Macroheterocyclic compounds as kinase inhibitors

• US 20070088019A1
• Filed: 09/27/2006
• Published: 04/19/2007
• Est. Priority Date: 09/29/2005
• Status: Abandoned Application

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Ye, Hong, Kuo, Gee-Hong, Zhang, Han-Cheng, Maryanoff, Bruce
• Application Number:
  US11/528,092
• Publication Number:
  US 20070088019A1
• Time in Patent Office: Days
• US Class Current: 514/211.100
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 498/22 : in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 513/22 : in which the condensed system contains four or more hetero rings

Abstract

This invention is directed to macroheterocyclic compounds useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disease, condition or disorder.

Claims

1. A compound of Formula (I):

wherein

A is CH or N, whereby the A-containing ring system of Formula (I) thus forms 1H-indole or 1H-pyrrolo[2,3-b]pyridine, respectively;

Z is O, OH, or H, H;

R₁ and R₃ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkylthio, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxy(C_1-4)alkyl, cyano, nitro, amino, and amino(C_1-4)alkyl;

wherein amino and the amino portion of amino(C_1-4)alkyl are optionally and independently substituted with one to two C_1-4alkyl substituents;

R₄ and R₅ are independently C_2-8alkylene optionally substituted with oxo;

R₂ is —

N(R_a)—

C_1-4alkyl-X—

C_1-4alkyl-N(R_b), wherein C_1-4alkyl is optionally substituted with one to four substituents independently selected from the group consisting of C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkoxy(C_1-4)alkyl, carboxyl, carboxyl(C_1-4)alkyl, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonyl(C_1-4)alkyl, amino, amino(C_1-4)alkyl, halogen, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, and oxo;

wherein amino and the amino portion of amino(C_1-4)alkyl are optionally and independently substituted with one to two C_1-4alkyl substituents;

R_a and R_b are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl;

wherein C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with fluoro;

X is O or S;

such that the —

R₄—

R₂—

R₅—

containing macrocycle does not exceed 25 atoms in size;

and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein A is CH, whereby the A-containing ring system of Formula (I) thus forms 1H-indole.

3. The compound according to claim 1 wherein Z is O.

4. The compound according to claim 1 wherein R₁ and R₃ are independently selected from the group consisting of hydrogen, methyl, methoxy, halogen, and hydroxy.

5. The compound according to claim 4 wherein R₁ and R₃ are each hydrogen.

6. The compound according to claim 1 wherein R₄ and R₅ are each C_2-4alkylene.

7. The compound according to claim 6 wherein R₄ and R₅ are each ethylene.

8. The compound according to claim 1 wherein R₂ is —

N(R_a)—

C_1-4alkyl-X—

C_1-4alkyl-N(R_b).

9. The compound according to claim 8 wherein R₂ is —

N(R_a)—

CH₂CH₂—

X—

CH₂CH₂—

N(R_b).

10. The compound according to claim 1 wherein R_a and R_b are independently hydrogen or C_1-6alkyl.

11. The compound according to claim 10 wherein R_a and R_b are independently hydrogen or methyl.

12. The compound according to claim 1 wherein X is S.

13. The compound according to claim 1 wherein X is O.

23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

24. A method for treating a kinase or dual kinase-mediated disease, condition or disorder in a subject in need thereof comprising the step of administering to the subject a therapeutically effective amount of the compound of claim 1.

25. The method according to claim 24 wherein the kinases are selected from the group consisting of protein kinase C α

, protein kinase C β

, protein kinase C γ and

glycogen synthase kinase-3β

.

26. The method of claim 24 wherein said therapeutically effective amount comprises a dose range of from about 0.001 mg/kg/day to about 300 mg/kg/day.

27. The method of claim 24 wherein the disease, condition or disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS disorders, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

28. The method of claim 27 wherein cardiovascular diseases are selected from acute stroke, heart failure, cardiovascular ischemia and impaired cardiac function following ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity or age-related macular degeneration.

29. The method of claim 27 wherein diabetes is selected from insulin dependent diabetes or Type II non-insulin dependent diabetes mellitus.

30. The method of claim 27 wherein diabetes-associated disorders are selected from impaired glucose tolerance, insulin signaling defects, insulin resistance, metabolic syndrome X, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiac hypertrophy associated with heart failure, cardiomyopathy, nephropathy or neuropathy.

31. The method of claim 27 wherein inflammatory diseases are selected from neutrophil and cytokine migration, bone marrow degranulation, vascular permeability, inflammation, asthma, rheumatoid arthritis or osteoarthritis.

32. The method of claim 27 wherein immunological disorders are selected from transplant tissue rejection, HIV-1 transcription and viral replication or immunological disorders treated or ameliorated by PKC modulation.

33. The method of claim 27 wherein dermatological disorders are selected from psoriasis, hair loss or baldness.

34. The method of claim 27 wherein oncological disorders are selected from cancer or tumor growth and other diseases associated with uncontrolled cell proliferation such as recurring benign tumors as well as including proliferative angiopathy and angiogenesis.

35. The method of claim 34 wherein cancer or tumor growth is selected from breast, brain, kidney, bladder, ovarian or colon cancer or lymphocytic leukemia.

36. Use of the compound of claim 1 as an adjunct to chemotherapy and radiation therapy.

37. The method of claim 27 wherein CNS disorders are selected from chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, mood disorders and ischemia-related diseases.

38. The method of claim 37 wherein chronic neurodegenerative conditions are selected from dementia or Alzheimer'"'"'s disease.

