 3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol-1- ylJphenyl }-N-(2-hydroxy-ethyl)acetamide (104 mg, 50% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.01 (s, 1H), 8.81 (s, 1H), 8.12 (m, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.92-7.87 (m, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.53-7.49 (m, 2H), 7.47-7.38 (m, 4H), 7.29 (d, J = 7.5 Hz, 1H), 6.39 (s, 1H), 3.49 (s, 2H), 3.35 (t, J = 6.0 Hz, 2H), 3.07 (q, J = 6.0 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 487 (M+H + ).

Example 349 (100 mg, 0.456 mmol) was acetylated to afford 1- [2-(2-acetyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-5-t-butyl-2H- pyrazol-3-yl]-3-(3-fluorophenyl)urea (60 mg, 90 % yield) as a white solid. 1 H NMR (300 MHz, CD 3 OD): δ 7.85 (m, 2H), 7.70 (m, 2H), 7.44-7.51 (m, 3H), 7.40 (s, 3H), 6.53 (d, J = 11.1 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H), 3.71 (q, J = 8.4 Hz, 2H), 3.01 (m, J = 19.2 Hz, 2H), 2.19 (d, J = 7.7 Hz, 3H), 1.35 (s, 9H); MS (ESI) m/z: 482 (M+H + ).

Example 349 (100 mg, 0.456 mmol) and methanesulfonyl chloride (63 mg, 0.274 mmol) were combined to afford l-[5-t- butyl-2-(2-methanesulfonyl-l,2,3,4-tetrahydroisoquinolin-7-y l)- 2H-pyrazol-3-yl]-3-(3-fluorophenyl)urea (60 mg, 87 % yield) as a white solid. 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.11 (s, 1H), 8.89 (s, 1H), 8.03 (m, 1H), 7.89-7.87 (m, 2H), 7.61 (m, 1H),

7.52-7.49 (m, 2H), 7.44 (m, 1H), 7.39-7.34 (m, 3H), 6.36 (s, 1H), 4.43 (s, 2H), 3.43 (m, J = 11.4, 2H), 2.93 (m, 5H), 1.24 (s, 9H); MS (ESI) m/z: 518 (M+H + ).

Using gerenal method A, Example A20 (200 mg, 0.61 mmol) and isocyanatobenzene (73 mg, 0.61 mmol) were combined to afford 1- [5-t-butyl-2-(3-pyridin-3-ylphenyl)-2H-pyrazol-3-yl]-3-pheny lurea (185 mg, 74% yield). 1 H NMR (300 MHz, DMSO-^ 6 ): δ 9.08 (s, 1H), 8.98 (s, 1H), 8.60 (d, J = 5.4 Hz, 1H), 8.51 (s, 1H), 8.23 (d, J = 6.6 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 6.9 Hz, 1H), 7.66-7.56 (m,

3H) 7.34 (d, / = 8.1 Hz, 2H), 7.20 (t, / = 7.8 Hz, 2H), 6.91 (t, J = 6.9 Hz, 1H), 6.37 (s, 1H), 1.25 (s, 9H); MS (ESI) m/z: 412 (M+H + ).

Using general method B, Example A18 (287 mg, 1.0 mmol), and 1,2,3,4-tetrahydro-naphthalen-1-ylamine (147 mg, 1.0 mmol) were combined to afford ethyl 4-(3-t-butyl-5-(3-(l, 2,3,4- tetrahydronaphthalen-4-yl)ureido)-1H-pyrazol-1-yl)benzoate (245 mg, 59% yield). Using general method E, ethyl 4-(3-t-butyl-5-(3-(l, 2,3,4-

tetrahydronaphthalen-4-yl)ureido)-1H-pyrazol-1-yl)benzoate (230 mg, 0.50 mmol) was reduced to afford 1-(3-t-butyl-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3- (l,2,3,4- tetrahydronaphthalen-4-yl)urea (170 mg, 81% yield). 1 H NMR (300 MHz, DMSO-d 6 ): D 7.97 (s, 1 H), 7.38 (s, 4 H), 7.14-7.04 (m, 4 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.29 (s, 1 H), 5.27 (t, J = 5.7 Hz, 1 H), 4.74 (m, 1 H), 4.52 (d, J = 5.7 Hz, 2 H), 2.70-2.62 (m, 2 H), 1.85-1.63 (m, 4 H), 1.23 (s, 9 H). MS (ESI) m/z: 419 (M+H + )

Using general method B, Example A3 (120 mg, 0.5 mmol), and indan-1-ylamine (133 mg, 1.0 mmol) were combined to afford 1- [3-t-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl]- 3-(2,3-dihydro- 1H-indan-1-yl)urea (52 mg, 26 % yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.17 (s, 1 H), 7.94 (s, 1 H), 7.83 (t, J = 8.4 Hz, 2 H),

7.67 (t, J = 8.4 Hz, 1 H), 7.19-7.08 (m, 4 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.31 (s, 1 H), 5.04 (m, 1 H), 2.86-2.73 (m. 2 H), 2.34 (m, 1 H), 1.70 (m, 1 H), 1.24 (s, 9 H); MS (ESI) m/z: 400 (M+H + ).

