Triazole-derived kinase inhibitors and uses thereof

• US 20030158238A1
• Filed: 04/26/2002
• Published: 08/21/2003
• Est. Priority Date: 04/27/2001
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Maltais, Francois, Hale, Michael R.
• Granted Patent: US 6,962,936 B2
• Time in Patent Office: Days
• US Class Current: 514/359
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/28 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• 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 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: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/06 : with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• 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
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

Described herein are compounds that are useful as protein kinase inhibitors having the formula:

where Ht, R², T, and m are as described in the specification. The compounds are useful for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein said compound is selected from the following:

3. The compound according to claim 2 wherein said compound is of formula II-A:

4. The compound according to any one of claims 1, 2, or 3 wherein said compound has one or more features selected from the group consisting of:

(a) T_mR² is hydrogen, N(R⁷)₂, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;

(b) Q is —

CO—

, —

CO₂—

, —

CONH—

, —

SO₂—

, —

SO₂NH—

, —

OC(O)NH—

, —

C(O)ONH—

, or —

CONHNH—

;

(c) R⁴ is —

NR⁵(CH₂)_yN(R⁵)₂, —

(CH₂)_yR⁶, —

(CH₂)_yCH(R⁶)₂, or —

(CH₂)_yCH(R⁸)CH(R⁶)₂;

(d) R⁵ is R, R⁷, or —

(CH₂)_yCH(R⁶)₂; and

(e) R⁶ is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.

5. The compound according to claim 4 wherein:

(a) T_mR² is hydrogen, N(R⁷)₂, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;

(b) Q is —

CO—

, —

CO₂—

, —

CONH—

, —

SO₂—

, —

SO₂NH—

, —

OC(O)NH—

, —

C(O)ONH—

, or —

CONHNH—

;

(c) R⁴ is —

NR⁵(CH₂)_yN(R⁵)₂, —

(CH₂)_yR⁶, —

(CH₂)_yCH(R⁶)₂, or —

(CH₂)_yCH(R⁸)CH(R⁶)₂;

(d) R⁵ is R, R⁷, or —

(CH₂)_yCH(R⁶)₂; and

(e) R⁶ is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.

6. The compound according to claim 5 wherein:

(a) T_mR² is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃;

(b) Q is —

CO—

, —

CONH—

, —

SO₂—

, or —

SO₂NH—

;

(c) R⁴ is —

(CH₂)_yR⁶, —

(CH₂)_yCH(R⁶)₂, or —

(CH₂)_yCH(R⁸)CH(R⁶)₂, wherein R⁸ is OH or CH₂OH; and

(d) R⁶ is —

CH₂OH, —

(CH₂)₂OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.

7. The compound according to claim 2 wherein said compound is selected from the following:

8. The compound according to claim 7 wherein said compound is of formula III-A:

9. The compound according to claim 7 wherein said compound has one or more features selected from the group consisting of:

(a) when m is one, T is —

NH—

or —

O—

;

(b) R² is an optionally substituted aliphatic or aryl group, more preferably an optionally substituted phenyl group;

(c) R⁴ is —

N(R⁵)₂, —

NR⁵(CH₂)_yN(RS)₂, —

(CH₂)_yR⁶, —

(CH₂)_yCH(R⁶)₂, or R⁶;

(d) R⁵ is R or R⁶; and

/or (e) R⁶ is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group.

10. The compound according to claim 2 wherein said compound is selected from the following:

11. The compound according to claim 10 wherein said compound has one or more features selected from the group consisting of:

(a) T_mR² is hydrogen, N(R⁷)₂, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and

(b) R⁶ is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.

12. The compound according to claim 11 wherein:

(a) T_mR² is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and

(b) R⁶ is cyclohexyl or an optionally substituted phenyl or pyridyl ring.

13. The compound according to claim 2 wherein said compound is selected from the following:

14. The compound according to claim 13 wherein said compound has one or more features selected from the group consisting of:

(a) T_mR² is hydrogen, N(R⁵)₂, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and

(b) R⁶ is R or OR⁷, and R⁸ is R⁷ or OR⁷.

15. The compound according to claim 14 wherein:

(a) T_mR² is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and

(b) R⁶ is OH, CH₂OH, phenyl, pyridyl, or cyclohexyl, and R⁸ is methyl, ethyl, OH, or CH₂OH.

16. The compound according to claim 2 wherein said compound is of formula II-A, II-B or II-D

17. The compound according to claim 16 wherein said compound is of formula II-A.

18. The compound according to claim 2 wherein said compound is of formula II-A, II-B or II-D

19. The compound according to claim 18 wherein said compound is of formula II-A.

20. The compound according to claim 2 wherein said compound is selected from any one of the following compounds:

21. The compound according to claim 2 wherein said compound is selected from any of the following compounds:

22. A composition comprising a compound according to claim 1 in an amount to detectably inhibit ERK kinase activity, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

23. The composition according to claim 22, additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

24. A method of inhibiting ERK 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 composition according to claim 22.

25. A method of treating or lessening the severity of an ERK-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to claim 22.

26. A method of treating or lessening the severity of an cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer'"'"'s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders, comprising the step of administering to said patient a composition according to claim 22.

27. The method according to claim 26, wherein said method is used to treat or prevent cancer.

28. The method according to claim 27, wherein said method is used to treat or prevent a cancer selected from breast;

ovary;

cervix;

prostate;

testis, genitourinary tract;

esophagus;

larynx, glioblastoma;

neuroblastoma;

stomach;

skin, keratoacanthoma;

lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma;

bone;

colon, adenoma;

pancreas, adenocarcinoma;

thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma;

seminoma;

melanoma;

sarcoma;

bladder carcinoma;

liver carcinoma and biliary passages;

kidney carcinoma;

myeloid disorders;

lymphoid disorders, Hodgkin'"'"'s, hairy cells;

buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;

small intestine;

colon-rectum, large intestine, rectum;

brain and central nervous system;

or leukemia.

29. The method according to claim 26, wherein said method is used to treat or prevent cardiovascular disease.

30. The method according to claim 29, wherein said method is used to treat or prevent a cardiovascular disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure.

31. The method according to claim 26, 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.

32. The method according to claim 26, comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

33. A composition for coating an implantable device comprising a compound according to claim 1 and a carrier suitable for coating said implantable device.

34. An implantable device coated with a composition according to claim 33.