RAF inhibitor compounds and methods
View Patent ↗Pyrazolyl compounds of Formulas Ia and Ib are useful for inhibiting Raf kinase and for treating disorders mediated thereby. Methods of using pyrazolyl compounds for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
1. A compound selected from Formulas Ia and Ib:
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein:
the A-ring is a 5 or 6 membered carbocyclic ring, wherein said carbocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , ═NOR 20 , ═NR 20 , ═N+(O)OR 20 , ═NNR 20 R 21 , ═O, —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR)NR 20 R 21 , ═S, —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, and a protecting group, and wherein said alkyl, alkenyl, alkynyl, aryl, carbocyclyl and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(O 21 ), —P(═Y)(OR)NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl;
X is a C 2 -C 20 heterocyclyl, wherein said heterocycle, is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, and C 2 -C 20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
R 1 is selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 1 -C 8 alkyl)NR 20 R 21 , a C 2 -C 20 heterocyclyl, a C 3 -C 12 carbocyclyl, and a C 6 -C 20 aryl, wherein said alkyl, alkenyl, alkynyl, heterocycle, carbocyclyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , OR 20 , CN, C(═O)NR 20 R 21 , C(═O)OR 20 , alkyl, (C 1 -C 8 alkyl)NR 20 R 21 , and heterocyclyl;
R 2 is selected from H, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, wherein said alkyl, alkenyl, and alkynyl, are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl,
or R 1 and R 2 of Formula Ia together with the atoms to which they are attached optionally form an aromatic 5 or 6 membered fused heterocycle ring having at least two heteroatoms independently selected from O, N and S, wherein said heterocycle ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, and C 2 -C 20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
R 3 , R 4 , and R 5 are independently selected from H, F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, and C 2 -C 20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
R 20 and R 21 are independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, and a protecting group, wherein said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R a , —C(═Y)OR a , —C(═Y)NR a R b , —OR a , —OC(═Y)R a , —OC(═Y)OR a , —OC(═Y)NR a R b , —OS(O) 2 (OR a ), —OP(═Y)(OR a )(OR b ), —OP(OR a )(OR b ), —P(═Y)(OR a )(OR b ), —P(═Y)(OR)NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —S(O) 2 NR a R b , —S(O)(OR a ), —S(O) 2 (OR a ), —SC(═Y)R a , —SC(═Y)OR a , and —SC(═Y)NR a R b ,
or R 20 and R 21 together with the atoms to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, alkyl, alkenyl and alkynyl;
R 23 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, or a protecting group;
R a and R b are independently H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 20 aryl, or C 2 -C 20 heterocyclyl;
Y is independently O, S, NR 20 , + N(O)R 20 , N(OR 20 ), + N(O)(OR 20 ), or N—NR 20 R 21 ; and
protecting group is selected from trialkylsilyl, dialkylphenylsilyl, benzoate, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethylenoxycarbonyl (Fmoc), and tetrahydropyranyl.
2. The compound of claim 1 wherein R 1 is H.
3. The compound of claim 1 wherein R 1 is an optionally substituted C 1 -C 8 alkyl.
4. The compound of claim 3 , wherein R 1 is methyl.
5. The compound of claim 3 , wherein R 1 is alkyl substituted with NR 20 R 21 .
6. The compound of claim 5 , wherein R 1 is CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NH 2 , or CH 2 CH 2 CH 2 NH 2 .
7. The compound of claim 5 , wherein R 1 is CH 2 CH 2 CH 2 NHCH 2 C(═O)OCH 3 .
8. The compound of claim 5 , wherein R 1 is CH 2 CH 2 NHCH 2 CH 2 OH.
9. The compound of claim 3 , wherein R 1 is alkyl substituted with a heterocyclyl.
10. The compound of claim 9 , wherein R 1 is selected from the structures:
11. The compound of claim 3 , wherein R 1 is alkyl substituted with OR 20 .
12. The compound of claim 11 , wherein R 1 is CH 2 CH 2 OH or CH 2 CH(OH)CH 2 OH.
13. The compound of claim 3 , wherein R 1 is alkyl substituted with C(═O)OR 20 .
14. The compound of claim 13 , wherein R 1 is CH 2 C(═O)OH.
15. The compound of claim 1 , wherein R 1 is an optionally substituted heterocyclyl.
16. The compound of claim 15 , wherein R 1 is selected from the structures:
17. The compound of claim 15 , wherein R 1 is selected from the structures:
18. The compound of claim 1 , wherein R 1 is an optionally substituted carbocyclyl.
19. The compound of claim 18 , wherein R 1 is selected from the structures:
20. The compound of claim 1 , wherein X is an optionally substituted C 2 -C 20 heterocyclyl.
21. The compound of claim 20 wherein X is an optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 4-oxazolyl, or 5-oxazolyl.
