Indazole compounds useful as protein kinase inhibitors

• US 20040009968A1
• Filed: 01/23/2003
• Published: 01/15/2004
• Est. Priority Date: 01/25/2002
• Status: Active Grant

• 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
• Granted Patent: US 7,041,687 B2
• Time in Patent Office: Days
• US Class Current: 514/217.05
• 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

8. A compound of formula Ia:

9. The compound according to claim 8, 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.

10. The compound according to claim 9, 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.

11. The compound according to claim 8, 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-0R⁵, 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.

12. The compound according to claim 11, 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.

13. Thc compound according to claim 8, wherein said compound is selected from the group consisting of:

14. A compound of formula IIb:

1. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase in:

(a) a patient;

or

(b) a biological sample;

 

which method comprises administering to said patient, or contacting said biological sample with, a compound of formula I′

;

 

or a pharmaceutically acceptable salt thereof, wherein;

R¹ is selected from halogen, CN, N(R⁴)₂, T-R, or T′

-Ar;

T is selected from a valence bond or a C_1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by —

O—

, —

N(R)—

, —

S—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

C(O)—

, or —

SO₂—

;

T′

is a C_1-6 alkylidene chain, wherein up to two methylene units of T′

are optionally, and independently, replaced by —

O—

, —

N(R)—

, —

S—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

C(O)—

, or —

SO₂—

;

each R is independently selected from hydrogen or an optionally substituted C_1-6 aliphatic group, or;

two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5-7 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R² is selected from Q-Ar, Q-N(R⁵)₂, or 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;

each Q is independently selected from a valence bond or a C_1-4 alkylidene chain;

each Ar is independently an optionally substituted ring selected from a 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected front nitrogen, oxygen, or sulfur;

R³ is selected from R′

, Ar¹, Q-OR⁵, Q-OC(O)R⁵, Q-CONHR⁵, Q-OC(O)NHR⁵, Q-SR⁵, Q-N(R⁴)₂, N(R)(Q-Ar), N(R)C(O)Q-N(R⁴)₂, or N(R)Q-N(R⁴)₂;

R′

is an optionally substituted C_1-6 aliphatic group;

each R⁴ is independently selected from R, COR⁵, CO₂R⁵, CON(R⁵)₂, SO₂R⁵, SO₂N(R⁵)₂, or Ar¹;

each R⁵ is independently selected from R or Ar;

V¹, V² and V³ are each independently selected from nitrogen or C(R⁶);

each R⁶ is independently selected from R, Ar¹, halogen, CN, NO₂, OR, SR, N(R⁴)₂, N(R)COR, N(R)CON(R⁴)₂, N(R)C(O)OR, CON(R⁴)₂, OC(O)N(R⁴)₂, CO₂R, OC(O)R, N(R)SO₂R, N(R)SO₂N(R⁴)₂, SO₂R, or SO₂N(R⁴)₂; and

each Ar¹ is independently selected from an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

provided that;

when V¹, V², and V³ are each CH and R¹ is hydrogen, then R² is Q-C(R)(Q-Ar)R³, wherein R³ is other than R′

, Q-OC(O)R⁵, or OCH₂phenyl.

2. The method according to claim 1, wherein:

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

R² is selected from Q-Ar or Q-N(R5)₂;

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;

Ar is an optionally substituted ring selected from a 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The method according to claim 1, wherein:

R₁ is selected from halogen, CN, N(R⁴)₂, or T-R; and

R₂ is selected from 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;

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; and

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.

4. The method according to claim 1, wherein:

R¹ is T′

-Ar, wherein;

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; and

T′

is selected from —

NHC(O)—

, —

NH—

, —

NHCH₂—

, —

NHSO₂—

, —

CH₂NH—

, —

C≡

C—

, —

CH₂—

or —

CH₂CH₂—

;

5. The method according to claim 4, wherein:

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;

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; and

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.

6. The method according to either of claims 3 or 5, wherein said compound has the formula III or IV:

7. The method according to claim 1, wherein said compound has the formula V:

15. The compound according to claim 14, wherein:

R¹ is T-Ar, wherein;

T is selected from —

NHC(O)—

, —

NH—

, —

NHCH—

, 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.

16. The compound according to claim 15, 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.

17. The compound according to claim 14, 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.

18. The compound according to claim 17, 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.

19. The compound according to claim 14, wherein said compound is selected from the group consisting of:

20. The compound according to claim 14, wherein said compound has the formula V:

21. The composition according to claim 20, 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.

22. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity in a biological sample comprising the step of contacting said biological sample with:

a) a compound according to claim 8;

b) a compound according to claim 14;

or

c) a composition according to claim 20.

23. A method of treating or lessening the severity of a disease or condition selected from a proliferative disorder, a cardiac disorder, an inflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, a viral disease, or a bone disorder, wherein said method comprises the step of administering an effective amount a composition according to claim 20.

24. The method according to claim 23, wherein said disease or condition is selected from cancer, rheumatoid arthritis, asthma, HIV, angina pectoris, peripheral circulation disorder, hypertension, arteriosclerosis, tuberous sclerosis, or osteoporosis.

25. The method according to claim 24, wherein said disease or condition is selected from cancer.

26. The method according to claim 25, wherein said cancer is selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid.

27. The method according to claim 26, wherein said cancer is selected from pancreatic, prostate, or ovarian.

28. 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.

20-1. A composition comprising a compound according to either of claims 8 or 14, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.