A solution of Example 295 (130 mg, 0.32 mmoL), DMF (2 mL) and CDI (65 mg, 0.38 mmoL) was stirred at RT for 40 mins then was treated with a solution of CH 3 SO 2 NH 2 (36 mg, 0.38 mmoL) and NaH (16 mg, 0.4 mmoL) in DMF (2 mL). The reaction mixture was stirred overnight, then quenched with water and extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated and purified via preparative TLC to yield \-{ 3-t- butyl-1-[1-(methanesulfonylureidoarnidomethyl)- naphthalen-3-yl]-7H-pyrazol-5-yl }-3-

(phenyl)urea (50 mg, 29% yield). 1 H NMR (300 MHz, DMSO-d 6 ): D 9.21 (br s, 1 H), 8.60 (br s, 1 H), 8.15 (br s, 1 H), 8.00 (m, 1 H), 7.99 (s, 1 H), 7.55-7.58 (m, 3 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.19 (t, / = 7.8 Hz, 2 H), 6.90 (t, J = 7.8 Hz, 1 H), 6.39 (s, 1 H), 4.69 (s, 2 H), 2.91 (s, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: 535 (M+H + )

Using general method D, Example Al (143 mg, 0.5 mmol) and 1,2,3,4-tetrahydro-naphthalen-1-ylamine (67 mg, 0.5 mmol) were combined • to afford ethyl 3- {3-t-butyl-5-[3-( 1,2,3,4- tetrahydronaphthalen-1-yl)ureido]-7H-pyrazol-1-yl }benzoate (60

mg, 26% yield).

Using general method C, the previous compound (55 mg, 0.12 mmol) was reduced to afford l-{3-t-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3- (l,2,3,4- tetrahydronaphthalen-1-yl)urea (40 mg, 80% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): D 7.97 (s, 1 H), 7.44-7.38 (m, 2 H), 7.30-7.28 (m, 2 H), 7.17-7.02 (m, 4 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.30 (s, 1 H), 4.74 (m, 1 H), 4.52 (s, 2 H), 2.71-2.64 (m, 2 H), 1.70-1.65 (m, 4 H), 1.24 (s, 9 H); MS (ESI) m/z: 419 (M+H + ).

Using general method A, Example Al 7 (5 g, 14.8 mmol) and 1- isocyanatonaphthalene (2.5 g, 15.0 mmol) were combined to afford ethyl 2-(4-{3-t-butyl-5-[3-(naphthalen-1-yl)ureido]-/H- pyrazol-1-yl }phenyl)acetate (1.7 g, 24% yield). MS (ESI) m/z: 471 (M+η + ). Using general method C, the previous compound (80 mg, 0.17 mmol) was reduced to afford l-{3-t-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5- yl }-3-(naphthalen-1-yl) urea (50 mg, 69% yield). 1 H NMR (DMSO-d 6 ): δ 9.05 (s, 1 H), 8.79 (s, 1 H), 8.00 (d, J = 7.2 Hz, 1 H), 7.93-7.89 (m, 2H), 7.63 (d, J = 8.1 Hz, 1 H), 7.55-7.51 (m, 2H), 7.47-7.37 (m, 5H), 6.39 (s, 1H), 4.68 (t, J = 5.1 Hz, 1 H), 3.65 (q, / = 7.2 Hz, 2 H), 2.79 (t, J = 6.9 Hz, 2 H), 1.26 (s, 9 H). MS (ESI) m/z: 429 (M+H + ).

Using general method A, Example A 17 (5 g, 14.8 mmol) and 1- chloro-4-isocyanato-benzene (2.2 g, 15.0 mmol) were combined to afford ethyl 2-(4-{3-t-butyl-5-[3-(4-chlorophenyl)ureido]-1H- pyrazol-1-yl}phenyl)acetate (2.7 g, 40% yield). 1 H NMR (DMSO-d 6 ): δ 9.12 (s, 1 H), 8.42 (s, 1 H), 7.46-7.37 (m, 6 H), 7.28 (d, J = 8.1 Hz, 2 H), 6.34 (s, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 2.79 (t, J = 7.2 Hz, 2 H), 3.72 (s, 2 H), 1.25 (s, 9 H), 1.18 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 455 (M+H + ).

