Pyrrolopyrimidines useful as inhibitors of protein kinase

• US 20060183761A1
• Filed: 02/01/2006
• Published: 08/17/2006
• Est. Priority Date: 02/03/2005
• Status: Active Grant

• Current Assignee: Albert Pierce, David Messersmith, Farmer LUC, Francesco Salituro, Guy Bemis, Jian Wang, John Duffy, Mark Ledeboer, Tiansheng Wang
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Ledeboer, Mark, Farmer, Luc, Messersmith, David, Wang, Tiansheng, Pierce, Albert, Bemis, Guy, Wang, Jian, Duffy, John, Salituro, Francesco
• Granted Patent: US 8,633,205 B2
• Time in Patent Office: Days
• US Class Current: 514/265.100
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• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
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• 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
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• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. 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

R¹ is H, —

NO₂, —

CN, —

OCF₃, halogen, or amino;

or C_1-6aliphatic, C_3-7cycloaliphatic, C_1-6alkoxy, or C_1-4haloalkyl optionally substituted with 0-10 J^R groups;

R² is H, —

NO₂, —

CN, —

OCF₃, halogen, or amino;

or C_1-6aliphatic, C_3-7cycloaliphatic, C_1-6alkoxy, or C_1-4haloalkyl optionally substituted with 0-10 J^R groups;

Z¹ is C_1-6aliphatic or C_3-10cycloaliphatic optionally substituted with 0-10 J^Z groups;

if the bond between Z¹ and C is a double bond, then Z¹ may also be ═

O, ═

NR, or ═

C(R)₂;

Z² is H or halogen;

or C_1-10haloalkyl, C_1-4haloalkoxy, Y, -(V_n)—

CN, -(V_n)—

NO₂, -(V_n)—

OH, -(V_n)-(C_1-6aliphatic), -(V_n)-(C_3-12heterocyclyl), -(V_n)-(C_6-10aryl), -(V_n)-(5-10 membered heteroaryl), or -(V_n)-(C_3-10cycloaliphatic) optionally substituted with 0-10 J^Z groups;

or

Z¹ and Z², together with the carbon atom to which they are attached, form ring Q;

Z³ is H or C_1-6alkyl optionally substituted with 0-3 J^Z groups;

or

Z¹, Z², and Z³, together with the carbon atom to which they are attached, form an 6-14 membered saturated, partially saturated, or unsaturated bicyclic ring having 0-3 heteroatoms;

if the bond between Z¹ and C is a triple bond, then Z² is absent;

if the bond between Z¹ and C is a double bond or a triple bond, then Z³ is absent;

Q is a 3-8 membered saturated or partially saturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said Q is optionally and independently fused to Q¹ or Q²;

or to both Q¹ and Q²;

wherein said Q is optionally substituted with 0-4 J^Q groups;

Q¹ is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said Q¹ group is optionally substituted with 0-4 J^Q groups;

Q² is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur wherein said Q² group is optionally substituted with 0-4 J^Q groups;

R is H, optionally substituted C_1-6 aliphatic, C_{3 -}10 cycloaliphatic, C_6-10 aryl, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl;

or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-14 membered saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein each R is optionally substituted with 0-10 J^R groups;

each J^Q and J^Z substituent on an unsaturated carbon atom is independently selected from hydrogen, —

OCF₃, C_1-6haloalkyl, N(R)₂, OR, halogen, Y, -(V_n)—

CN, -(V_n)—

NO₂, -(V_n)—

OH, -(V_n)-(C_1-6aliphatic), -(C_1-3cycloaliphatic)—

C(O)R, -(C_3-10cycloaliphatic)-(C_3-12heterocyclyl);

-(V_n)-(C_3-12heterocyclyl), -(V_n)-(C_6-10aryl), -(V_n)-(5-10 membered heteroaryl), -(V_n)-(C_3-10cycloaliphatic);

wherein each J^Q and J^Z is optionally substituted with up to 10 J^R groups;

each J^Q and J^Z substituent on a saturated carbon atom is selected from those listed above for an unsaturated carbon and also the following;

═

O, ═

NN(R^a)₂, ═

NNHC(O)R^a, ═

NNHCO₂(C_1-4alkyl), ═

NNHSO₂(C_1-4alkyl), and ═

NR^a wherein each J^Q and J^Z is optionally substituted with up to 10 J^R groups;

each J^Q and J^Z substituent on a nitrogen atom is independently selected from hydrogen, Y, -(V_n)—

CN, -(V_n)—

NO₂, -(V_n)—

OH, -(V_n)-(C_1-6aliphatic), -(C_3-10-cycloaliphatic)-C(O)R, -(C_3-10cycloaliphatic)-(C_3-12heterocyclyl), -(V_n)-(C_3-12heterocyclyl), -(V_n)-(C_6-10aryl), -(V_n)-(5-10 membered heteroaryl), -(V_n)-(C_3-10cycloaliphatic);

wherein two J^Z groups, on the same substituent or different substituents, together with the atom(s) to which each J^Z group is bound, can optionally form an optionally substituted 3-14 membered saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein each J^Q and J^Z is optionally substituted with up to 10 J^R groups;

J^R is selected from halogen, —

N(R^b)₂, SR^b, OR^b, oxo, C_1-4haloalkoxy, C_1-4haloalkyl, L, -(L_n)-(C_1-6alkyl), -(L_n)-(C_3-12heterocyclyl), -(L_n)-(C_6-10aryl), -(L_n)-(5-10 membered heteroaryl), -(L_n)-(C_3-10cycloalipahtic), -(L_n)—