39. The method of claim 37 wherein mood disorders are selected from schizophrenia, manic depression or neurotraumatic, cognitive decline.

40. The method of claim 37 wherein ischemia-related diseases are selected from diseases resulting from head trauma, such as from acute ischemic stroke, injury or surgery or from transient ischemic stroke, such as from coronary bypass surgery or other transient ischemic conditions.

41. The method of claim 24 wherein the disease, condition or disorder is selected from the group consisting of treating or ameliorating diabetes or Alzheimer'"'"'s disease.

42. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

43. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutical acceptable carrier.

44. Use of the compound of claim 1 in the manufacture of a medicament for treating or ameliorating a kinase or dual-kinase mediated disease, condition or disorder.

14. A compound of Formula (Ia):

wherein

R₁ and R₃ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkylthio, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxy(C_1-4)alkyl, cyano, nitro, amino, and amino(C_1-4)alkyl;

wherein amino and the amino portion of amino(C_1-4)alkyl are optionally and independently substituted with one to two C_1-4alkyl substituents;

R₄ and R₅ are independently C_2-8 alkylene optionally substituted with oxo;

R₂ is —

N(R_a)—

C_1-4alkyl-X—

C_1-4alkyl-N(R_b), wherein C_1-4alkyl is optionally substituted with one to four substituents independently selected from the group consisting of C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkoxy(C_1-4)alkyl, carboxyl, carboxyl(C_1-4)alkyl, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonyl(C_1-4)alkyl, amino, amino(C_1-4)alkyl, halogen, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, and oxo;

wherein amino and the amino portion of amino(C_1-4)alkyl are optionally and independently substituted with one to two C_1-4alkyl substituents;

R_a and R_b are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl;

wherein C_1-6alkyl, C₂-₆alkenyl, and C_2-6alkynyl are optionally substituted with fluoro;

X is O or S;

such that the —

R₄—

R₂—

R₅—

containing macrocycle does not exceed 25 atoms in size;

and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.

15. The compound according to claim 14 wherein:

R₁ and R₃ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, halogen, and hydroxy;

R₄ and R₅ are each C_2-4alkylene;

R₂ is —

N(R_a)—

C_1-4alkyl-X—

C_1-4alkyl-N(R_b)—

; and

,

R_a and R_b are independently hydrogen or C_1-4alkyl.

16. The compound according to claim 14 wherein R_a and R_b are independently hydrogen or methyl and R₁ and R₃ are independently selected from the group consisting of hydrogen, methyl, methoxy, halogen, and hydroxy.

17. The compound according to claim 14 wherein R₁ and R₃ are each hydrogen;

R₄ and R₅ are each ethylene;

R₂ is —

N(R_a)—

CH₂CH₂—

X—

CH₂CH₂—

N(R_b); and

R_a and R_b are independently hydrogen or methyl.

18. A compound of Formula (Ib):

wherein

R₄ and R₅ are independently C_2-8alkylene optionally substituted with oxo;

R₂ is —

N(R_a)—

C_1-4alkyl-X—

C_1-4alkyl-N(R_b)—

, wherein C_1-4alkyl is optionally substituted with one to four substituents independently selected from the group consisting of C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkoxy(C_1-4)alkyl, carboxyl, carboxyl(C_1-4)alkyl, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonyl(C_1-4)alkyl, amino, amino(C_1-4)alkyl, halogen, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, and oxo;

wherein amino and the amino portion of amino(C_1-4)alkyl are optionally and independently substituted with one to two C_1-4alkyl substituents;

R_a and R_b are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl;

wherein C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with fluoro;

X is O or S;

such that the —

R₄—

R₂—

R₅—

containing macrocycle does not exceed 25 atoms in size;

and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.

19. The compound according to claim 18 wherein R₄ and R₅ are each C_2-4alkylene;

and, R_a and R_b are independently hydrogen or C_1-4alkyl.

20. The compound according to claim 18 wherein R₄ and R₅ are each ethylene;

R₂ is-N(R_a)—

CH₂CH₂—

X—

CH₂CH₂—

N(R_b)—

; and

, R_a and R_b are independently hydrogen or methyl.

21. A compound selected from the group consisting of:

22. A compound selected from the group consisting of:

10,11,12,13,14,16,17,18,19,20-decahydro-15-thio-2,9,12,18,21-pentaaza-1H-diindolo[1,2,3-m,n;

3′

,2′

,1′

-r,s]cyclononadec-14,16,18-trien[16,17-c]-pyrrole-2,5-dione,

12,18-dimethyl-10,11,12,13,14,16,17,18,19,20-decahydro-15-oxa-2,9,12,18,21-pentaaza-1H-diindolo[1,2,3-m,n;

3′

,2′

,1′

-r,s]cyclononadec-14,16,18-trien[16,17-c]-pyrrole-2,5-dione,

10,11,12,13,14,16,17,18,19,20-decahydro-15-oxa-2,9,12,18,21-pentaaza-1H-diindolo[1,2,3-m,n;

3′

,2′

,1′

-r,s]cyclononadec-14,16,18-trien[16,17-c]-pyrrole-2,5-dione, and

18-methyl-10,11,12,13,14,16,17,18,19,20-decahydro-15-oxa-2,9,12,18,21-pentaaza-1H-diindolo[1,2,3-m,n;

3′

,2′

,1′

-r,s]cyclononadec-14,16,18-trien[16,17-c]-pyrrole-2,5-dione.