Inhibitors of Src and other protein kinases
View Patent ↗The present invention provides compounds of formula I: wherein A is N or CR, and G, R 1 , R 2 and R 3 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of Src mammalian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
G is —XR or —XAr;
each X is independently selected from a C 1-4 alkylidene chain, wherein one or two non-adjacent methylene units of X are independently replaced by —S—, —SO—, —SO 2 —, —O—, or —NH—;
A is N;
each R is independently selected from hydrogen or an optionally substituted C 1-8 aliphatic group;
Ar is an optionally substituted ring selected from phenyl, pyridyl, imidazolyl, thienyl, thiazolyl, [1,3]dioxanyl, piperidinyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, pyranyl, imidazolyl, benzimidazolyl, pyrrolyl, piperazinyl, thiomorpholinyl, naphthyl, oxazolyl, triazinyl, tetrazolyl, dithiolanyl, dioxalanyl, benzofuranyl, benzothienyl, or indolyl;
R 1 is T (n) -R or T (n) attached to an optionally susbtituted ring selected from phenyl, cyclohexyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, or indanyl;
n is zero or one;
T is selected from —C(O)—, —CO 2 —, —C(O)C(O)—, —C(O)CH 2 C(O)—, —CONR—, —S(O) 2 —, or —S(O) 2 NR—;
R 2 is selected from hydrogen, Ar, or a C 1-8 aliphatic group optionally substituted with 1-3 groups independently selected from oxo, OR, SR, SO 2 R, C(O)R, CO 2 R, CN, N(R) 2 , ═N—OR, ═NN(R) 2 , ═NNHC(O)R, ═NNHCO 2 R, ═NNHSO 2 R, Ar, NRC(O)N(R) 2 , NRC(O)R, NRCO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , or NRSO 2 N(R) 2 ; and
R 3 is selected from R or an optionally substituted ring selected from cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, or pyridazinyl.
2. The compound according to claim 1 , wherein:
R is a C 1-4 aliphatic group optionally substituted with halo, CN, oxo, N(R o ) 2 , OH, OR o , CO 2 R o , C(O)R o , C(O)N(R o ) 2 , NR o CO 2 R o , SR o , NR o SO 2 R o , SO 2 R o , NR o C(O)R o , OC(O)R o , or NR o C(O)N(R o ) 2 , wherein each R o group is independently selected from hydrogen or C 1-4 aliphatic;
Ar is an optionally substituted ring selected from phenyl, pyridyl, imidazolyl, thienyl, thiazolyl, [1,3]dioxanyl, piperidinyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, pyranyl, imidazolyl, benzimidazolyl, pyrrolyl, piperazinyl, thiomorpholinyl, naphthyl, oxazolyl, triazinyl, tetrazolyl, dithiolanyl, dioxalanyl, benzofuranyl, benzothienyl, or indolyl; and
R 3 is selected from an optionally substituted cyclohexyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, or pyridazinyl ring.
3. The compound according to claim 1 , wherein:
R 2 is selected from R, CH 2 N(R) 2 , or CH 2 Ar, wherein:
each R is independently selected from hydrogen or optionally substituted C 1-4 aliphatic, and
Ar is an optionally substituted ring selected from phenyl, pyridyl, [1,3]dioxanyl, piperidinyl, morpholinyl pyranyl, or piperazinyl.
4. The compound according to claim 1 , wherein:
when n is zero, then R 1 is T (n) attached to an attached to an optionally subsbtituted rin selected from phenyl, cyclohehyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, or indanyl.
5. The compound according to claim 4 , wherein:
R 1 is phenyl, cyclohexyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, or indanyl, wherein:
R 1 is optionally substituted with 1-3 groups independently selected from R o , halogen, NO 2 , CN, OR o , SR o , N(R o ) 2 , CO 2 R o , C(O)R o , CON(R o ) 2 , phenyl, SO 2 R o , or NR o C(O)R o , wherein each R o is independently selected from hydrogen or an optionally substituted C 1-4 aliphatic.
6. The compound according to claim 5 , wherein R 1 is optionally sutstituted with 1-3 groups independently selected from methyl, ethyl, oxo, CF 3 , Ome, C(O)Me, C(O)phenyl, CH═CH, CO 2 H, C(O)NH 2 , SMe, CO 2 Me, fluoro, SO 2 Me, NO 2 , OC, chloro, N(Me) 2 , NHC(O)Me, NH 2 , cyanophenyl, CO 2 Et, CH 2 OH, CH 2 OMe, 3-CH 2 CO 2 H-phenyl, or 3-CH 2 CH 2 CO 2 H-phenyl.
