Heterocyclic inhibitors of ERK2 and uses thereof

• US 20040029857A1
• Filed: 04/25/2003
• Published: 02/12/2004
• Est. Priority Date: 04/26/2002
• Status: Active Grant

• Current Assignee: Alexander Aronov, Francois Maltais, Judith Straub, Michael Robin Hale, Qing Tang
• Original Assignee: Alexander Aronov, Francois Maltais, Judith Straub, Michael Robin Hale, Qing Tang
• Inventors: Maltais, Francois, Aronov, Alexander, Tang, Qing, Hale, Michael Robin, Straub, Judith
• Granted Patent: US 7,304,061 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 207/333 Radicals substituted by oxygen or sulfur atoms
• CPC Class Codes: C07D 207/337 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

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

wherein A¹, A², T_mR¹, X, R², R³, R⁹, R¹², and R¹³ are as described in the specification. The compounds are especially useful as inhibitors of ERK2, Aurora2, GSK3, CDK2, AKT3, and ROCK protein kinases and for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, neurodegenerative disorders, inflammatory disorders, restenosis, diabetes, and cardiovascular disease.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein said compound has one or more features selected from the group consisting of:

(a) X is selected from —

C(O)—

or —

C(O)NR⁷—

;

(b) R³ is —

N(optionally substituted C_1-6 aliphatic)₂;

—

SH;

S(C_1-6 aliphatic);

—

OH;

—

O(C_1-6 aliphatic);

3-6 membered carbocyclyl;

or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;

(c) T_mR¹ is hydrogen, amino, 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;

(d) R² is —

NR⁴(CH₂)_yN(R⁴)₂, —

(CH₂)_yR⁵, —

(CH₂)_yCH(R⁵)₂, —

(CH₂)_yCH(R⁸)(R⁵), or —

(CH₂)_yCH(R⁸)CH(R⁵)₂;

(e) R⁴ is R, R⁷, or —

(CH₂)_yCH(R⁵)₂; and

(f) R⁵ is an optionally substituted group selected from C_1-6 aliphatic, phenyl, naphthyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.

3. The compound according to claim 2 wherein said compound has one or more features selected from the group consisting of:

(a) X is —

C(O)—

;

(b) R³ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, N(methyl)₂, N(ethyl)₂, N(CH₂CH₂OH)₂, pyridinyl, morpholinyl, piperidinyl, piperazinyl, S-methyl, OH, O-methyl, O-ethyl, or —

CH₂-morpholin-4-yl;

(c) T_mR¹ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃;

(d) R² is —

(CH₂)_yR⁵, —

(CH₂)_yCH(R⁵)₂, —

(CH₂)_yCH(R⁸)(R⁵), or —

(CH₂)_yCH(R⁸)CH(R⁵)₂, wherein R⁸ is OH, NH₂, CH₂OH, CH₂NH₂, or CH₂CH₂NH₂; and

(e) R⁵ is —

CH₂OH, —

(CH₂)₂OH, isopropyl, or an optionally substituted group selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, methyldiazepanyl, phenylpiperazineyl, pyridinyl, imidazolyl, furanyl, tetrahydroisoquinoline, tetrahydrofuranyl, cyclohexyl, phenyl, or benzyl.

4. The compound according to claim 1 wherein said compound is of formula I′

;

5. The compound according to claim 4 wherein said compound has one or more features selected from the group consisting of:

(a) X is selected from —

C(O)—

or —

C(O)NR⁷—

;

(b) R³ is N(optionally substituted C_1-6 aliphatic)₂;

—

SH;

—

S(C_1-6 aliphatic);

—

OH;

—

O(C_1-6 aliphatic);

3-6 membered carbocyclyl;

or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;

(c) T_mR¹ is hydrogen, amino, 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

(d) R⁵ is R, OR⁷, or N(R⁷)₂, wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.

6. The compound according to claim 5 wherein said compound has one or more features selected from the group consisting of:

(a) X is —

C(O)—

;

(b) R³ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, N(methyl)₂, N(ethyl)₂, N(CH₂CH₂OH)₂, pyridinyl, moipholinyl, piperidinyl, piperazinyl, S-methyl, OH, O-methyl, O-ethyl, or —

CH₂-morpholin-4-yl;

(c) T_mR¹ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and

(d) R⁵ is OH, NH₂, carbocyclic, or an optionally substituted phenyl or pyridyl ring.

7. The compound according to claim 1 wherein said compound is of formula I″

;

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

(a) R³ is —

N(optionally substituted C_1-6 aliphatic)₂;

—

SH;

—

S(C_1-6 aliphatic);

—

OH;

—

O(C_1-6 aliphatic);

3-6 membered carbocyclyl;

or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;

(b) T_mR¹ 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

(c) R⁵ is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.

9. The compound according to claim 8 wherein said compound has one or more features selected from the group consisting of:

(a) R³ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, N(methyl)₂, N(ethyl)₂, N(CH₂CH₂OH)₂, pyridinyl, morpholinyl, piperidinyl, piperazinyl, S-methyl, OH, O-methyl, O-ethyl, or —

CH₂-morpholin-4-yl;

(b) T_mR¹ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and

(c) R⁵ is cyclohexyl or an optionally substituted phenyl or pyridyl ring.

10. The compound according to claim 1 wherein said compound is of formula I^o:

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

(a) R³ is —

N(optionally substituted C_1-6 aliphatic)₂;

—

SH;

—

S(C_1-6 aliphatic);

—

OH;

—

O(C_1-6 aliphatic);

3-6 membered carbocyclyl;

or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;

(b) T_mR¹ is hydrogen, amino, 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

(c) R⁵ is R, OR⁷, or N(R⁷)₂, wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.

