SUBSTITUTED 1H-PYRAZOLO[3,4-D]PYRIMIDINE-6-AMINE COMPOUNDS

• US 20100172867A1
• Filed: 12/30/2009
• Published: 07/08/2010
• Est. Priority Date: 12/30/2008
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Tandon, Manish, Hill, Jason, Ashwell, Mark A., Lapierre, Jean-Marc, Moussa, Magdi, Ali, Syed M., Nicewonger, Robert, Yang, Rui-Yang, Namdev, Nivedita
• Granted Patent: US 8,273,754 B2
• Time in Patent Office: Days
• US Class Current: 424/85.400
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to substituted 1H-pyrazolo-[3,4-d]pyrimidine-6-amine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted 1H-pyrazolo-[3,4-d]pyrimidine-6-amine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

Claims

1. A compound having the formula Ia:

or a salt, solvate, hydrate or prodrug thereof, wherein;

R_n4 is H, or unsubstituted or substituted C₁-C₆ alkyl;

R_q1 is H, unsubstituted or substituted C₁-C₆ alkyl;

R_q2 is H, unsubstituted or substituted C₁-C₆ alkyl,

or R_q1 and R_q2, together with the atoms they attach to, form a 5- or 6-membered ring, wherein said ring is optionally unsaturated and optionally contains from 1 to 4 heteroatoms selected form N, O and S, and is optionally substituted;

Z is —

(CH₂)_m—

, —

C(O)—

, —

C(O)C(O)—

, —

C(O)O—

, —

C(O)NR₁—

, —

S(O)₂—

, —

S(O)₂NR₁—

or a bond;

R₁ is H, or unsubstituted or substituted C₁-C₆ alkyl;

R is unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, unsubstituted or substituted C₆-C₁₀ aryloxy, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S, —

C(O)R₂, —

C(O)OR₂, —

C(O)NR₂R₂′

, —

NR₂R₂′

, —

NR₂′

C(O)R₂, or —

NR₂′

C(O)OR₂;

R₂ and R₂′

are each independently H, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S;

m is 0, 1, 2, 3, or 4, and

w is 1 or 2.

2. The compound according to claim 1, having the formula IIe:

or a salt, solvate, hydrate or prodrug thereof, wherein

R_p is unsubstituted or substituted C₁-C₆ alkyl, hydroxyl, halogen, cyano, nitro, —

C(O)R₃, —

C(O)OR₃, —

NR₃R₃′

, —

NR₃′

C(O)R₃, or —

NR₃′

C(O)OR₃;

R₃ and R₃′

are each independently H, or unsubstituted or substituted C₁-C₆ alkyl; and

n is 0, 1, 2, 3, or 4.

3. The compound of claim 2, wherein R_n4 is H and n is 0.

4. The compound of claim 3, wherein R is unsubstituted or substituted phenyl.

5. The compound of claim 4, wherein R is phenyl substituted with one or more groups, each of which can be the same or different, selected from hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, unsubstituted or substituted aryloxy, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member ring and 1-4 heteroatoms selected from N, O and S, -T₂-Q₂, —

OR₄, —

C(O)R₆, —

C(O)OR₆, —

C(O)NR₆R₆′

, —

S(O)₂R₆, —

S(O)₂NR₆R₆′

, —

NHC(O)R₆, —

NHC(O)OR₆, and —

NHC(O)NR₆R₆′

wherein;

T₂ is a bond, or unsubstituted or substituted C₁-C₆ alkyl linker;

Q₂ is —

C(O)R₅, or —

C(O)OR₅;

R₅ is H, or unsubstituted or substituted C₁-C₆ alkyl;

R₄ is unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted or substituted C₃-C₁₀ carbocycle;

R₆ and R₆′

are each independently H, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₅ aryl, or -T₃-Q₃;

T₃ is a bond, or unsubstituted or substituted C₁-C₆ alkyl linker; and

Q₃ is unsubstituted or substituted C₆-C₁₀ aryl.