Using general method C, the previous compound (100 mg, 0.22 mmol) was reduced to afford l-{3-t-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl }-3-(4-chlorophenyl) urea (65 mg, 72% yield). 1 H NMR (DMSO-d 6 ): δ 9.57 (s, 1 H), 8.92 (s, 1 H), 7.45-7.39 (m, 4 H), 7.34-7.25 (m, 4 H), 6.30 (s, 1H), 4.65 (t, J = 5.1 Hz, 1 H), 3.62 (q, J = 7.2 Hz, 2 H), 2.70 (t, J = 6.9 Hz, 2 H), 1.25 (s, 9 H). MS (ESI) m/z: 413 (M+H + ).

Using general method C, Example Al (20.0 g, 69.6 mmol) was reduced to afford [3-(5-amino-3-t-butyl-lH-pyrazol-1-yl)phenyl]methanol (15.2 g, 89%). 1 H NMR (DMSO-de): 7.49 (s, 1H), 7.37 (m, 2H), 7.19 (d, J = 7.2 Hz, 1H), 5.35 (s, 1H), 5.25 (t, J =5.6 Hz, 1H), 5.14 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 1.19 (s, 9H); MS (ESI) m/z: 246.19 (M+H + ). The crude material from the previous reaction (5.0 g, 20.4 mmol) was dissolved in dry THF (50 mL) and SOCl 2 (4.85 g, 40.8 mmol), stirred for 2h at RT, concentrated in vacuo to yield 3-t-butyl-1-(3-chloromethylphenyl)-lH-pyrazol-5-amine (5.4 g), which was added to NaN 3 (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixture was heated at 30 °C for 2 h, poured into H 2 O (50 mL), and extracted with CH 2 C1 2 . The organic layers were combined, dried (MgSO 4 ), filtered and concentrated in vacuo to yield crude 3-t-butyl-1-[3-(azidomethyl)phenyl]-lH-pyrazol-5-arnine (1.50 g, 5.55 mmol).

Using general method A, Example A88 and 1-isocyano naphthalene (1.13 g, 6.66 mmol) were combined to yield l-[2-(3- azidomethyl-phenyl)-5-t-butyl-2η-pyrazol-3-yl]-3-naphthalen -1- yl-urea (2.4 g, 98%) as a white solid.

The crude material from the previous reaction and 10% Pd/C (0.4 g) in THF (30 mL) was reduced under H 2 (1 atm) at RT for 2 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 1-(3-t-butyl-1-(3-(aminomethyl)phenyl)-1H- pyrazol-5-yl)-3-(naphthalen-1-yl)urea (2.2 g, 96%) as a yellow solid. 1 H NMR (DMSO-^ 6 ): 9.02 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, 1H), 3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H + ).

The material from the previous reaction, 1-(3-t-butyl-1-(3-(aminomethyl)phenyl)-1H- pyrazol-5-yl)-3-(naphthalen-1-yl)urea (100 mg, 0.24 mmol) and methanesulfonamide (500 mg, 5.0 mmol) were combined to yield N-{7-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol- l-yl]-3-benzylamine-2-carbonyl }methanesulfonamide (45 mg, 35% yield). 1 H-NMR (300 MHz, DMSO-(Z 6 ): δ 10.35 (s, 1 H), 9.15 (s, 1 H), 8.88 (s, 1 H), 8.00 (d, J = 8.1 Hz, 1 H), 7.85-7.91 (m, 2 H), 7.61 (d, J = 6.0 Hz, 2 H), 7.40-7.53 (m, 6 H), 7.27 (d, J = 6.9 Hz, 1 H), 7.15 (t, J = 6.9 Hz, 1 H), 6.39 (s, 1 H), 4.33 (d, J = 5.4 Hz, 2 H), 3.18 (s, 3 H), 1.27 (s, 9 H).

Using general method J, Example 373 (200 mg, 0.44 mmol) and (5)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (100 mg, 0.60 mmol) were combined to afford (2S)-methyl-1-[2-(3-{ 3- r-butyl-5-[3-(2,3-dichlorophenyl)-ureido]-lH-pyrazol-1- yl}phenyl)acetyl]pyrrolidine-2-carboxylate (165 mg, 66% yield). 1 H-NMR (300 MHz, DMSO-d 6 ): D9.23 (s, 1 H), 8.75 (s, 1 H), 8.04 (m, 1 H), 7.46-7.23 (m, 6 H), 6.35 (s, 1 H), 4.25 (m, 1 H), 3.74 (s, 2 H), 3.57-3.55 (m, 2 H), 3.54 (s, 3 H), 1.85-1.74 (m, 4 H), 1.23 (s, 9 H); MS (ESI) m/z: 572 (M+H + ).