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

(a) R³ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, N(methyl)₂, N(ethyl)₂, N(CH₂CH₂OH)₂, pyridinyl, morpholinyl, piperidinyl, piperazinyl, S-methyl, OH, O-methyl, O-ethyl, or —

CH₂-morpholin-4-yl;

(b) T_mR¹ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃; and

(c) R⁵ is OH, NH₂, carbocyclic, or an optionally substituted phenyl or pyridyl ring.

13. The compound according to claim 1 wherein said compound is of formulae (Ia), (Ib), (Ic), or (Id):

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

(a) X is selected from —

C(O)—

or —

C(O)NR⁷—

;

(b) R³ is —

N(optionally substituted C_1-6 aliphatic)₂;

—

SH;

—

S(C_1-6 aliphatic);

—

OH;

—

O(C_1-6 aliphatic);

3-6 membered carbocyclyl;

or an optionally substituted group selected from C_1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;

(c) T_mR¹ is hydrogen, amino, 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;

(d) R² is —

NR⁴(CH₂)_yN(R⁴)₂, —

(CH₂)_yR⁵, —

(CH₂)_yCH(R⁵)₂, —

(CH₂)_yCH(R⁸)(R⁵), or —

(CH₂)_yCH(R⁸)CH(R⁵)₂;

(e) R⁴ is R, R⁷, or —

(CH₂)_yCH(R⁵)₂; and

(f) R⁵ is an optionally substituted group selected from C_1-6 aliphatic, phenyl, naphthyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.

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

(a) X is —

C(O)—

;

(b) R³ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, N(methyl)₂, N(ethyl)₂, N(CH₂CH₂OH)₂, pyridinyl, morpholinyl, piperidinyl, piperazinyl, S-methyl, OH, O-methyl, O-ethyl, or —

CH₂-morpholin-4-yl;

(c) T_mR¹ is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH₂OCH₃, CH₂OH, OH, NH₂, NHCH₃, NHAc, NHC(O)NHCH₃, or CH₂NHCH₃;

(d) R² is —

(CH₂)_yR⁵, —

(CH₂)_yCH(R⁵)₂, —

(CH₂)_yCH(R⁸)(R⁵), or —

(CH₂)_yCH(R⁸)CH(R⁵)₂, wherein R⁸ is OH, NH₂, CH₂OH, CH₂NH₂, or CH₂CH₂NH₂; and

(e) R is —

CH₂OH, —

(CH₂)₂OH, isopropyl, or an optionally substituted group selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, methyldiazepanyl, phenylpiperazineyl, pyridinyl, imidazolyl, furanyl, tetrahydroisoquinoline, tetrahydrofuranyl, cyclohexyl, phenyl, or benzyl.

16. The compound according to claim 1 of the formula I:

17. The compound according to claim 1 of the formula I:

18. The compound according to claim 1 selected from any of the following compounds:

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

20. The composition according to claim 19, 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.

21. A method of inhibiting ERK2, CDK2, Aurora2, GSK3, AKT3, or ROCK 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 19.

22. A method of inhibiting ERK2, CDK2, Aurora2, GSK3, AKT3, or ROCK in a patient comprising the step of administering to said patient:

a) a compound according to claim 1;

or

b) a composition according to claim 19.

23. A method of treating or lessening the severity of a disease or disorder selected from proliferative disorders, cardiovascular diseases, viral diseases, neurological disorders, autoimmune disorders, inflammatory disorders, allergic disorders, baldness, immunodeficiency disorder, destructive bone disorder, diabetes, or liver disease in a patient in need thereof, said method comprising the step of administering to said patient a composition according to claim 19.

24. A method of treating or lessening the severity of a disease or disorder selected from cancer, stroke, diabetes, hepatomegaly, Alzheimer'"'"'s disease, cytomegalovirus, HIV, herpes, psoriasis, Parkinson'"'"'s disease, multiple sclerosis (MS), schizophrenia, AIDS, AIDS-associated dementia, cystic fibrosis, arterioscloerosis, atherosclerosis, restenosis, rheumatoid arthritis, conditions associated with organ transplantation, osteoperosis, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), a pathologic immune condition involving T cell activation, cardiomycete hypertrophy, baldness, hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, spasm, retinopathy, or a CNS disorder, said method comprising the step of administering to said patient a composition according to claim 19.

25. The method according to claim 24, wherein said method is used to treat or lessen the severity of cancer.

26. The method according to claim 25, wherein said method is used to treat or lessen the severity of a cancer selected from breast;

ovary;

cervix;

prostate;

testis, genitoutrinary 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;

seminomoia;

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.

27. The method according to claim 23, wherein said method is used to treat or lessen the severity of a cardiovascular disease.

28. The method according to claim 27, wherein said method is used to treat or lessen the severity of a cardiovascular disease selected from restenosis, cardiomycete hypertrophy, cardiomegaly, artherosclerosis, angina pectoris, hypertension, myocardial infarction, or congestive heart failure.

29. The method according to claim 23, wherein said method is used to treat or lessen the severity of a neurodegenerative disease selected from Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Huntington'"'"'s disease, cerebral ischemia, stroke, retinopathy, or a neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.

30. The method according to claim 23, 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.

31. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient comprising the step of administering to said patient a composition according to claim 19.

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

33. An implantable device coated with a composition according to claim 32.