22. The compound of claim 21 wherein X is optionally substituted 4-pyridyl.
23. The compound of claim 1 wherein the A-ring is an optionally substituted ring selected from cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
24. The compound of claim 1 wherein R 1 and R 2 of Formula Ia together with the atoms to which they are attached form a 5 or 6 membered fused heterocycle ring having at least two heteroatoms selected from O, N and S.
25. The compound of claim 24 wherein R 1 and R 2 together with the atoms to which they are attached form a fused pyrimidine ring.
26. The compound of claim 24 wherein the A-ring is an optionally substituted ring selected from cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
27. The compound of claim 1 selected from Formulas IIa-h and IIIa-f:
wherein Z is selected from CR 20 R 21 , and C(═Y).
28. The compound of claim 27 wherein Z is CH 2 .
29. The compound of claim 27 wherein Y is O.
30. The compound of claim 27 wherein Y is N—OR 20 .
31. The compound of claim 30 wherein Y is N—OH.
32. The compound of claim 27 wherein Z is CH 2 , and Y is N—OR 20 .
33. The compound of claim 27 selected from Formulas IIa, IIc, IIe, IIg, IIIa, IIIc, and IIIe wherein R 1 and R 2 together with the atoms to which they are attached form a 5 or 6 membered fused heterocycle ring having at least two heteroatoms selected from O, N and S.
34. The compound of claim 33 wherein R 1 and R 2 together with the atoms to which they are attached form a fused pyrimidine ring.
35. The compound of claim 27 selected from Formulas VIa, VIb, VIIa and VIIb:
36. The compound of claim 35 wherein R 1 and R 2 of Formulas VIa and VIIa together with the atoms to which they are attached form a 5 or 6 membered fused heterocycle ring having at least two heteroatoms selected from O, N and S.
37. The compound of claim 36 wherein R 1 and R 2 together with the atoms to which they are attached form a fused pyrimidine ring.
38. The compound of claim 35 selected from Formulas VIIIa, VIIIb, IXa and IXb:
wherein R 6 , R 7 , R 8 , and R 9 are independently selected from II, F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) d (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, and C 2 -C 20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl.
39. The compound of claim 38 wherein R 2 , R 3 , R 4 , and R 5 are H.
40. The compound of claim 38 wherein R 6 , R 7 , R 8 , and R 9 are H.
41. The compound of claim 38 wherein R 1 is H or an optionally substituted C 1 -C 8 alkyl.
42. The compound of claim 38 wherein R 1 and R 2 of Formulas VIIIa and IXa together with the atoms to which they are attached form a 5 or 6 membered fused heterocycle ring having at least two heteroatoms selected from O, N and S.
43. The compound of claim 1 selected from Formulas XIIa-d and XIIIa-j:
wherein R 11 , R 12 , and R 13 are independently selected from H, F, Cl, Br, I, —OR 20 , —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, and C 2 -C 20 heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocycle are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocycle.
44. The compound of claim 43 wherein X is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and substituted forms thereof.
45. The compound of claim 43 wherein X is an optionally substituted 4-pyridyl.
46. The compound of claim 43 wherein the A-ring is an optionally substituted ring selected from cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
47. The compound of claim 1 selected from:
5-(1-(2-aminoethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3-aminopropyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(4-aminobutyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(pyrrolidin-3-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(piperidin-4-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(4-methylpiperidinyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3R-tetrahydrofuranyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3S-tetrahydrofuranyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(4-tetrahydropyranyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3S-(1R-hydroxy)cyclohexyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2,3dihydroxypropyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden -1-one oxime;
5-(1-(3-cyano-pyridin-2-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3S-(1S-hydroxy)cyclohexyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3-aminomethyl-pyridin-2-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(5-(aminomethyl)pyridin-2-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3S-(1S, 2R-dihydroxy)cyclohexyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(3-methoxyacetamidopropyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(4-aminomethylphenyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(5-(acetamido)pyridin-2-yl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-Methyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2-hydroxyethyl)-5-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidin-3-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2S-(1S-hydroxy)cyclopentyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-cyclopentyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2-(4-methylpiperazinyl)ethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden -1-one;
5-(1-(2-(2-hydroxyethyl)aminoethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2-(4-methylpiperazinyl)ethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-amine;
5-(2-hydroxyethyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-amine;
5-(1-(2S-(1S-hydroxy)cyclopentyl)-3-pyridin4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-amine;
5-(1-(2-(N-piperidyl)ethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one;
5-(1-(4-(N-methylpiperidyl))-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime;
5-(3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one;
5-(1-acetic acid-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime; and
5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-amine.
48. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier.
49. A composition comprising the compound of claim 1 in an amount to detectably inhibit Raf kinase activity and a pharmaceutically acceptable carrier, adjuvant, or vehicle.