Azaindoles useful as inhibitors of JAK and other protein kinases

• US 8,188,281 B2
• Filed: 11/19/2008
• Issued: 05/29/2012
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Salituro, Francesco, Farmer, Luc, Bethiel, Randy, Harrington, Edmund, Green, Jeremy, Come, Jon, Lauffer, David, Aronov, Alex, Binch, Hayley, Boyall, Dean, Charrier, Jean-Damien, Everitt, Simon, Fraysse, Damien, Mortimore, Michael, Pierard, Francoise, Robinson, Daniel, Wang, Jian, Pinder, Joanne, Wang, Tiansheng, Pierce, Albert, Court, John
• Primary Examiner(s): Chandrakumar, Nizal
• Application Number:
  US12/273,799
• Publication Number:
  US 20090176763A1
• Time in Patent Office: 1,287 Days
• Field of Search: 546/113
• US Class Current: 546/113
• 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-B)

2. The compound according to claim 1, wherein y is 1, 2, or 3 and each occurrence of R⁷ is independently —

F, —

Cl, —

Br, —

CN, —

OH, —

NH₂, —

CH₂OH, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

CH₂O(C₁-C₆ alkyl), —

CO(C₁-C₆ alkyl), —

COO(C₁-C₆ alkyl), —

NHSO₂(C₁-C₆ alkyl), —

SO₂NH₂, —

CONH₂, —

CONH(C₁-C₆ alkyl), —

SO₂(C₁-C₆ alkyl), —

SO₂-phenyl, phenyl, benzyl, —

N(C₁-C₆ alkyl)₂, or —

S(C₁-C₆ alkyl), wherein each of the foregoing phenyl, benzyl, and C₁-C₆ alkyl groups is independently and optionally substituted, and wherein each of the foregoing C₁-C₆ alkyl groups is linear, branched, or cyclic.

3. The compound according to claim 1, wherein R², R³, and R⁴ are each independently selected from hydrogen, R′

, halogen, —

CN, —

NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

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, wherein each occurrence of R′

in R², R³, and R⁴ is independently hydrogen or an optionally substituted group selected from a C₁-C₆ aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R′

are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated or partially unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The compound according to claim 1 wherein R² and R⁴ are both hydrogen.

5. The compound according to claim 1, wherein R′

is selected from hydrogen, C₁-C₄ alkyl, —

COR′

, —

SO₂R′

, or —

Si(R′

)₃, wherein each occurrence of R′

in R¹ is independently hydrogen or an optionally substituted group selected from a C₁-C₆ aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R′

are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated or partially unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound according to claim 5, wherein R¹ is hydrogen.

7. The compound according to claim 3, wherein R², R³, and R⁴ are each independently selected from hydrogen, —

Cl, —

Br, —

F, —

CN, —

COOH, —

COOMe, —

NH₂, —

N(CH₃)₂, —

N(Et)₂, —

N(iPr)₂, —

O(CH₂)₂OCH₃, —

CONH₂, —

COOCH₃, —

OH, —

CH₂OH, —

NHCOCH₃, —

SO₂NH₂, —

SO₂N(Me)₂, or an optionally substituted group selected from C₁-C₄ alkyl, C₁-C₄ 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.

8. The compound according to claim 1, wherein R³ is selected from —

H, —

Cl, —

F, —

Br, —

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.

9. The compound according to claim 8, wherein R² and R⁴ are both hydrogen.

10. The compound according to claim 9, wherein x is 2 or 3, and at least one occurrence of R⁵ is halogen.

11. The compound according to claim 1, wherein at least one occurrence of R⁵ is —

N(R′

)₂, wherein one R′

in R⁵ is hydrogen and the second R′

in R⁵ is a ring selected from

12. The compound according to claim 11, wherein y is 1, 2, or 3 and each occurrence of R⁷ is independently —

F, —

Cl, —

Br, —

OH, —

NH₂, —

CH₂OH, C₁-C₆ alkyl, —

O(C₁-C₆ alkyl), —

CH₂O(C₁-C₆ alkyl), —

CO(C₁-C₆ alkyl), —

COO(C₁-C₆ alkyl), —

NHSO₂(C₁-C₆ alkyl), —

SO₂NH₂, —

CONH₂, —

CONH(C₁-C₆ alkyl), —

SO₂(C₁-C₆ alkyl), —

SO₂-phenyl, phenyl, benzyl, —

N(C₁-C₆ alkyl)₂, or —

S(C₁-C₆ alkyl), wherein each of the foregoing phenyl, benzyl, and C₁-C₆ alkyl groups is independently and optionally substituted, and wherein each of the foregoing C₁-C₆ alkyl groups is linear, branched, or cyclic.

13. The compound according to claim 12, wherein x is 2 or 3, and at least one occurrence of R⁵ is halogen.

14. A pharmaceutical composition comprising a compound according to any one of claim 1 or 11 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

15. The composition of claim 14, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s Disease, a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.