Tyrosine kinase inhibitors

1. A compound of Formula I

wherein

R 1a is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) OR 8 , and

(4) N(R 8 ) 2 ;

R 1 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted C 3 –C 10 cycloalkyl,

(4) unsubstituted or substituted aryl,

(5) unsubstituted or substituted heterocycle,

(6) halo,

(7) CF 3 ,

(8) —(CH 2 ) t R 9 C(O)R 8 ,

(9) —C(O)R 9 ,

(10) —(CH 2 ) t OR 8 ,

(11) unsubstituted or substituted C 2 –C 6 alkenyl,

(12) unsubstituted or substituted C 2 –C 6 alkynyl,

(13) CN,

(14) —(CH 2 ) t NR 7 R 8 ,

(15) —(CH 2 ) t C(O)NR 7 R 8 ,

(16) —C(O)OR 8 , and

(17) —(CH 2 ) t S(O) q (CH 2 ) t NR 7 R 8 ;

R 2 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted C 3 –C 10 cycloalkyl,

(4) unsubstituted or substituted aryl,

(5) unsubstituted or substituted heterocycle,

(6) halo,

(7) CF 3 ,

(8) —(CH 2 ) t R 9 C(O)R 8 ,

(9) —C(O)R 9 ,

(10) —(CH 2 ) t OR 8 ,

(11) unsubstituted or substituted C 2 –C 6 alkenyl,

(12) unsubstituted or substituted C 2 –C 6 alkynyl,

(13) CN,

(14) —(CH 2 ) t NR 7 R 8 ,

(15) —(CH 2 ) t C(O)NR 7 R 8 ,

(16) —C(O)OR 8 , and

(17) —(CH 2 ) t S(O) q (CH 2 ) t NR 7 R 8 ;

R 3 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted aralkyl,

(4) CN,

(5) halo,

(6) N(R 8 ) 2 ,

(7) OR 8 , and

(8) unsubstituted or substituted aryl;

R 7 is selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aralkyl;

R 8 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted aryl,

(4) unsubstituted or substituted heterocycle,

(5) unsubstituted or substituted C 3 –C 10 cycloalkyl, and

(6) unsubstituted or substituted aralkyl;

R 7 and R 8 , when attached to the same nitrogen atom may be joined to form a 5–7 membered heterocycle containing, in addition to the nitrogen, one or two more heteroatoms selected from N, O, or S, said heterocycle being optionally substituted with one to three R 2 substituents;

R 9 is independently selected from:

(1) unsubstituted or substituted C 1 –C 10 alkyl,

(2) unsubstituted or substituted heterocycle, and

(3) unsubstituted or substituted aryl;

V is selected from:

(1) a bond,

(2) aryl, and

(3) heterocycle;

W is selected from:

(1) aryl, and

(2) heterocycle;

m is 0, 1, or 2;

n is independently 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, or 4;

q is independently 0, 1, or 2;

t is independently 0, 1, 2, 3, 4, 5, or 6;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound, according to claim 1 , as illustrated by Formula I:

wherein

R 1a is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 6 alkyl, and

(3) OR 8 ;

R 1 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) halo,

(4) CF 3 ,

(5) —(CH 2 ) t R 9 C(O)R 8 ,

(6) —C(O)R 9 ,

(7) —(CH 2 ) t OR 8 ,

(8) —(CH 2 ) t C(O)NR 7 R 8 ,

(9) —C(O)OR 8 ,

(10) —(CH 2 ) t NR 7 R 8 , and

(11) —(CH 2 ) t S(O) q (CH 2 ) t NR 7 R 8 ;

R 2 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted aryl,

(4) unsubstituted or substituted heterocycle,

(5) unsubstituted or substituted C 3 –C 10 cycloalkyl,

(6) unsubstituted or substituted C 2 –C 6 alkenyl,

(7) unsubstituted or substituted C 2 –C 6 alkynyl,

(8) CN,

(9) halo,

(10) N(R 8 ) 2 , and

(11) OR 8 ;

R 3 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aralkyl;

R 7 is selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aralkyl;

R 8 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aryl;

R 7 and R 8 , when attached to the same nitrogen atom may be joined to form a 5–7 membered heterocycle containing, in addition to the nitrogen, one or two more heteroatoms selected from N, O, or S, said heterocycle being optionally substituted with one to three R 2 substituents;

R 9 is independently selected from

(1) unsubstituted or substituted aryl, and

(2) unsubstituted or substituted heterocycle;

V is selected from:

(1) a bond,

(2) aryl, and

(3) heterocycle;

W is selected from:

(1) aryl, and

(2) heteroaryl, selected from pyridyl, pyrimidinyl, isoxazolyl, or pyrazinyl;

m is 0, 1, or 2;

n is independently 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, or 4;

q is independently 0, 1, or 2;

t is independently 0, 1, 2, 3, 4, 5, or 6,

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound, according to claim 1 , as illustrated by Formula II:

wherein

R 1 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) halo,

(4) unsubstituted or substituted aryl,

(5) unsubstituted or substituted heterocycle,

(6) CF 3 ,

(7) —(CH 2 ) t R 9 C(O)R 8 ,

(8) —C(O)R 9 , and

(9) —(CH 2 ) t OR 8 ;

R 2 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl,

(3) unsubstituted or substituted aryl,

(4) unsubstituted or substituted heterocycle,

(5) unsubstituted or substituted C 2 –C 6 alkenyl,

(6) unsubstituted or substituted C 2 –C 6 alkynyl,

(7) OR 8 ,

(8) CN, and

(9) unsubstituted or substituted C 3 –C 10 cycloalkyl;

R 3 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aralkyl;

R 8 is independently selected from:

(1) H,

(2) unsubstituted or substituted C 1 –C 10 alkyl, and

(3) unsubstituted or substituted aryl;

R 9 is independently selected from

(1) unsubstituted or substituted aryl, and

(2) unsubstituted or substituted heterocycle;

V is selected from:

(1) a bond,

(2) aryl, and

(3) heterocycle;

m is 0, 1, or 2;

n is 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, or 4;

t is independently 0, 1, 2, 3, 4, 5, or 6,

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A compound selected from:

N-(3-chlorophenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine;

4-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

4-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

4-[1-(2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl) pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-{1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl }pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3-ethynylphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

4-(1-phenyl-1H-pyrazol-5-yl)-N-(4-piperazin-1-ylphenyl)pyrimidin-2-amine;

4-(1-phenyl-1H-pyrazol-5-yl)-N-(piperidin-4-ylmethyl)pyrimidin-2-amine;

methyl 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino }benzoate;

4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino }benzoic acid;

N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl }-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine;

4-(4-cyano-1H-pyrazol-5-yl)-2-[(3,5-dimethylphenyl)amino]pyrimidine;

or a pharmaceutically acceptable salt thereof.

5. The compound, according to claim 4 , which is selected from:

N-(3-chlorophenyl)-4-(1-phenyl1H-pyrazol-5-yl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine;

4-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3-ethynylphenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine;

N-(3,5-dimethylphenyl)-4-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]pyrimidin-2-amine

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

7. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.

8. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and breast carcinoma.

9. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier.

10. The composition of claim 6 further comprising a second compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

11. The composition of claim 10 , wherein the second compound is another angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.

12. The composition of claim 10 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.

13. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy.

14. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

15. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy and a compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) another angiogenesis inhibitor.

16. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab.

17. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist.

18. The method of claim 17 wherein the GPIIb/IIIa antagonist is tirofiban.

19. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a COX-2 inhibitor.