Using general method E,, (25)-methyl-1-[2-(3-{ 3-t-butyl-5-[3-(2,3-dichlorophenyl)- ureido]-1H-pyrazol-1-yl }phenyl)acetyl]pyrrolidine-2-carboxylate (100 mg, 0.22 mmol) was saponified to afford (25')-1-[2-(3-{3-t-butyl-5-[3-(2,3-dichlorophenyl)ureido]-1H -pyrazol- 1- yl}phenyl)acetyl]pyrrolidine-2-carboxylic acid (68 mg, 55% yield) . 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.28 (s, 1 H), 8.78 (s, 1 H), 8.04 (m, 1 H), 7.46-7.25 (m, 6 H), 6.34 (s, 1 H), 4.17 (m, 1 H), 3.73 (s, 2 H), 3.35-3.50 (m, 2 H), 1.73-2.05 (m, 4 H), 1.27 (s, 9 H); MS (ESI) m/z: 558 (M+H + ).

Example 373 (100 mg, 0.23 mmol) and 4-methyl-piperidin-4-ol (35 mg, 0.3 mmol) were combined to afford 1-(3-t-butyl-1-{ 3-[2- (4-hydroxy-4-methylpiperidin- 1 -yl)-2-oxoethyl]phenyl } - 1 H- pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (50 mg, 39% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.20 (s, 1H), 8.74 (s, 1H), 8.02 (m, 1H), 7.45-7.20 (m, 6H), 6.35 (s, 1H), 3.90 (m, 1H), 3.75 (s, 2H),

3.57 (m, 1H), 3.31 (m, 1H), 2.95 (m, 1H), 1.41-1.25 (m, 4H), 1.24 (s, 9H), 1.04 (s, 3H); MS

(ESI) m/z: 558 (M+H + ).

Using general method B, Example A34 (1.0 g, 3.5 mmol) benzo[d]thiazol-6-amine (1.0 g, 7.0 mmol) were combined to yield 1 -(benzo[d]thiazol-6-yl)-3-(3-butyl- 1 -(I -oxo- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea (650 mg, 41% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.22 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.93-

7.90 (m, 2H), 7.60 (m, 1H), 7.44-7.40 (m, 2H), 6.35 (s, 1H), 3.37 (t, J = 6.6 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H), 1.25 (s, 9H); MS (ESI): m/z: 461 (M+H + ). Using general method C, 1-

(benzo[d]thiazol-6-yl)-3-(3-butyl- 1 -( 1 -oxo- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazol-5- yl)urea (650 mg, 1.4 mmol) was reduced to afford 1-(benzo[d]thiazol-6-yl)-3-(3-butyl-1- (l,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea (400 mg, 63% yield). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.55 (s, 1H), 9.33 (s, 1H), 9.05 (m, 2H), 8.22 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.43-7.28 (m, 3H), 6.38 (s, 1H), 4.30 (m, 2H), 3.34 (m, 2H), 3.00 (t, J = 6.9 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 447 (M+H + ).

Using general method A, Example A36 (0.15 g, 0.40 mmol) and phenylisocyanate (53 mg, 0.45 mmol) were combined to afford t- butyl 6-(3-t-butyl-5-(3-phenylureido)-lH-pyrazol-1-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate which was deprotected using general method F to yield 1 -(3-t-butyl- 1 -( 1 ,2,3,4- tetrahydroisoquinolin-6-yl)-lH-pyrazol-5-yl)-3-phenylurea HCl salt as white solid (0.14 g, 80% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.37 (m, 2H), 8.68 (brs,1H), 7.3-7.5 (m, 4H), 7.25 (m, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.35 (s, 1H), 4.30 (m, 2H), 3.38 (m, 2H), 3.08 (t, J = 6.0 Hz, 2H), 1.28 (s, 9H); MS (ESI) m/z: 390.2 (M+H + ).

Using the general procedures outlined herein, the following examples were prepared.

AbI Kinase Assay

Assay Al

The activity of AbI kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 259, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A34Onm) was continuously monitored spectrophotometrically. The reaction mixture (100 μl) contained AbI kinase (1.9 nM, nominal concentration), peptide substrate (EAIYAAPFAKKK, 0.2 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM) in 60 mM Tris buffer containing 0.13 % octyl-glucoside, 13 mM MgCl 2 and 3.5 % DMSO at pH 7.5. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3h at 30 °C on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the Ih to 2h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Assay A2

AbI kinase assay A2 is the same as for assay Al except that (1) a nominal concentration of 1.1 nM of enzyme was employed (2) the reaction was pre-incubated at 30 °C for 2h prior to initiation with ATP (3) 0.5 mM ATP (final concentration) was used to initiate the reaction.