7. The compound according to claim 4 , wherein:
R 2 is selected from R, CH 2 N(R) 2 , or CH 2 Ar, wherein:
each R is independently selected from hydrogen or optionally substituted C 1-4 aliphatic, and
Ar is an optionally substituted ring selected from phenyl, cyclohexyl, or pyridyl.
8. A compound selected from:
No.
S-R
R 2
R 3
R 4
R 5
R 6
R 7
IIA-1
SCH 3
Me
Ph
H
H
H
H
IIA-2
SCH 3
Me
Ph
H
H
OMe
H
IIA-3
SCH 3
Me
Ph
H
OMe
OMe
H
IIA-4
SCH 3
Me
Ph
Me
H
H
H
IIA-5
SCH 3
Me
Ph
Me
H
CONH 2
H
IIA-6
SCH 3
Me
Ph
Me
H
CN
H
IIA-7
SCH 3
Me
Ph
H
CN
H
H
IIA-8
SCH 3
Me
Ph
Me
F
H
H
IIA-9
SCH 3
Me
Ph
Me
H
F
H
IIA-10
SCH 3
Me
Ph
CF 3
H
H
H
IIA-11
SCH 3
Et
Ph
H
CN
H
H
IIA-12
SCH 3
Et
Ph
H
CO 2 H
H
H
IIA-13
SCH 3
Me
Ph
H
F
H
H
IIA-14
SCH 3
Me
Ph
H
H
F
H
IIA-15
SCH 3
Me
Ph
H
H
COMe
H
IIA-16
SCH 3
Me
Ph
H
H
COPh
H
IIA-17
SCH 3
Me
Ph
H
H
CONH 2
H
IIA-18
SCH 3
Me
Ph
H
OMe
H
OMe
IIA-19
SCH 3
Me
Ph
H
F
H
H
IIA-20
SCH 3
Me
Ph
H
H
CN
H
IIA-21
SCH 3
Me
Ph
H
H
COMe
H
IIA-22
SCH 3
Me
Ph
H
CH═CH
H
H
IIA-23
SCH 3
Me
Ph
H
SMe
H
H
IIA-24
SCH 3
Me
Ph
H
Me
CN
H
IIA-25
SCH 3
Me
Ph
H
COMe
H
H
IIA-26
SCH 3
Et
Ph
H
H
H
H
IIA-27
SCH 3
Me
Ph
OMe
H
H
H
IIA-28
SCH 3
Me
Ph
H
H
F
H
IIA-29
SCH 3
Me
Ph
H
CO 2 H
H
H
IIA-30
SCH 3
Me
Ph
H
H
Ph
H
IIA-31
SCH 3
Me
Ph
H
Me
H
Me
IIA-32
SCH 3
Me
Ph
H
H
SMe
H
IIA-33
SCH 3
Me
Ph
H
H
OMe
H
IIA-34
SCH 3
Me
Ph
H
OMe
H
H
IIA-35
SCH 3
Me
Ph
OMe
H
H
CN
IIA-36
SCH 3
Me
Ph
H
CO 2 Me
H
H
IIA-37
SCH 3
Me
Ph
F
H
H
CN
IIA-38
SCH 3
Me
Ph
H
H
H
H
IIA-39
SCH 3
Me
Ph
H
H
CO 2 H
H
IIA-40
SCH 3
Me
Ph
Me
H
CN
H
IIA-41
SCH 3
Me
Ph
F
H
F
H
IIA-42
SCH 3
Me
Ph
Me
H
CONH 2
H
IIA-43
SCH 3
Me
Ph
Me
Cl
H
H
IIA-44
SCH 3
Me
Ph
F
H
H
H
IIA-45
SCH 3
Me
Ph
Me
H
OMe
H
IIA-46
SCH 3
Me
Ph
OMe
H
H
H
IIA-47
SCH 3
Me
Ph
H
H
SO 2 Me
H
IIA-48
SCH 3
Me
Ph
H
H
CO 2 Me
H
IIA-49
SCH 3
Me
Ph
NO 2
H
H
H
IIA-50
SCH 3
Me
Ph
H
CN
H
H
IIA-51
SCH 3
Me
Ph
H
H
CN
H
IIA-52
SCH 3
Me
Ph
CHCH
H
H
H
IIA-53
SCH 3