6. The compound of claim 5, wherein Z is —

(CH₂)_m—

.

7. The compound of claim 6, wherein m is 1 or 2.

8. The compound of claim 7, wherein R is phenyl substituted with one or more groups, each of which can be the same or different, selected from halogen, cyano, unsubstituted or substituted C₁-C₆ alkyl, and unsubstituted or substituted C₁-C₆ alkoxy.

9. The compound of claim 8, wherein said halogen is selected from fluorine, chlorine, and bromine.

10. The compound of claim 8, wherein said unsubstituted or substituted C₁-C₆ alkoxy is selected from methoxy, ethoxy, propyloxy, i-propyloxy, and butoxy.

11. The compound of claim 8, wherein said unsubstituted or substituted C₁-C₆ alkoxy is methoxy.

12. The compound of claim 8, wherein R is phenyl substituted with two groups, each of which can be the same or different, selected from halogen, cyano, unsubstituted or substituted C₁-C₆ alkyl, and unsubstituted or substituted C₁-C₆ alkoxy.

13. The compound of claim 5, wherein Z is —

S(O)₂—

.

14. The compound of claim 13, wherein R is phenyl substituted with one or more groups, each of which can be the same or different, selected from halogen, unsubstituted or substituted C₁-C₆ alkyl, and —

NHC(O)NR₆R₆′

, wherein R₆′

is H and R₆ is unsubstituted or substituted phenyl.

15. The compound of claim 14, wherein said halogen is selected from fluorine, chlorine, and bromine.

16. The compound of claim 14, wherein R₆ is phenyl substituted with one or more groups, each of which can be the same or different, selected from methyl, trifluoromethyl, chlorine, fluorine, bromine, and cyano.

17. The compound of claim 2, selected from:

and a salt, solvate, hydrate or prodrug thereof.

18. The compound according to claim 1 having the formula IIIb:

or a salt, solvate, hydrate or prodrug thereof, wherein

R_p is unsubstituted or substituted C₁-C₆ alkyl, hydroxyl, halogen, cyano, nitro, —

C(O)R₃, —

C(O)OR₃, —

NR₃R₃′

, —

NR₃′

C(O)R₃, or —

NR₃′

C(O)OR₃;

R₃ and R₃′

are each independently H, or unsubstituted or substituted C₁-C₆ alkyl; and

n is 0, 1, 2, 3, or 4.

19. The compound of claim 18, wherein R_n4 is H and n is 0.

20. The compound according to claim 1 or a salt, solvate, hydrate, or prodrug thereof, wherein the compound is selected from a compound of Table 1.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 20, or a salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

22. A method of treating a cell proliferative disorder, comprising administering, to a subject in need thereof, a therapeutically effective amount of the composition of claim 21, wherein said cell proliferation disorder is treated.

23. The method of claim 22, wherein said cell proliferative disorder is a precancerous condition.

24. The method of claim 22, wherein said cell proliferative disorder is a hematologic tumor or malignancy.

25. The method of claim 22, wherein said cell proliferative disorder is a solid tumor.

26. The method of claim 22, wherein said cell proliferative disorder is a cancer.

27. The method of claim 26, wherein said cancer is lung cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, renal cancer, cervical cancer, brain, gastric/stomach cancer, bladder cancer, endometrial cancer, uterine cancer, intestinal cancer, hepatic cancer, chronic myelogenous leukemia, melanoma, ovarian cancer, translocation-associated renal cell carcinoma (RCC), alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), or hepatocellular carcinoma.

28. The method of claim 26, wherein said cancer is a metastatic cancer.

29. The method of claim 22, wherein said subject is a human.

30. The method of claim 22, further comprising administering a therapeutically effective amount of a second anti-proliferative agent.

31. The method of claim 30, wherein the second anti-proliferative agent is a kinase inhibitor, an alkylating agent, an antibiotic, an anti-metabolite, a detoxifying agent, an interferon, a polyclonal or monoclonal antibody, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, or a cytidine analogue drug.

32. The method of claim 22, further comprising administering radiation therapy.