AbI protein sequence used for screening:

SPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLK EAAVM KEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAWLLYMATQISSAM E YLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLA YN KFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRA CW QWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGK

KDR Kinase Assay

Assay Kl

The activity of KDR kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A 3 4Onm) was continuously monitored spectrophotometrically. The reaction mixture (100 μl) contained KDR (1.5 nM to 7.1 nM, nominal concentration), PoIyE 4 Y (1 mg/ml), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM) in 60 mM Tris buffer containing 0.13 % octyl-glucoside, 13 mM MgCl 2 , 6.8 mM DTT, and 3.5 % DMSO at pH 7.5. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3h at 30 °C on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the Ih to 2h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Assay K2

KDR kinase assay K2 is the same as for assay Kl except that (1) a nominal concentration of 2.1 nM of enzyme was employed (2) the reaction was pre-incubated at 30 °C for 2h prior to initiation with ATP (3) 1.0 mM ATP (final concentration) was used to initiate the reaction.

KDR protein sequence used for screening:

DPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCR TVAVK MLKEGATHSEHRALMSELKILIHIGHHLNWNLLGACTKPGGPLMVIVEFCKFGNLSTYLR S KRNEFVPYKVAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKN W KICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLG AS PYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLL QA NAQQD

B-Raf(V599E) Kinase Assay

Assay B1

The activity of B-Raf(V599E) kinase was determined by following the formation of

ADP from the reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 μl) contained B- Raf(V599E) kinase (0.34 nM nominal concentration, construct 1), unphosphorylated, full-length MEKl (42 nM), MgCl 2 (13 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer, containing 0.13% octyl-glucoside and 3.5 % DMSO concentration at pH 7.5. The test compounds were incubated with the reaction mixture at 30 °C for 2h. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3h at 30 °C on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 1.5h to 2.5h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Assay B2

Same as assay Bl except that (1) construct 2 was employed at a nominal concentration of 2 nM (2) the reaction was pre-incubated at 30 °C for Ih prior to initiation with ATP (3) a reading time frame of 0.5h to 1.5 h.

B-Raf(V599E) construct 1 protein sequence used for screening:

KSPGQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGK WHGDV

AVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSL YHHLH

IIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLAT EKSRW

SGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINN RDQII

FMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPK IHRSA

SEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH

B-Raf(V599E) construct 2 protein sequence used for screening:

EDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTA PTPQQ LQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLI DI ARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATEKSRWSGSHQFEQLSGS IL

WMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLS PDLSK VRSNCPKAMKRLMAECLKKKR DERPLFPQILASIELLARSLPKIHR

MEKl protein sequence used for screening:

MELKDDDFEKISELGAGNGGWFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVL HECNS PYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYLREK HKI MHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHYSVQSDI WSM GLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSYGMDSRPPMA IFE LLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFA GWL CSTIGLNQPSTPTHAAGV

P-38 alpha Kinase Assay

Assay P1

The activity of phosphorylated p-38-alpha kinase was determined by following the formation of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938- 1942). In this assay, the oxidation of NADH (thus the decrease at A340n m ) was continuously measured spectrophotometrically. The reaction mixture (100 μl) contained phosphorylated p-38 alpha kinase (7.1-9 nM nominal concentration), peptide substrate (IPTSPITTTYFFFKKK-OH, 0.2 mM), MgC1 2 (13 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM) in 60 mM Tris buffer at pH 7.5, containing 130 uM n- Dodecyl-B-D-maltopyranoside and 3.5 % DMSO concentration. The test compounds were incubated with the reaction mixture at 30 "C for 2h before the addition of ATP (0.3 mM final concentration). The absorption at 340 nm was monitored continuously for up to 3h at 30 °C on Polarstar Optima plate reader (BMG). The reaction rate was calculated using the time frame from 1.5h to 2.5h. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC 5O values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Assay P2

Same as assay Pl except that (1) the reaction was not pre-incubated.

P38-alpha protein sequence used for screening:

MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSR PFQSI IHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQKL TD DHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMTGYVA TR WYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHINQLQQIMRLTGTPPAYL IN RMPSHEARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYF AQ YHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES

AbI Kinase Assay Data

KDR Kinase Assa Data

BRaf Kinase Assa Data




 
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