Pyrazole kinase modulators and methods of use

1. A compound or pharmaceutically acceptable salt thereof of either formula VIIc or VIId,

R 3a and R 3b , together with the nitrogen to which they are attached, combine to form an optionally substituted piperazinyl;

R 6 is —H, halogen, haloalkyl, —CN, —NO 2 , —OR 3 , —N(R 3 )R 3 , —S(O) 0-2 R 3 , —N(R 3 )C(═O)C(═O)N(R 3 )R 3 , —CO 2 R 3 , —C(═O)N(R 3 )R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —NCO 2 R 3 , —C(═O)R 3 , optionally substituted alkoxy, optionally substituted heterocyclyl, or optionally substituted lower alkyl; and

R 3 is —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl;

p is one to five;

wherein when any of said “alkyl, aryl, or heterocyclyl” are substituted, one or more hydrogen atoms of said alkyl, aryl, and heterocyclyl are replaced by alkyl, trifluoromethyl, hydroxypropyl, nitromethyl, aminoethyl, aryl, 4-hydroxyphenyl, 2,3-difluorophenyl, arylalkyl, 1-phenyl-ethyl, para-methoxyphenylethyl, heterocyclylalkyl, 1-pyridin-3-yl-ethyl, N-ethylmorphonlino, heterocyclyl, 5-chloro-pyridin-3-yl, 1-methyl-piperidin-4-yl, alkoxy, methoxyethoxy, hydroxypropyloxy, methylenedioxy, amino, methylamino, diethylamino, trifluoroacetylamino, amidino, aryloxy, para-chlorophenoxy, meta-aminophenoxy, para-phenoxyphenoxy, arylalkyloxy, 3-chlorobenzyloxy, meta-phenoxybenzyloxy, carboxy, carboalkoxy, carboxamido, benzyloxycarbonylamino, cyano, acyl, halogen, hydroxy, nitro, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, thiol, oxo, carbamyl, acylamino, hydrazino, hydroxylamino, or sulfonamide.

2. The compound according to claim 1 or pharmaceutically acceptable salt thereof wherein for VIIc, —N(R 3a )R 3b is either meta- or para- to the pyrazole moiety; and the phenyl urea in VIId is either meta- or para- to the pyrazole moiety.

3. A compound selected from Table 3 or pharmaceutically acceptable salt thereof,

TABLE 3

Entry

Name

Structure

2

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-ethylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

3

N-(3-ethylphenyl)-N′-(4-{3-[5- (4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

4

N-(4-{3-[5-(4-ethylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[3- (trifluoromethyl)phenyl]urea

5

N-(3-acetylphenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

6

N-(3,4-dichlorophenyl)-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl}phenyl)urea

7

N-(3-bromophenyl)-N′-(4-{3-[6- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

8

N-[4-fluoro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

9

N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[4- (phenyloxy)phenyl]urea

10

N-(3-chlorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- yl}phenyl)urea

11

N-[3,5-bis(methyloxy)phenyl]- N′-(4-{3-[6-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

12

N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-{4- [(trifluoromethyl)oxy]phenyl} urea

13

N-(4-{3-[6-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[4- (trifluoromethyl)phenyl]urea

14

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

15

N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[3- (trifluoromethyl)phenyl]urea

16

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea

17

N-(3,4-dimethylphenyl)-N′-(4- {5-[4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-3- yl}phenyl)urea

18

N-(4-chlorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

19

N-(3,5-difluorophenyl)-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

20

N-[3-(methyloxy)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

21

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[4-(4-ethylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea

22

N-(3-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

23

N-(4-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

24

N-(3-cyanophenyl)-N′-(4-{3-[6- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

25

N-(3,4-difluorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

26

N-[3,4-bis(methyloxy)phenyl]- N′-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

27

N-[5-chloro-2- (methyloxy)phenyl]-N′-(4-{5-[4- (4-methylpiperazin-1-yl)phenyl]- 1H-pyrazol-3-yl}phenyl)urea

28

N-(4-{5-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-3- yl}phenyl)-N′-[4- (phenyloxy)phenyl]urea

29

N-(2,4-difluorophenyl)-N′-(4-{3- [6-(4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

30

N-{4-[3-(1H-benzimidazol-2- yl)-1H-pyrazol-5-yl]phenyl}-N′- [4-chloro-3- (trifluoromethyl)phenyl]urea

31

N-{4-[3-(1H-benzimidazol-2- yl)-1H-pyrazol-5-yl]phenyl}-N′- [2-fluoro-5- (trifluoromethyl)phenyl]urea

32

N-(2,4-difluorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

34

N-[3,5- bis(trifluoromethyl)phenyl]-N′- (4-{3-[5-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

35

N-(2-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

38

N-(5-fluoro-2-methylphenyl)-N′- (4-{3-[6-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea

39

N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′- phenylurea

40

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[3-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea

41

N-(2,4-difluorophenyl)-N′-(4-{3- [4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea

42

N-(2,3-dihydro-1,4-benzodioxin- 6-yl)-N′-(4-{5-[4-(4- methylpiperazin-1-yl)phenyl]- 1H-pyrazol-3-yl}phenyl)urea

43

N-[2,4-bis(methyloxy)phenyl]- N′-(4-{5-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-3- yl}phenyl)urea

46

N-(4-{3-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-5- yl}phenyl)-N′-(2- phenylethyl)ethanediamide

50

N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-[4- (3-phenyl-1H-pyrazol-5- yl)phenyl]urea

52

1,1-dimethylethyl{4-[3-(1H- benzimidazol-2-yl)-1H-pyrazol- 5-yl]phenyl}carbamate

53

N-(5-fluoro-2-methylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea

64

N-(1,1-dimethylethyl)-N′-(4-{3- [5-(4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea

76

N-phenyl-N′-[4-(3-phenyl-1H- pyrazol-5-yl)phenyl]urea

77

4-[3-(1H-benzimidazol-2-yl)- 1H-pyrazol-5-yl]aniline

4. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 and a pharmaceutically acceptable carrier.

5. A method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of a composition comprising at least one of the compounds or a pharmaceutically acceptable salt thereof according to any of claims 1 - 3 , wherein the kinase is c-Kit or flt-3.

6. A method of treating a c-Kit- or flt-3-mediated diseases or disorders, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of a composition comprising at least one of the compounds or a pharmaceutically acceptable salt thereof according to any of claims 1 - 3 .

7. A method of screening for a modulator of a kinase, the method comprising combining at least one of the compounds or a pharmaceutically acceptable salt thereof according to any of claims 1 - 3 and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase, wherein the kinase is c-Kit or flt-3.

8. A method of inhibiting proliferative activity in a cell or a plurality of cells, the method comprising administering an effective amount of at least one of the compounds or a pharmaceutically acceptable salt thereof according to any of claims 1 - 3 to said cell or said plurality of cells, wherein the proliferative activity is modulated by c-Kit or flt-3.