NO₂, -(L_n)—

CN, -(L_n)—

OH, —

CO₂R^b, —

COR^b, —

OC(O)R^b, —

NC(O)R^b;

L is C_1-10alkyl wherein up to three methylene units are replaced by —

NR^b, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NR^b—

, —

C(═

N-CN), —

NR^bCO—

, —

NR^bC(O)O—

, —

SO₂NR^b—

;

—

NR^bSO₂—

, —

NR^bC(O)NR—

, —

OC(O)NR^b—

, -NR^bSO₂NR^b, —

SO—

, or —

SO₂—

;

V is C_1-10aliphatic wherein up to three methylene units are replaced by G^V, wherein G^V is selected from —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NR—

, —

C(═

N—

CN), —

NRCO—

, —

NRC(O)O—

, —

SO₂NR—

, —

NRSO₂—

, —

NRC(O)NR—

, —

OC(O)NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

;

Y is C_1-10aliphatic, wherein up to three methylene units are replaced by G^Y wherein G^Y is selected from —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NR—

, —

C(═

N—

CN), —

NRCO—

, —

NRC(O)O—

, —

SO₂NR—

, —

NRSO₂—

, —

NRC(O)NR—

, —

OC(O)NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

;

R^a is hydrogen or C_1-6 aliphatic group optionally substituted with 0-3 J^R groups;

R^b is hydrogen or an unsubstituted C_1-6 aliphatic group;

n is 0 or 1;

provided that;

when R¹ and R² are H, and Z² and Z³ are H, then Z¹ is not methyl;

when R¹ is CH₃ and R² is H, then Z¹, Z², and Z³ are not all H;

when R¹ and R² are H, and Z² and Z³ are H, then Z¹ is not unsubstituted phenyl, 4-pyridyl, or one of the structures shown below;

when R¹ and R² are H, Z¹ and Z² taken together are not -C≡

C-CH₂CH₂COOH.

2. The compound according to claim 1 wherein Z¹, Z², and Z³, together with the carbon atom to which they are attached, form the bicyclic ring shown in Formula II:

wherein

Q³ is 3-8 membered saturated, unsaturated, or partially saturated monocyclic ring;

Q and Q³ are each optionally and independently substituted with 0-4 J^Q groups.

3. The compound according claim 1 wherein Q³ is a cyclopropyl group and both Q and Q³ are each optionally substituted with 0-2 J^Q groups as shown in formula III:

4. The compound according to claim 1, wherein Z¹ and Z², together with the carbon atom to which they are attached, form a compound as shown in Formula IV:

wherein

Z¹¹ is selected from C, N, O, or S;

Z¹² is selected from C, N, O, or S;

Q is a 3-8 membered saturated or partially saturated monocyclic ring, optionally fused to Q¹ or Q²;

Q¹ and Q² are each independently a 3-8 membered saturated, unsaturated, or partially saturated monocyclic ring;

Q, Q¹ and Q² each independently contain up to three heteroatoms selected from O, N, or S;

m is is 0-4; and

is independently selected for Q, Q¹ and Q²; and

Z³ is H;

or if the bond between C and Z^{11 1} is a double bond, then Z³ is absent.

24. The compound according to claim 1, wherein Q or Q-Q¹ is represented is selected from

wherein

both R⁷ and J^Q are each independently selected from hydrogen, Y, -(V_n)—

CN, -(V_n)—

NO₂, -(V_n)—

OH, -(V_n)-(C_1-6aliphatic), -(V_n)-(C_3-12heterocyclyl), -(V_n)-(C_6-10aryl), -(V_n)-(5-10 membered heteroaryl), -(V_n)-(C_3-10cycloaliphatic), and -(C_3-10cycloaliphatic)-(C_3-12heterocyclyl);

each Q and Q¹, m is independently 0-3; and

each R⁷ and J^Q is optionally and independently substituted with 0-10 J^R groups.

36. The compound according to claim 1 having formula VII:

wherein A is selected from;

37. The compound according to claim 1, wherein Z¹ and Z² do not join to form a ring and Z³ is H or is absent.

38. The compound according to claim 37, wherein Z¹ is H or C_1-6aliphatic optionally substituted with 0-3 J^Z groups.

60. The compound according to claim 1 having formula VIII:

wherein A is selected;

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

63. The composition of claim 62, 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 diabetes, or an agent for treating immunodeficiency disorders.

65. A method of inhibiting JAK3 kinase activity in a patient comprising administering to said patient a compound according to claim 1 or a composition comprising said compound.

66. A method of inhibiting JAK3 kinase activity in a biological sample comprising administering to contacting said biological sample with a compound according to claim 1 or a composition comprising said compound.

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

72. A method of inhibiting JAK2 kinase activity in a patient comprising administering to said patient a compound according to claim 1 or a composition comprising said compound.

73. A method of inhibiting JAK2 kinase activity in a biological sample comprising administering to contacting said biological sample with a compound according to claim 1 or a composition comprising said compound.

74. A method of treating or lessening the severity of a myeloproliferative disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1 or a composition comprising said compound.

77. A method of inhibiting ROCK kinase activity in a patient comprising administering to said patient a compound according to claim 1 or a composition comprising said compound.

79. 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.

5-23. -23. (canceled)

25-35. -35. (canceled)

39-59. -59. (canceled)

61. A compound selected from Table 3.

64. (canceled)

68-71. -71. (canceled)

75-76. -76. (canceled)

78. (canceled)

80-86. -86. (canceled)