Indazole compounds useful as protein kinase inhibitors

• US 7,041,687 B2
• Filed: 01/23/2003
• Issued: 05/09/2006
• Est. Priority Date: 01/25/2002
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Binch, Hayley, Knegtel, Ronald, Mortimore, Michael, Rutherford, Alistair, Patel, Sanjay, Golec, Julian M. C., Brenchley, Guy
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Johnsen, Jason H.
• Application Number:
  US10/350,806
• Publication Number:
  US 20040009968A1
• Time in Patent Office: 1,202 Days
• Field of Search: 514/359, 548/364.2, 548/300.1, 548/358.1
• 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 11/06 Antiasthmatics
• 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 19/10 for osteoporosis
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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 9/08 Vasodilators for multiple indications
• 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 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides compounds of formula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹, R², V¹, V², and V³ are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of AKT, PKA, PDK1, p70S6K, or ROCK kinase, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions in the treatment of various disorders.

Claims

1. A compound of formula IIa:

2. The compound according to claim 1, wherein:

R¹ is selected from halogen, N(R⁴)₂, or optionally substituted C_1-6 aliphatic; and

R² is Q-C(R)(Q-Ar)R3, wherein;

R and R³ optionally form a 5–

7 membered saturated or partially unsaturated ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is selected from R′

, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and

Ar is an optionally substituted 5–

6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or all optionally substituted 9–

10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound according to claim 2, wherein:

R¹ is selected from chloro, bromo, fluoro, NH₂, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, or d t-butyl; and

R³ is selected from CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, or NHCH₂-imidazol-4-yl.

4. The compound according to claim 1, wherein:

R¹ is hydrogen; and

R² is Q-C(R)(Q-Ar)R³, wherein;

R and R³ optionally form a 5–

7 membered saturated or partially unsaturated ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is selected from Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and

Ar is an optionally substituted 5–

6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–

10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5. The compound according to claim 4, wherein:

R³ is selected from OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, NHCO₂t-butyl, phenyl, NH(CH₂)₃NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, or NHCH₂-imidazol-4-yl.

6. The compound according to claim 1, wherein said compound is selected from the group consisting of:

14. A composition comprising a compound according to either of claim 1 or 7, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity comprising the step of contacting the kinase with a compound according to acyone of claims 1 through 13.

7. A compound of formula IIb:

8. The compound according to claim 7, wherein:

R¹ is T-Ar, wherein;

T is selected from —

NHC(O)—

, —

NH—

, —

NHCH₂—

, NHSO₂—

, —

CH₂NH—

, —

C≡

—

, —

CH₂—

or —

CH₂CH₂—

; and

Ar is an optionally substituted 5–

6 membered aryl ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–

10 membered aryl ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R² is Q-C(R)(Q-Ar)R³, wherein;

R³ is R′

, Q-OR⁵, Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂;

each Q is independently selected from a valence bond, —

CH₂—

, or —

CH₂CH₂—

; and

Ar is an optionally substituted 5–

6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–

10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9. The compound according to claim 8, wherein:

R³ is CH₂OH, OH, NH₂, CH₂NH₂, CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂CH₂NH₂, NHCO₂t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

10. The compound according to claim 7, wherein:

T is a valence bond; and

R² is Q-C(R)(Q-Ar)R³, wherein;

R and R³ optionally form a 5–

7 membered saturated or partially unsaturated ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is Q-N(R⁴)₂, Ar¹, N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂; and

Ar is an optionally substituted 5–

6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–

10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–

4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

11. The compound according to claim 10, wherein:

R³ is CH₂NHMe, CH₂N(Me)₂, CH₂CH₂NH₂, CH₂CH₂NHMe, CH₂CH₂N(Me)₂, CH₂C(Me)₂NH₂, CH₂C(Me)₂CHMe, NHCO₂(t butyl), phenyl, NH(CH₂)₃NH₂, NH(CH₂)₂NH₂, NH(CH₂)₂NHEt, NHCH₂pyridyl, NHSO₂phenyl, NHC(O)CH₂C(O)Ot-butyl, NHC(O)CH₂NH₃, and NHCH₂-imidazol-4-yl.

12. The compound according to claim 7, wherein said compound is selected from the group consisting of:

13. The compound according to claim 7, wherein said compound has the formula V:

15. The composition according to claim 13, additionally comprising a 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.