Bicyclic inhibitors of Rho kinase

• US 20060122185A1
• Filed: 11/22/2005
• Published: 06/08/2006
• Est. Priority Date: 11/22/2004
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Gao, Huai, Green, Jeremy, Bandarage, Upul, Cao, Jingrong, Forster, Cornelia
• Application Number:
  US11/285,516
• Publication Number:
  US 20060122185A1
• Time in Patent Office: Days
• US Class Current: 514/248
• 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 15/10 for impotence
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 27/06 Antiglaucoma agents or miotics
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 37/00 Drugs for immunological or allergic disorders
• 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 9/00 : Drugs for disorders of the cardiovascular system
• 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 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of ROCK. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

wherein

Z₁, Z₂, Z₃ and Z₄ are each independently selected from N or CR¹, wherein at least one of Z₁, Z₂, or Z₄ is N;

each R¹ is independently selected from H, halogen, —

CN, —

NO₂, or —

V_mR′

;

G is —

NR²—

or —

CO—

;

Q¹ is —

CO—

, —

SO₂—

, —

NR², —

NR²CO—

, —

CONR²—

, —

SO₂NR²—

, or is a bond;

R² is —

U_nR″

;

R³ is Q²-Ar¹, or when G is —

NR², R² and Q¹-R³, taken together with the nitrogen atom, may form the cyclic group;

where s is 1 or 2, Z is CH or N;

wherein each occurrence of Y is independently —

CO—

, —

CS—

, —

SO₂—

, —

O—

, —

S—

, —

NR⁵—

, or —

C(R⁵)₂—

, and R⁵ is U_nR′

;

X₁ and X₂ are each independently selected from CR⁴ or N;

each occurrence of R⁴ is independently selected from halogen, CN, NO₂, or V_mR;

each occurrence of U or V is independently selected from an optionally substituted C_1-6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —

NR—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR—

, —

NRCO—

, —

NRCO₂—

, —

SO₂NR—

, —

NRSO₂—

, —

CONRNR—

, —

NRCONR—

, —

OCONR—

, —

NRNR—

, —

NRSO₂NR—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR—

;

m and n are each independently 0 or 1;

each occurrence of R is independently selected from hydrogen or a C_1-6 aliphatic group, wherein said aliphatic group is optionally substituted with up to five occurrences of J^R;

each occurrence of R′

is independently selected from hydrogen, a C_1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said aliphatic group, monocyclic ring or bicyclic ring is optionally substituted with up to five occurrences of J^R′

;

R″

is selected from hydrogen, a C_1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said aliphatic group, monocyclic ring or bicyclic ring is optionally substituted with up to five occurrences of J^R″

;

or two occurrences of R, R′ and

R″

, in any combination thereof, are taken together with the atom(s) to which they are bound to form a 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said monocyclic or bicyclic ring is optionally substituted with J^R;

each occurrence of J^R, J^R′

and J^R″

is independently selected from halogen, L, -(L_p)-R^J, -(L_p)-N(R^J)₂, -(L_p)-SR^J, -(L_p)-OR^J, -(L_p)-(C_3-10 cycloaliphatic), -(L_p)-(C_6-10 aryl), -(L_p)-(5-10 membered heteroaryl), -(L_p)-(5-10 membered heterocyclyl), oxo, C_1-4haloalkoxy, C_1-4haloalkyl, -(L_p)-NO₂, -(L_p)-CN, -(L_p)-OH, -(L_p)-CF₃, —

CO₂R^J, —

CO₂H, —

COR^J, —

COH, —

OC(O)R^J or —

NC(O)R^J;

or any two J^R, J^R′

or J^R″

groups, on the same substituent or different substituents, together with the atom(s) to which each J^R, J^R′

or J^R″

group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R^J is H or C_1-6 aliphatic;

or two R^J groups or an R^J group and an R, R′

or R″

group, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —

OR*, —

SR*, —

NO₂, —

CF₃, —

CN, —

CO₂R*, —

COR*, OCOR* or NHCOR*, wherein R* is H or an unsubstituted C_1-6 aliphatic;

L is a C_1-6 aliphatic wherein up to three methylene units are replaced by —

NH—

, —

NR^L—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR⁶—

, —

C(═

N—

CN), —

NHCO—

, —

NR^LCO—

, —

NHC(O)O—

, —

NR^LC(O)O—

, —

SO₂NH—

, —

SO₂NR^L—

, —

NHSO₂—

, —

NR^LSO₂—

, —

NHC(O)NH—

, —

NR^LC(O)NH—

, —

NHC(O)NR^L—

, —

NR^LC(O)NR^L, —

OC(O)NH—

, —

OC(O)NR^L—

, —

NHSO₂NH—

, —

NR^LSO₂NH—

, —

NHSO₂NR^L—

, —

NR^LSO₂NR^L—

, —

SO—

or —

SO₂—

;

R^L is selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

or two R^L groups, on the same substituent or different substituents, together with the atom(s) to which each R^L group is bound, form a 3-8 membered heterocyclyl;

each p is independently 0 or 1;

Q² and Q³ are each independently selected from a bond or a C_1-6 alkylidene chain, wherein up to two methylene units of the chain are each optionally and independently replaced by —

