SUBSTITUTED 5,6-DIHYDRO-6-PHENYLBENZO[F]ISOQUINOLIN-2-AMINE COMPOUNDS

• US 20100239525A1
• Filed: 12/30/2009
• Published: 09/23/2010
• 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, Wu, Hui, Ashwell, Mark A., Liu, Yanbin, Vensel, David, Lapierre, Jean-Marc, Ali, Syed M., Yang, Rui-Yang, Westlund, Neil, Palma, Rocio, Namdev, Nivedita, Kelleher, Eugene, Eathiraj, Sudharshan
• Granted Patent: US 8,357,694 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: C07D 221/10 Aza-phenanthrenes
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention relates to substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-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 I:

2. The compound of claim 1 having the formulae III or IIIa:

3. The compound of claim 2, wherein R_c is cyano.

4. The compound of claim 2, wherein:

R₁ is H;

R₂ is -T₁-Q₁; and

R_p1, R_p2, R_p3, R_p4 and R_p5 are each independently H, halogen, —

NR₄R₅, —

NR₆C(O)R₄, or —

NR₆S(O)₂R₄.

5. The compound of claim 4, wherein:

T₁ is a bond; and

Q₁ is unsubstituted or substituted phenyl, or —

C(O)OR₇.

6. The compound of claim 5, wherein Q₁ 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 C₆-C₁₀ aryloxy, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

7. The compound of claim 6, wherein said C₁-C₆ alkyl is substituted with amino, wherein said amino is substituted with one or two groups, each of which can be the same or different, selected from unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₀ aryl-C₁-C₆ alkyl, unsubstituted or substituted heteroaryl-C₁-C₆ alkyl, unsubstituted or substituted heterocycle-C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

8. The compound of claim 7, wherein said amino is substituted with one or two unsubstituted or substituted C₁-C₆ alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

9. The compound of claim 8, wherein said C₁-C₆ alkyl is substituted with C₁-C₆ alkoxy selected from methoxy, ethoxy, propyloxy, and i-propyloxy.

10. The compound of claim 7, wherein said amino is substituted with one or two unsubstituted or substituted C₃-C₁₀ carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

11. The compound of claim 7, wherein said amino is substituted with two groups, each of which can be the same or different, selected from:

unsubstituted or substituted C₁-C₆ alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl; and

unsubstituted or substituted C₃-C₁₀ carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

12. The compound of claim 6, wherein said C₁-C₆ alkyl is substituted with unsubstituted or substituted heterocycle selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, and morpholinyl.

13. The compound of claim 5, wherein Q₁ is —

C(O)OR₇, wherein;

R₇ is -T₃-Q₃;

T₃ is unsubstituted or substituted C₁-C₆ alkyl linker;

Q₃ is H, hydroxyl, halogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, unsubstituted or substituted C₆-C₁₀ aryloxy, unsubstituted or substituted amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings 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 rings and 1-4 heteroatoms selected from N, O and S.

14. The compound of claim 13, wherein T₃ is a methyl, ethyl, or n-propyl linker.

15. The compound of claim 14, wherein Q₃ is H.

16. The compound of claim 14, wherein Q₃ is unsubstituted or substituted C₁-C₆ alkylamino selected from dimethylamino, diethylamino, dipropylamino, and dibutylamino.

17. The compound of claim 5, wherein R_p1, R_p2, R_p3, R_p4 and R_p5 are each independently H, or halogen selected from fluorine, chlorine, and bromine.

18. The compound of claim 4, wherein:

T₁ is unsubstituted or substituted C₁-C₆ alkyl linker; and

Q₁ is unsubstituted or substituted di-C₁-C₆ alkylamino, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

19. The compound of claim 18, wherein said unsubstituted or substituted di-C₁-C₆ alkylamino is selected from dimethylamino, diethylamino, dipropylamino, and di-i-propylamino.

20. The compound of claim 18, wherein said unsubstituted or substituted heterocycle is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyranyl, and dihydrobenzodioxinyl.

21. The compound of claim 18, wherein R_p1, R_p2, R_p3, R_p4 and R_p5 are each independently H, —

NR₄R₅, —

NR₆C(O)R₄, or —

NR₆S(O)₂R₄.

22. The compound of claim 21, wherein:

R₆ is H;

R₄ is -T₂-Q₂;

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

Q₂ is unsubstituted or substituted phenyl.

23. The compound of claim 22, wherein Q₂ 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 C₆-C₁₀ aryloxy, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

24. The compound of claim 4, selected from:

25. The compound of claim 1 having the formula II:

35. The compound according to claim 1, wherein the compound is selected from a compound of any one of Tables 1-23.

36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 35, or salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

37. 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 36, wherein said cell proliferation disorder is treated.

38. The method of claim 37, wherein said cell proliferative disorder is a precancerous condition.

39. The method of claim 37, wherein said cell proliferative disorder is a hematologic tumor or malignancy.

40. The method of claim 37, wherein said cell proliferative disorder is a solid tumor.

41. The method of claim 37, wherein said cell proliferative disorder is a cancer.

42. The method of claim 41, 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.

43. The method of claim 41, wherein said cancer is a metastatic cancer.

44. The method of claim 37, wherein said subject is a human.

45. The method of claim 37, further comprising administering a therapeutically effective amount of a second anti-proliferative agent.

46. The method of claim 45, 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.

47. The method of claim 45, wherein the second anti-proliferative agent is (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

48. The method of claim 37, further comprising administering radiation therapy.

26. The compound of claim 26, wherein:

R₁ is H;

R₂ is -T₁-Q₁;

G is —

S(O)₂—

, —

C(O)—

, —

C(O)NR₆—

, or —

(CH₂)_m—

;

R₆ is H; and

m is 0 or 1.

27. The compound of claim 26, wherein:

T₁ is unsubstituted or substituted C₁-C₆ alkyl linker;

Q₁ is H or unsubstituted or substituted phenyl; and

R₃ is H or unsubstituted or substituted phenyl.

28. The compound of claim 27, wherein T₁ is a methyl linker.

29. The compound of claim 28, wherein Q₁ is H.

30. The compound of claim 29, wherein R₃ 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 C₆-C₁₀ aryloxy, amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, and unsubstituted or substituted C₁-C₆ alkylcarbonylamino.

31. The compound of claim 30, wherein R₃ is phenyl substituted with one or more groups, each of which can be the same or different, selected from halogen, cyano, unsubstituted C₁-C₆ alkyl, and unsubstituted C₁-C₆ alkoxy.

32. The compound of claim 28, wherein R₃ is H;

G is —

(CH₂)_m—

; and

m is 0.

33. The compound of claim 32, wherein Q₁ 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 C₆-C₁₀ aryloxy, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

34. The compound of claim 26, selected from: