Heterocyclic inhibitors of protein arginine methyl transferases

• US 20060235037A1
• Filed: 04/13/2006
• Published: 10/19/2006
• Est. Priority Date: 04/15/2005
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wan, Honghe, Huynh, Tram N., Purandare, Ashok Vinayak
• Application Number:
  US11/403,790
• Publication Number:
  US 20060235037A1
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

A compound of formula I, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof, methods of using such compounds in the treatment of hyperproliferative, inflammatory, infectious, and immunoregulatory disorders and diseases; and to pharmaceutical compositions containing such compounds.

Claims

1. A compound of formula I, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein:

Ring Q is

bond (a) is an optional double or single bond;

X is C (i.e., carbon) or N (i.e., nitrogen);

Y is NH, N-Me, or CH;

Z is N-R₆, O, or S, where R₆ is C₁-C₆ alkyl;

wherein when bond (a) is a single bond, X is —

CR—

, R is indenpendently H or C_1-4 alkyl and CR₂ is H or C_1-4 alkyl;

alternatively, R₂ and R may join to form a 3-6 membered cycloalkyl ring;

A, B and D are each independently N or C, in which C may be optionally substituted with H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃;

R₁ is aryl, substituted aryl, aryalkyl, heterocycle, or substituted heterocycle;

R₂ is H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃, provided that when X is N, R₂ is nil;

R₃ is H or C₁-C₄ alkyl; and

R₄ is independently H or C_1-4 alkyl;

R₅ is independently H, C_1-4 alkyl;

alternatively, R₅ and R₃ may join to form a 4, 5, or 6 membered saturated ring containing one N; and

n is 1, 2, or 3.

2. A compound of claim 1, wherein the compound is of formula Id

wherein:

Ring Q is

X is C (i.e., carbon) or N (i.e., nitrogen);

Y is NH, N-Me, or CH;

A, B and D are each independently N or C, in which C may be optionally substituted with H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃;

R₁ is aryl, substituted aryl, aryalkyl, heterocycle, or substituted heterocycle;

R₂ is H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃, provided that when X is N, R₂ is nil;

R₃ is H or C₁-C₄ alkyl; and

R₄ is independently H or C_1-4 alkyl; and

n is 1, 2, or 3.

3. The compound of claim 1, wherein ring Q is

4. The compound of claim 3, wherein A, B and D are each independently C, which may be optionally substituted with H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃.

5. The compound of claim 3, wherein R₁ is aryl or substituted aryl.

6. The compound of claim 3, wherein R₁ is heteroaryl or substituted heteroaryl.

7. The compound of claim 3, wherein A, B and D are each independently C, which may be optionally substituted with H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃.

8. The compound of claim 7, wherein R₁ is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

9. The compound of claim 8, wherein n is 1.

10. The compound of claim 9, wherein R₃ is Me.

11. The compound of claim 1 having the following substructure Ia,

wherein:

Ring Q is

R₁ is aryl, substituted aryl, heterocycle, or substituted heterocycle;

R₃ is H or C₁-C₄ alkyl;

R₂, R₄, R₅ and R₆ are each independently H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF3; and

n is 1, 2, or 3.

12. The compound of claim 1 having the following substructure Ib,

wherein:

Ring Q is

R₁ is aryl, substituted aryl, heterocycle, or substituted heterocycle;

R₃ is H or C₁-C₄ alkyl;

R₄, R₅ and R₆ are each independently H, Me, Et, halogen, CN, NO₂, OMe, OEt, SMe, SO₂Me, CF₃, or OCF3; and

n is 1, 2, or 3.

13. The compound of claim 12, wherein ring Q is

14. The compound of claim 13, wherein R₁ is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

15. The compound of claim 14, wherein n is 1.

16. The compound of claim 14, wherein R₄ and R₅ are each independently H.

17. The compound of claim 16, wherein R₆ is H or Me.

18. The compound of claim 17, wherein R₃ is Me.

19. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

20. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound of claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof,

wherein said condition or disorder is selected from the group consisting of proliferate diseases, cancers, benign prostate hypertrophia, benign prostatic hyperplasia, adenomas and neoplasies of the prostate, benign or malignant tumor cells containing the androgen receptor, brain cancer, skin cancer, bladder cancer, lymphatic cancer, liver cancer, kidney cancer, pancreatic cancer, prostate cancer, hirsutism, acne, precocious puberty, angiogenic conditions or disorders, hyperpilosity, inflammation, immune modulation, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppressing spermatogenesis, male and female sexual dysfunction, libido, cachexia, anorexia, inhibition of muscular atrophy in ambulatory patients, androgen supplementation for age related decreased testosterone levels in men, cancers expressing the estrogen receptor, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, hot flushes, vaginal dryness, menopause, amennoreahea, dysmennoreahea, contraception, pregnancy termination, cancers containing the progesterone receptor, cyclesynchrony, meniginoma, fibroids, labor induction, autoimmune diseases, Alzheimer'"'"'s disease, psychotic disorders, drug dependence, non-insulin dependent Diabetes Mellitus, dopamine receptor mediated disorders, heart disease, congestive heart failure, disregulation of cholesterol homeostasis, and attenuating the metabolism of a pharmaceutical agent.