Azaindoles useful as inhibitors of JAK and other protein kinases

• US 20070043063A1
• Filed: 03/30/2005
• Published: 02/22/2007
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Court, John, Come, Jon, Farmer, Luc, Wang, Tiansheng, Green, Jeremy, Wang, Jian, Aronov, Alex, Lauffer, David, Harrington, Edmund, Bethiel, Randy, Salituro, Francesco, Binch, Hayley, Fraysse, Damien, Boyall, Dean, Charrier, Jean-Damien, Mortimore, Michael, Everitt, Simon, Pierard, Francoise, Robinson, Daniel, Pinder, Joanne
• Granted Patent: US 7,507,826 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 27/06 : Antiglaucoma agents or miotics
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07F 7/0805 : comprising only Si, C or H atoms

Abstract

The present invention relates to inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein:

a) R¹ is T-R′

, wherein T is a bond or is an optionally substituted C₁-C₆alkylidene chain wherein up to two methylene units are optionally and independently replaced with —

O, —

S—

, —

NR′

—

, —

OCO—

, —

COO—

, —

SO₂—

or —

CO—

, and R′

is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered aryl or heteroaryl group;

or

R¹ is —

Si(R′

)₃, R′

is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5. The compound of claim 1, wherein R², R³, and R⁴ are each independently hydrogen, R′

, halogen, CN, NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COCH2R′

, or —

NR′

CO(CH₂)₂R′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

(CH₂)₂N(R′

)₂, —

CONR′

(CH₂)₃N(R′

)₂, —

CONR′

(CH₂)₄N(R′

)₂, —

O(CH₂)₂OR′

, O(CH₂)₃OR′

, O(CH₂)₄OR′

, —

O(CH₂)₂N(R′

)₂, —

O(CH₂)₃N(R′

)₂, or —

O(CH₂)₄N(R′

)₂.

11. The compound of claim 1, wherein two of X¹, X², or X³ is N, and the remaining one of X¹, X², or X³ is CH, wherein the hydrogen atom of CH is optionally replaced by R⁵.

12. The compound of claim 1, wherein one of X¹, X², or X³ is N, and the remaining two of X¹, X², or X³ is CH, wherein the hydrogen atom of CH is optionally replaced by R⁵.

14. The compound of claim 1, wherein compounds have one of formulae I-A, I-B, I-C or I-D:

15. The compound of claim 1, wherein each occurrence of R⁵ is independently hydrogen, R′

, —

CH₂R′

, halogen, CN, NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COCH₂R′

, —

NR′

CO(CH₂)₂R′

, —

NR′

COOR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

(CH₂)₂N(R′

)₂, —

CONR′

(CH₂)₃N(R′

)₂, —

CONR′

(CH₂)₄N(R′

)₂, —

O(CH₂)₂OR′

, O(CH₂)₃OR′

, O(CH₂)₄OR′

, —

O(CH₂)₂N(R′

)₂, —

O(CH₂)₃N(R′

)₂, —

O(CH₂)₄N(R′

)₂, —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

(CH₂)R′

, —

NR′

(CH₂)₂R′

, —

NR′

(CH₂)₃R′

, —

NR′

(CH₂)₄R′

, —

NR′

(CH₂)N(R′

)₂, —

NR′

(CH₂)₂N(R′

)₂, —

NR′

(CH₂)₃N(R′

)₂, —

NR′

(CH₂)₄N(R′

)₂, —

NR′

(CH₂)OR′

, —

NR′

(CH₂)₂OR′

, —

NR′

(CH₂)₃OR′

, or —

NR′

(CH₂)₄OR′

.