Me
Ph
Me
F
H
H
IIA-54
SCH 3
Me
Ph
Cl
H
H
OMe
IIA-55
SCH 3
Me
Ph
H
Me
OMe
H
IIA-56
SCH 3
Me
Ph
Me
H
F
H
IIA-57
SCH 3
Me
Ph
SMe
H
H
H
IIA-58
SCH 3
Me
Ph
OMe
H
H
OMe
IIA-59
SCH 2 CH 3
Me
Ph
H
H
H
H
IIA-60
SCH 2 CH 3
Me
Ph
H
CN
H
H
IIA-61
SCH 2 CH 3
Me
Ph
H
H
CN
H
IIA-62
SCH 2 CH 3
Me
Ph
H
F
H
H
IIA-63
SCH 2 CH 3
Me
Ph
H
H
F
H
IIA-64
SCH 2 CH 3
Me
Ph
H
Me
CN
H
IIA-65
SCH 2 CH 3
Me
Ph
H
F
CN
H
IIA-66
SCH 2 CH 3
Me
Ph
H
H
SMe
H
IIA-67
SCH(CH 3 ) 2
Me
Ph
H
H
H
H
IIA-68
SCH 2 CH(CH 3 ) 2
Me
Ph
H
H
H
H
IIA-69
S-propyl
Me
Ph
H
H
H
H
IIA-70
S-butyl
Me
Ph
H
H
H
H
IIA-71
S-pentyl
Me
Ph
H
H
H
H
IIA-72
S-hexyl
Me
Ph
H
H
H
H
IIA-73
S-heptyl
Me
Ph
H
H
H
H
IIA-74
S-octyl
Me
Ph
H
H
H
H
IIA-75
SCH 2 CN
Me
Ph
H
H
H
H
IIA-76
SCH 2 CH 2 OCH 3
Me
Ph
H
H
H
H
IIA-77
SCH 2 CH 2 CF 3
Me
Ph
H
H
H
H
IIA-78
SCH 2 (cyclopropyl)
Me
Ph
H
H
H
H
IIA-79
SCH 2 C(═O)CH 3
Me
Ph
H
H
H
H
IIA-80
SCH 2 CH 2 N(CH 3 ) 2
Me
Ph
H
H
H
H
IIA-81
SCH 2 CH 2 NHCOCH 3
Me
Ph
H
H
H
H
IIA-82
SCH 2 CH 2 NHCO 2 CH 3
Me
Ph
H
H
H
H
IIA-83
SCH 2 CH 2 OC(═O)CH 3
Me
Ph
H
H
H
H
IIA-84
SCH 2 CH(NH 2 )CO 2 Et
Me
Ph
H
H
H
H
IIA-85
SCH 2 C≡CCH 3
Me
Ph
H
H
H
H
IIA-86
S-propyl
Me
Ph
H
H
COMe
H
IIA-87
S-propyl
Me
Ph
H
CN
H
H
IIA-88
S-propyl
Me
Ph
H
H
CN
H
IIA-89
S-propyl
Me
Ph
H
F
H
H
IIA-90
S-propyl
Me
Ph
H
H
F
H
IIA-91
S-propyl
Me
Ph
H
CN
F
H
IIA-92
S-propyl
Me
Ph
H
H
SMe
H
IIA-93
SCH 3
Me
Ph
H
H
NMe 2
H
IIA-94
SCH 3
Me
Ph
H
NO 2
H
H
IIA-95
SCH 3
Me
Ph
H
NHAc
H
H
IIA-96
SCH 3
Me
Ph
H
NH 2
H
H
IIA-97
SCH 3
Me
Ph
H
Me
H
H
IIA-98
SCH 3
Me
Ph
H
H
Me
H
IIA-99
S-butyl
Me
Ph
H
F
CN
H
IIA-100
S-butyl
Me
Ph
H
F
H
H
IIA-101
S-butyl
Me
Ph
H
H
CN
H
IIA-102
S-butyl
Me
Ph
H
Me
H
H
IIA-103
S-butyl
Me
Ph
H
CN
H
H
IIA-105
S-pentyl
Me
Ph
H
F
CN
H
IIA-106
S-pentyl
Me
Ph
H
CN
H
H
IIA-107
SCH 2 CH(CH 3 ) 2
Me
Ph
H
F
CN
H
IIA-108
SCH 2 CH(CH 3 ) 2
Me
Ph
H
CN
H
H
IIA-109
SCH 2 CH(CH 3 ) 2
Me
Ph
IIA-110
SCH 2 C≡CCH 3
Me
Ph
H
F
CN
H
