Substituted pyrazolyl urea derivatives useful in the treatment of cancer

1. A method of treating ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt

stereoisomer, alkyl ester prodrug or phenyl(C 1 -C 5 ) alkyl ester prodrug thereof,

wherein

R 1 and R 2 are independently:

(a) hydrogen;

(b) (C 1 -C 5 )alkyl, optionally substituted with one or more of hydroxy or fluoro; or

(c) halogen;

A is phenyl, pyridine, or pyrimidine, optionally substituted with 1 or 2 substituents that are independently (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, (C 1 -C 5 )haloalkoxy, or halogen;

B is phenylene or naphthalene, optionally substituted with 1 to 4 substituents that are independently (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, (C 1 -C 5 )haloalkoxy, or halogen;

L is a bridging group which is —O—, —S—, or —CH 2 —;

M is phenyl, pyridine or pyrimidine, optionally substituted with 1 to 3 substituents that are independently:

(1) (C 1 -C 5 )alkyl;

(2) (C 1 -C 5 )haloalkyl;

(3) —O—R 3 ;

(4) —NR 3 R 4 ;

(5) halogen;

(6) —C(O)NR 3 R 4 ;

(7) cyano;

(8) C(O)R 3 ;

(9) —C≡C—R 3 or

(10) nitro;

n is zero or one and

X is:

(1) —O—;

(2) —SO 2 —;

(3) —NR 5 —;

(4) —NR 5 —SO 2 —;

(5) —N(SO 2 NR 7 R 8 )—;

(6) —SO 2 —NR 5 —;

(7) —NR 5 —C(O)—;

(8) —C(O)—NR 5 —;

(9) —C(O)— or

(10) a single bond;

Y is a linear or branched C 1 to C 6 alkyl fragment that is substituted with one or two Z groups, where each Z group is independently:

(1) —OR 6 ;

(2) —O—C(O)—R 6 ;

(3) —NR 7 R 8 ;

(4) —SO 2 —(C 1 -C 5 )alkyl;

(5) —C(O)—O—R 6 ;

(6) —NH—C(O)—R 6 ;

(7) —C(O)—NR 7 R 8 or

(8) a monocyclic, saturated, partially saturated, or aromatic heterocycle of 5-7 ring atoms containing at least one heteroatom selected from N, O, or S, that is optionally substituted with 1 to 3 substituents selected from (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, hydroxy, amino, halogen, or oxo;

with the proviso that when n is zero and X is —O—, —NR 3 —, or a single bond, then Z is not morpholine, piperidine, imidazole, or tetrazole;

with the further proviso that when n is zero and X is a single bond, then Z is not —NR 7 R 8 ;

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or (C 1 -C 5 )alkyl optionally substituted with hydroxy; and

R 7 and R 8 are independently hydrogen, or (C 1 -C 5 )alkyl optionally substituted with hydroxy; or

the group —NR 7 R 8 forms a monocyclic saturated heterocyclic ring having 5 to 7 ring atoms optionally substituted on a carbon atom with hydroxy, where, in addition to the nitrogen atom in the group —NR 7 R 8 , zero to two of the other ring atoms is a hetero atom selected from N, O and S, and the remaining ring atoms are carbon.

2. A method according to claim 1 , wherein said cancer is of the breast.

3. A method according to claim 2 , wherein said breast cancer is invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ.

4. A method according to claim 1 , wherein said cancer is prostate cancer.

5. A method according to claim 1 , wherein said cancer is pancreatic cancer.

6. A method of treating diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, age-related macular degeneration, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, rheumatoid arthritis, restenosis, in-stent restenosis, or vascular graft restenosis, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt stereoisomer, alkyl ester prodrug or phenyl(C 1 -C 5 ) alkyl ester prodrug thereof,

wherein

R 1 and R 2 are independently:

(a) hydrogen;

(b) (C 1 -C 5 )alkyl, optionally substituted with one or more of hydroxy or fluoro; or

(c) hydrogen;

A is phenyl, pyridine, or pyrimidine, optionally substituted with 1 or 2 substituents that are independently (C 1 -C 5 )alkyl, (C 1 -C 2 )alkoxy, (C 1 -C 5 )haloalkyl, (C 1 -C 5 )haloalkoxy, or halogen;

B is phenylene or naphthylene optionally substituted with 1 to 4 substituents that are independently (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, (C 1 -C 5 )haloalkoxy, or halogen;

L is a bridging group which is —O—, —S—, or —CH 2 —;

M is phenyl, pyridine or pyrimidine, optionally substituted with 1 to 3 substituents that are independently:

(1) (C 1 -C 5 )alkyl;

(2) (C 1 -C 5 )haloalkyl;

(3) —O—R 3 ;

(4) —NR 3 R 4 ;

(5) halogen;

(6) —C(O)NR 3 R 4 ;

(7) cyano;

(8) C(O)R 3 ;

(9) —C≡C—R 3 or

(10) nitro;

n is zero or one and

X is:

(1) —O—;

(2) —SO 2 ;

(3) —NR 5 ;

(4) —NR 5 —SO 2 —;

(5) —N(SO 2 NR 7 R 8 )—;

(6) —SO 2 —NR 5 —;

(7) —NR 5 —C(O)—;

(8) —C(O)—NR 5 —;

(9) —C(O)— or

(10) a single bond;

Y is a linear or branched C 1 to C 6 alkyl fragment that is substituted with one or two groups, where each Z group is independently:

(1) —OR 6 ;

(2) —O—C(O)—R 6 ;

(3) —NR 7 R 8 ;

(4) —SO 2 —(C 1 -C 5 )alkyl;

(5) —C(O)—O—R 6 ;

(6) —NH—C(O)—R 6 ;

(7) —C(O)—NR 7 R 8 or

(8) a monocyclic, saturated, partially saturated, or aromatic heterocycle of 5-7 ring atoms containing at least one heteroatom selected from N, O, or S, that is optionally substituted with 1 to 3 substituents selected from (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, hydroxy, amino, halogen, or oxo;

with the proviso that when n is zero and X is —O—, —NR 3 —, or a single bond, then Z is not morpholine, piperidine, imidazole, or tetrazole;

with the further proviso that when n is zero and X is a single bond, then Z is not —NR 7 R 8 ;

R 3 , R 4 , R 5 and R 6 are each independently hydrogen or (C 1 -C 5 )alkyl optionally substituted with hydroxy; and

R 7 and R 8 are independently hydrogen, or (C 1 -C 5 )alkyl optionally substituted with hydroxy; or

the group —NR 7 R 8 forms a monocyclic saturated heterocyclic ring having 5 to 7 ring atoms optionally substituted on a carbon atom with hydroxy, where, in addition to the nitrogen atom in the group —NR 7 R 8 , zero to two of the other ring atoms is a hetero atom selected from N, O and S, and the remaining ring atoms are carbon.