NR′

—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR′

—

, —

NR′

CO—

, —

NR′

CO₂—

, —

SO₂NR′

—

, —

NR′

SO₂—

, —

CONR′

NR′

—

, —

NR′

CONR′

—

, —

OCONR′

—

, —

NR′

NR′

—

, —

NR′

SO₂NR′

—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR′

—

; and

wherein any carbon atom in the one or more methylene units is optionally substituted with one or two occurrences of R⁶, wherein each occurrence of R⁶ is independently halogen, —

CN, —

NO₂, or —

U_nR′

, or two occurrences of R⁶, or R′ and

R⁶, taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring; and

Ar¹ and Ar² are each independently selected from a C_1-6 aliphatic, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein Ar¹ and Ar² are each optionally substituted with 0-5 independent occurrences of TR⁷;

wherein T is a bond or is a C₁-C₆ alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —

NR—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR—

, —

NRCO—

, —

NRCO₂—

, —

SO₂NR—

, —

NRSO₂—

, —

CONRNR—

, —

NRCONR—

, —

OCONR—

, —

NRNR—

, —

NRSO₂NR—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR—

; and

each occurrence of R⁷ is independently selected from —

R′

, halogen, —

NO₂, —

CN or ═

O.

2. The compound according to claim 1, having one of formulae II-VII:

wherein R^1Z1, R^1Z2, R^1Z3 and R^1Z4 are each independently selected from H, halogen, —

CN, —

NO₂, or —

V_mR′

.

5. The compound according to claim 1, wherein X₁ is CR⁴ and X₂ is N or CR⁴.

7. The compound according to claim 1, wherein each R¹ is independently selected from H, halogen or C_1-3 aliphatic.

14. The compound according to claim 1, wherein Q¹ is —

CO—

, —

SO₂—

, —

NR², —

NR²CO—

, —

CONR²—

, —

SO₂NR².

15. The compound according to claim 14, wherein G is —

NR² and Q¹ is —

CO—

, or G is —

CO— and

Q¹ is —

NR²—

.

16. The compound according to claim 15, wherein R² is H, —

C_1-4 aliphatic, -cyclopropyl, (CH₂)_1-3OH or

18. The compound according to claim 1, wherein R³ is Q²-Ar¹.

19. The compound according to claim 18, wherein Q² is —

(CHR⁶)_q—

, —

(CHR⁶)_qO—

, —

(CHR⁶)_qS—

, —

(CHR⁶)_qS(O)₂—

, —

(CHR⁶)_qS(O)—

, —

(CHR⁶)_qNR—

, or —

(CHR⁶)_qC(O)—

, wherein q is 0, 1, 2, or 3, and each R⁶ is R′

, —

N(R)(R′

), —

(CH₂)_1-4N(R)(R′

), —

(CH₂)_1-4C(CH₃)₂N(R)(R′

), —

(CH₂)_1-4CH(CH₃)N(R)(R′

), —

OR′

, —

(CH₂)_1-4OR′

, —

NR(CH₂)_1-4N(R)(R′

), —

NR(CH₂)_1-4SO₂R′

, —

NR(CH₂)_1-4COOR′

, or —

NR(CH₂)_1-4COR′

, or two occurrences of R⁶, taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or fully unsaturated ring.

22. The compound according to claim 18, wherein Ar¹ is a C_3-6 aliphatic, a 5-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein Ar¹ is optionally substituted with 0-5 independent occurrences of TR⁷.

23. The compound according to claim 22, wherein Ar¹ is

wherein t is 0, 1, 2, 3, 4, or 5, and wherein any Ar¹ is bonded to Q² through any substitutable nitrogen or carbon atom, and wherein one or more hydrogen atoms on any substitutable nitrogen or, carbon atom is substituted with one or more independent occurrences of TR⁷.

27. The compound according to claim 22, wherein TR⁷ is selected from —

F, —

Cl, —

CN, —

NH₂, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

OR^x, —

OCF₃, —

NR^xSO₂R^x, —

NR^xSO₂N(R^x)₂, —

COOC(CH₃)₃, —

OSO₂CH₃, —

OH, —

SO₂N(R^x)₂, —

SO₂N(R^x)₂, —

SO₂R^x, -pyrollidinone, tetrahydrofuran or -D-(CH₂)_p—

Y, wherein R^x is a H or a C_1-4 alkyl, D is —

SO₂—

, —

SO₂NH—

, —

NHSO₂—

or —

O—

, p is 0-3, and Y is selected from;

wherein R^y is H or C_1-3 alkyl, and wherein one or more carbon atoms of Y is optionally substituted with ═

O.

32. The compound according to claim 1, wherein said compound has a structure depicted in Table 1.

33. A composition comprising an effective amount of compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

34. The composition of claim 33, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, 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.

35. A method of inhibiting ROCK kinase activity in a biological sample;

which method contacting said biological sample with a compound of claim 1 or a composition comprising said compound.

36. A method of treating or lessening the severity of a disease condition or disorder selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a compound according to claim 1 or a composition comprising said compound.

37. The method of claim 36, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an anti-psychotic agent, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, 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.

3-4. -4. (canceled)

6. (canceled)

8-13. -13. (canceled)

17. (canceled)

20-21. -21. (canceled)

24-26. -26. (canceled)

28-31. -31. (canceled)

38-40. -40. (canceled)