31. The compound according to claim 1, wherein the compound has one of formulae I-A, I-B or I-E:

32. The compound according to claim 31, wherein R² and R⁴ are each independently selected from H, Cl, Br, F, —

CN, —

COOH, —

COOR′

, —

NH₂, —

N(CH₃)₂, —

N(Et)₂, —

N(iPr)₂, —

NHR′

, —

OR′

, —

SR′

, —

O(CH₂)₂OCH₃, —

CONH₂, —

CONHR′

, CON(R′

)₂, —

OH, —

CH₂OH, CH₂NH₂, —

CH₂NHR′

, —

CH2N(R′

)₂, —

C(R′

)₂N(R′

)₂, —

NHCOCH₃, —

N(R′

)COR′

, —

SO₂NH₂, —

SO₂N(Me)₂, or an optionally substituted group selected from C₁-C₆ aliphatic, C₁-C₆ alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

34. The compound according to claim 31, wherein R¹ is selected from hydrogen, C₁-C₄alkyl, —

COR′

, —

SO₂R′

, or —

Si(R′

)₃.

36. The compound according to claim 31, wherein R³ is selected from H, Cl, Br, F, —

CN, —

COOH, —

COOMe, —

NH₂, —

N(R′

)₂, —

NO₂, —

OR′

, —

CON(R′

)₂, —

COOR′

, —

OH, —

SR′

, —

C(R′

)₂OR′

, —

N(R′

)COR′

, —

N(R′

)C(O)OR′

, —

SO₂NH₂, —

SO₂N(R′

)₂, or an optionally substituted group selected from C₁-C₄ aliphatic, C₁-C₄ alkyloxy or —

C≡

C—

C₁-C₄ aliphatic.

44. The compound according to claim 31, wherein x is 1, 2, or 3;

wherein each occurrence of R⁵ is independently selected from R′

, —

CH₂R′

, halogen, CN, NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COR⁸R′

, —

NR′

COOR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

R⁸N(R′

)₂, —

OR⁸OR′

, —

OR⁸N(R′

)₂, —

NR′

CH(R⁹)R′

, —

NR′

CH(R⁹)C(O)OR′

, —

N(R′

)R⁸R′

, —

N(R′

)R⁸R′

, —

N(R′

)R⁸N(R′

)₂, —

N(R′

) R⁸OR′

, —

NR′

CH(R⁹)R′

, —

NR′

CH₂C(O)N(R′

)₂, or —

NR′

CH(R⁹)C(O)N(R′

)₂, wherein R⁸ is an optionally substituted C₁-C₄ alkyl and R⁹ is an optionally substituted C₁-C₆ aliphatic.

55. The compound according to claim 31, wherein x is 2, 3 or 4 and at least two R⁵ on adjacent ring members are R′

, and wherein said two R⁵ are taken together with the atoms to which they are bound to form an optionally substituted 3-12 membered saturated, partially saturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

58. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

60. A method of inhibiting JAK-3, ROCK or Aurora kinase activity in a biological sample, comprising the step of contacting said biological sample with:

a) a compound according to claim 1;

or

b) a a composition comprising said compound.

61. A method of treating or alleviating a disease or disorder selected from immune responses such as allergic or type I hypersensitivity reactions or asthma;

autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis;

neurodegenerative disorders;

or solid and hematologic malignancies, comprising administering to a patient in need thereof a compound according to claim 1 or a composition comprising said compound.

62. The method of claim 61, comprising the further step of administering to said patient an additional therapeutic agent

65. A method of treating, preventing or lessening the severity of a disease or disorder selected from heart disease, diabetes, Alzheimer'"'"'s disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders, osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases, viral diseases, hyperplasia, reperfusion/ischemia in stroke, heart attacks, organ hypoxia, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, hepatic ischemia, myocardial infarction, congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders comprising administering to a patient in need thereof a compound according to claim 1 or claim 31 or a composition comprising said compound.

3-4. -4. (canceled)

6-10. -10. (canceled)

13. (canceled)

16-29. -29. (canceled)

30. A compound selected from Table 1.

33. (canceled)

35. (canceled)

37-43. -43. (canceled)

45-54. -54. (canceled)

56. (canceled)

57. A compound selected from Table 2.

59. (canceled)

63-64. -64. (canceled)

66. (canceled)