Kinase inhibitors

• US 8,741,931 B2
• Filed: 04/09/2012
• Issued: 06/03/2014
• Est. Priority Date: 01/31/2007
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Bemis, Guy William, Maltais, Francois, Wang, Tiansheng, Knegtel, Ronald Marcellus Alphonsus, Davis, Christopher John, Fraysse, Damien, Boyall, Dean, Settimo, Luca, Young, Stephen, Mortimore, Michael Paul
• Primary Examiner(s): MCDOWELL, BRIAN E
• Application Number:
  US13/442,244
• Publication Number:
  US 20120214799A1
• Time in Patent Office: 785 Days
• Field of Search: 546/262
• US Class Current: 514/332
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/24 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 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 7/06 Antianaemics
• 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: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

The present invention relates to compounds having formula:

• • which are useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1 wherein:

Z is O.

3. The compound of claim 2 wherein:

R₂ is —

H.

4. The compound of claim 3 wherein:

R₁ is —

H, halogen, or -T1-Q1;

T1 is absent or C1-10 aliphatic, wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

N(R₄)—

, or —

C(O)—

;

T1 is optionally and independently substituted with one or more JT1;

Q1 is absent, or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Q1 is independently optionally and independently substituted with J1;

J1 is —

Y1-M1;

Y1 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —

N(R^$)—

, —

O—

, —

C(O)—

, or —

S(O)₂—

, Y1 is optionally and independently substituted with one or more JT1; and

M1 is C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, —

OR^$, —

SR^$, —

N(R^$)₂, —

P(O) R^$, —

P(O)₂R^$, P(O)(R^$)₂, or PO(OR^$)₂, wherein M1 is optionally and independently substituted with one or more J;

or M1 is absent, —

CN, —

NO₂, or halogen.

5. The compound of claim 4 wherein:

T1 is absent or C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, or —

N(R₄)—

;

T1 is optionally and independently substituted with one or more JT1;

Y1 is absent or C1-10 aliphatic wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —

N(R^$)—

, —

O—

—

C(O)—

, or —

S(O)₂;

Y1 is optionally and independently substituted with one or more JT1; and

M1 is C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, —

N(R^$)₂, or —

OR^$;

wherein M1 is optionally and independently substituted with one or more J;

or M1 is absent, —

CN, or halogen.

6. The compound of claim 5 wherein:

each J is independently halogen, C1-6 aliphatic, —

NO₂, —

CN, —

N(R^$)₂, —

OR^$, —

C(O)R^$, —

C(O)N(R^$)₂, —

C(O)₂R^$, oxo, or halo C1-4 aliphatic.

7. The compound of claim 6 wherein:

T1 is absent, C1-C10 alkyl, C2-10 alkenyl, or C2-C10 alkynyl wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, or —

N(R₄)—

;

T1 is optionally and independently substituted with one or more JT1;

Q1 is absent, phenyl, indolyl, quniolyl, isoindolyl, isoquinolyl, indazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, benzothienyl, furyl, benzofuryl, piperidinyl, piperizinyl, pyrrolodinyl, pyrazinyl, pyrimidinyl, or pyridyl;

wherein Q1 is optionally and independently substituted with J1;

Y1 is absent or C1-10 alkyl group wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —

O—

, Y1 is optionally and independently substituted with one or more JT1; and

M1 is phenyl, —

N(R^$)₂, or —

OR^$;

wherein M1 is optionally and independently substituted with one or more J;

or M1 is absent, or —

CN.

8. The compound of claim 4 wherein:

R₁ is —

H, or halogen.

9. The compound of claim 7 wherein:

J2 is —

Y2-M2;

Y2 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y2 are independently and optionally replaced with G1′

wherein G1′

is —

N(R^$)—

, —

O—

, —

C(O)—

, or —

S(O)₂—

, Y2 is optionally and independently substituted with one or more JT2;

M2 is C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, 5-12 membered aryl, —

N(R^$)₂, —

OR^$, —

C(O)R^$, —

C(O)₂R^$, —

S(O)R^$, or —

S(O)₂R^$ wherein M2 is optionally and independently substituted with one or more J;

or M2 is absent, —

NO₂, or —

CN; and

each J is independently halogen, C1-6 aliphatic, —

NO₂, —

CN, N(R^$)₂, —

OR^$, —

COR^$, —

CON(R^$)₂, —

CO₂R^$, oxo or halo C1-4 aliphatic.

10. The compound of claim 9 wherein:

Y2 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y2 are optionally and independently replaced with G1′

wherein G1′

is —

O—

, —

N(R^$)—

, —

C(O)—

, or —

SO₂—

, Y2 is optionally and independently substituted with one or more JT2;

M2 is —

OR^$, —

N(R^$)₂, —

C(O)R^$, —

C(O)₂R^$, —

S(O)R^$, or —

S(O)₂R^$, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyranyl, tetrahydropyranyl, isooxazolyl, piperidinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, cyclopropyl, naphthyl, or phenyl, wherein M2 is optionally and independently substituted with one or more J;

or M2 is absent, —

N(O)₂, or —

CN; and

each J is independently halogen, C1-6 aliphatic, —

NO₂, —

CN, —

N(R^$)₂, —

OR^$, oxo, or halo C1-4 aliphatic.

11. The compound of claim 10 wherein Q2 is represented by a structural formula represented by:

12. The compound of claim 11 wherein the compound is represented by a structural formula selected from the group consisting of:

13. The compound of claim 11 wherein Q2 is represented by a structural formula represented by:

15. A pharmaceutical composition comprising a compound of pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

14. A compound selected from the group consisting of: