Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases

• US 20020111353A1
• Filed: 12/05/2001
• Published: 08/15/2002
• Est. Priority Date: 12/05/2000
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Moon, Young-Choon, Ledeboer, Mark, Salituro, Francesco
• Application Number:
  US10/005,133
• Publication Number:
  US 20020111353A1
• Time in Patent Office: Days
• US Class Current: 514/235.8
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
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• 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
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• CPC Class Codes: A61P 13/12 of the kidneys
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• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
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• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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]
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• 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• 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
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• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings

Abstract

The present invention provides compounds of formula I:

wherein G is a small group selected from hydrogen or C_1-3 alkyl, Q is pyridine or pyrimidine, and R¹-R³ are as defined in the specification. These compounds are selective JNK inhibitors showing good activity against the three isoforms of JNK (JNK1, JNK2 and JNK3) and relatively low activity against p38 kinase. The compounds are therefore useful for treating JNK-mediated diseases, especially neurodegenerative diseases in which all three JNK isoforms are implicated.

Claims

1. A compound of formula I:

2. The compound of claim 1 having at least one feature selected from the group consisting of:

(a) R¹ is selected from hydrogen, T_(n)—

R, or T_(n)—

Ar¹;

(b) R² is selected from hydrogen, —

R, —

CH₂OR, CH₂OH, CH₂ (heterocyclyl), —

CH₂ (substituted heterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl);

(c) R³ is selected from —

R, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl and;

(d) G is hydrogen or methyl.

3. The compound of claim 2 wherein:

(a) R¹ is selected from hydrogen, T_(n)—

R, or T_(n)—

Ar¹;

(b) R² is selected from hydrogen, —

R, —

CH₂OR, CH₂OH, CH₂(heterocyclyl), —

CH₂(substituted heterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl);

(c) R³ is selected from —

R, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl and;

(d) G is hydrogen or methyl.

4. The compound of claim 3 wherein G is hydrogen or methyl;

R¹ is selected from phenyl, cyclohexyl, pyridyl, naphthyl, or quinolinyl;

R² is selected from hydrogen, methyl, alkoxymethyl, benzyloxymethyl, or heterocyclylmethyl; and

R³ is phenyl or benzyl;

wherein each of R¹-R³ is optionally substituted.

5. The compound of claim 3 wherein G is hydrogen or methyl;

R¹ is phenyl or cyclohexyl;

R² is methoxymethyl, methoxyethoxymethyl, ethoxymethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, or tetrahydrofuran-3-ylmethyl; and

R³ is phenyl or benzyl;

wherein each of R¹-R³ is optionally substituted.

6. A compound selected from the compounds listed in Table 1.

7. A method for treating a disease or condition in a mammal that is alleviated by treatment with a JNK kinase inhibitor, comprising administering to a mammal in need of such a treatment a therapeutically effective amount of a compound of formula I:

8. The method of claim 7 wherein the disease is selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation or conditions associated with proinflammatory cytokines.

9. The method according to claim 7, wherein said method is used to treat or prevent an inflammatory disease selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, or adult respiratory distress syndrome.

10. The method according to claim 7, wherein said method is used to treat or prevent an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves'"'"' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, psoriasis, or graft vs. host disease.

11. The method according to claim 7, wherein said method is used to treat or prevent a destructive bone disorders selected from osteoarthritis, osteoporosis or multiple myeloma-related bone disorder.

12. The method according to claim 7, wherein said method is used to treat or prevent a proliferative disease selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, or multiple myeloma.

13. The method according to claim 7, wherein said method is used to treat or prevent neurodegenerative disease selected from Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Huntington'"'"'s disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.

14. The method according to claim 7, wherein said method is used to treat or prevent ischemia/reperfusion in stroke or myocardial ischemia, renal ischemia, heart attacks, organ hypoxia or thrombin-induced platelet aggregation.

15. The method according to claim 7, wherein said method is used to treat or prevent a condition associated with T-cell activation or pathologic immune responses.

16. The method according to claim 7, wherein said method is used to treat or prevent an angiogenic disorder selected from solid tumors, ocular neovasculization, or infantile haemangioma.