Inhibitors of protein arginine methyl transferases

• US 20070060589A1
• Filed: 12/20/2005
• Published: 03/15/2007
• Est. Priority Date: 12/21/2004
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Chen, Zhong, Purandare, Ashok
• Application Number:
  US11/312,812
• Publication Number:
  US 20070060589A1
• Time in Patent Office: Days
• US Class Current: 514/252.50
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• 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 405/12 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 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• 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, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein:

Ring Q is phenyl;

5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S;

or 6-membered heteroaryl, in which Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently C, or N, and at least one of Z₁, Z₂, Z₃, Z₄ and Z₅ is N;

W is —

C(═

O)NR₈—

, —

NR₉C(═

O)—

, —

NR₉C(═

O)NR₉—

,

alternatively, W—

(CH₂)—

(O)n-R₇ is

R₁ is H, halogen, CN, alkyl or substituted alkyl, O—

C₁-C₄ alkyl, S—

C₁-C₄ alkyl, or SO₂—

C₁-C₄ alkyl;

R₂ is H or C₁-C₄ alkyl;

R₃ is H, Me or Et, or optionally R₃ together with R₄ may form a 5- or 6-membered heterocycle

R₄ is H, Me, Et, iso-propyl, CH₂Ph, OH, or OPh, or optionally R₄ together with R₃ may form a 5- or 6-membered heterocycle;

R₅ is nil, H, Me, Et, propyl, iso-propyl, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃;

R₆ is nil, H, Me, or Et, or optionally R₆ together with R₈ may form a 5- or 6-membered heterocycle;

R₇ is cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl;

R₈ is H, or Me, or optionally R₈ together with R₆ may form a 5- or 6-membered heterocycle;

or alternatively R₈ together with R₇ may form a 5- or 6-membered heterocycle or substituted heterocycle;

R₉ is H, or Me;

R₁₀ is hydrogen, halogen, haloalkyl, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR, SR, S(═

O)R, S(═

O)₂R, P(═

O)₂R, S(═

O)₂OR, P(═

O)₂OR, NRR, NRS(═

O)₂R, NRP(═

O)₂R, S(═

O)₂NRR, P(═

O)₂NRR, C(═

O)OR, C(═

O)R, C(═

O)NRR, OC(═

O)R, OC(═

O)NRR, NRC(═

O)OR, NRC(═

O)NRR, NRS(═

O)₂NRR, NRP(═

O)₂NRR, NR_bC(═

O)R_a, or NRP(═

O)₂R, wherein R is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl;

m is 0, 1, 2 or 3;

n is 0 or 1; and

p is 1, 2 or 3.

2. The compound of claim 1, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S;

or 6-membered heteroaryl, in which Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently C, or N, and at least one of Z₁, Z₂, Z₃, Z₄ and Z₅ is N.

3. The compound of claim 2, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

4. The compound of claim 3, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

5. The compound of claim 4, wherein R₇ is aryl or substituted aryl.

6. The compound of claim 5, wherein R₇ is phenyl or substituted phenyl.

7. The compound of claim 1, wherein W is —

C(═

O)NR₈—

.

8. The compound of claim 7, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

9. The compound of claim 8, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

10. The compound of claim 9, wherein R₇ is aryl or substituted aryl.

11. The compound of claim 10, wherein R₇ is phenyl or substituted phenyl.

12. The compound of claim 1, wherein W is

13. The compound of claim 12, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

14. The compound of claim 13, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

15. The compound of claim 14, wherein R₇ is aryl or substituted aryl.

16. The compound of claim 15, wherein R₇ is phenyl or substituted phenyl.

17. The compound of claim 1, wherein R₂ is H, R₃ is H, R₄ is Me, Et, OH, or Ph.

18. The compound of claim 17, wherein R₄ is Me.

19. The compound of claim 18, wherein R₄ is (S—

) Me.

20. The compound of claim 19, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

21. The compound of claim 20, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

22. The compound of claim 19, wherein W is —

C(═

O)NR₈—

.

23. The compound of claim 22, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

24. The compound of claim 23, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

25. The compound of claim 19, wherein W is

26. The compound of claim 25, wherein ring Q is 5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S.

27. The compound of claim 26, wherein Z₄ is a bond, Z₁ and Z₂, are each independently N;

Z₃ and Z₅ are each independently C.

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

29. A pharmaceutical composition of claim 28, further comprising at least one other anti-cancer agent or cytotoxic agent.

30. The pharmaceutical composition of claim 29, wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine, paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers, androgen receptor antagonists, LH/RH antagonists, taxane analogues, and estrogen receptor antagonists.

33. A method for treating cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound having the formula I according to claim 1, wherein the cancer is breast cancer, lung cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, glioblastoma, brain cancer, melanoma, or colon cancer.

31. A method of inhibiting the activity of CARM-1 which comprises administering to a mammalian species in need thereof an effective amount of at least one compound of formula I:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof,

wherein;

Ring Q is phenyl;

5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S;

or 6-membered heteroaryl, in which Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently C, or N, and at least one of Z₁, Z₂, Z₃, Z₄ and Z₅ is N;

W is —

C(═

O)NR₈—

, —

NR₉C(═

O)—

,

R₁ is H, halogen, CN, alkyl or substituted alkyl, O—

C₁-C₄ alkyl, S—

C₁-C₄ alkyl, or SO₂—

C₁-C₄ alkyl;

R₂ is H or C₁-C₄ alkyl;

R₃ is H, Me or Et, or optionally R₃ together with R₄ may form a 5- or 6-membered heterocycle

R₄ is H, Me, Et, iso-propyl, CH₂Ph, OH, or OPh, or optionally R₄ together with R₃ may form a 5- or 6-membered heterocycle;

R₅ is nil, H, Me, Et, propyl, iso-propyl, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃;

R₆ is nil, H, Me, or Et, or optionally R₆ together with R₈ may form a 5- or 6-membered heterocycle;

R₇ is cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl;

R₈ is H, or Me, or optionally R₈ together with R₆ may form a 5- or 6-membered heterocycle;

or alternatively R₈ together with R₇ may form a 5- or 6-membered heterocycle or substituted heterocycle;

R₉ is H, or Me;

m is 0, 1, 2 or 3;

n is 0 or 1; and

p is 1, 2 or 3.

32. 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 formula I:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof,

wherein;

Ring Q is phenyl;

5-membered heteroaryl, in which Z₄ is a bond, Z₁, Z₂, Z₃ and Z₅ are each independently C, N, O, or S, and at least one of Z₁, Z₂, Z₃ and Z₅ is a heteroatom selected from N, O and S;

or 6-membered heteroaryl, in which Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently C, or N, and at least one of Z₁, Z₂, Z₃, Z₄ and Z₅ is N;

W is —

C(═

O)NR₈—

, —

NR₉C(═

O)—

,

R₁ is H, halogen, CN, alkyl or substituted alkyl, O—

C₁-C₄ alkyl, S—

C₁-C₄ alkyl, or SO₂—

C₁-C₄ alkyl;

R₂ is H, or C₁-C₄ alkyl;

R₃ is H, Me or Et, or optionally R₃ together with R₄ may form a 5- or 6-membered heterocycle

R₄ is H, Me, Et, iso-propyl, CH₂Ph, OH, or OPh, or optionally R₄ together with R₃ may form a 5- or 6-membered heterocycle;

R₅ is nil, H, Me, Et, propyl, iso-propyl, OMe, OEt, SMe, SO₂Me, CF₃, or OCF₃;

R₆ is nil, H, Me, or Et, or optionally R₆ together with R₈ may form a 5- or 6-membered heterocycle;

R₇ is cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl;

R₈ is H, or Me, or optionally R₈ together with R₆ may form a 5- or 6-membered heterocycle;

or alternatively R₈ together with R₇ may form a 5- or 6-membered heterocycle or substituted heterocycle;

R₉ is H, or Me;

m is 0, 1, 2 or 3;

n is 0 or 1; and

p is 1, 2 or 3; and

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.