IIA-111
SCH 2 C≡CCH 3
Me
Ph
H
CN
H
H
IIA-112
SCH 2 C≡CCH 3
Me
Ph
H
H
H
H
IIA-113
SCH 3
Me
Ph
H
CO 2 Et
H
H
IIA-114
SCH 3
Me
Ph
H
H
Cl
H
IIA-115
SCH 3
Me
Ph
H
Cl
H
H
IIA-116
SCH 3
Me
Ph
H
H
NO 2
H
IIA-117
SCH 3
Me
Ph
H
OCH 2 Ph
H
H
IIA-118
SCH 3
Me
Ph
H
H
OCH 2 Ph
H
IIA-119
SCH 3
Me
Ph
H
OH
H
H
IIA-120
SCH 3
Me
Ph
IIA-121
SCH 3
Me
Ph
IIA-122
SCH 3
Me
Ph
IIA-123
SCH 3
Me
2-Pyr
H
H
H
H
IIA-124
SCH 3
Me
2-Pyr
H
OCH 2 Ph
H
H
IIA-125
SCH 3
Me
3-Pyr
H
OCH 2 Ph
H
H
IIA-126
SCH 3
Me
4-Pyr
H
OCH 2 Ph
H
H
IIA-127
SCH 3
Me
Ph
H
Cl
H
H
IIA-128
SCH 3
Me
2-Pyr
H
H
OCH 2 Ph
H
IIA-129
CH 2 CH 2 SCH 3
Me
Ph
H
OCH 2 Ph
H
H
IIA-130
CH 2 CH 2 SCH 3
Me
Ph
H
OPh
H
H
IIA-131
CH 2 CH 2 SCH 3
Me
Ph
H
Cl
H
H
IIA-132
CH 2 CH 2 SCH 3
Me
Ph
H
OMe
H
H
IIA-133
CH 2 CH 2 SCH 3
Me
Ph
H
CO 2 CH 3
H
H
IIA-134
SCH 3
Me
Ph
H
OH
H
H.
9. A compound selected from:
No.
S-R
A
R 1
IIA-137
SCH 3
N
IIA-138
SCH 3
N
IIA-139
SCH 3
N
IIA-140
SCH 3
N
IIA-141
SCH 3
N
IIA-142
SCH 3
N
IIA-143
SCH 3
N
IIA-144
SCH 3
N
IIA-145
SCH 3
N
IIA-146
SCH 3
N
IIA-147
SCH 3
N
IIA-148
S-propyl
N
IIA-149
SCH 3
N
IIA-150
SCH 3
N
IIA-151
SCH 3
N
IIA-152
SCH 3
N
IIA-153
S-butyl
N
IIA-154
S-butyl
N
IIA-155
S—CH 2 CN
N
10. A compound selected from:
11. A compound selected from:
TABLE 5
No.
G
A
R 1
R 2
IC-2
—NH-propyl
N
phenyl
CH 3
IC-3
—NH-butyl
N
3-CN-phenyl
CH 3
IC-4
—NH-isobutyl
N
phenyl
CH 3
IC-5
—NH—CH 2 CH 2 N(CH 3 ) 2
N
3-OCH 3 -phenyl
CH 3
ID-1
—NH-phenyl
N
3-OCH 3 -phenyl
CH 3
ID-2
—NH-benzyl
N
phenyl
CH 3
ID-3
N
phenyl
CH 3
ID-4
N
3,5-(OCH 3 ) 2 -phenyl
CH 3
ID-5
N
3,5-(OCH 3 ) 2 -phenyl
CH 3
ID-6
N
3,5-(OCH 3 ) 2 -phenyl
CH 3
ID-7
N
3,5-(OCH 3 ) 2 -phenyl
CH 3
ID-8
N
3,5-(OCH 3 ) 2 -phenyl
CH 3
ID-9
N
phenyl
CH 3
IE-1
—O—CH 2 CH 2 N(CH 3 ) 2
N
4-CH 3 -phenyl
CH 3
IE-2
—O-isobutyl
N
phenyl
CH 3
IF-1
—O-benzyl
N
3,4-(OCH 3 ) 2 -phenyl
CH 3
IG-2
—SO 2 -butyl
N
phenyl
CH 3
IG-3
—SO 2 CH 3
N
3-OBn-phenyl
CH 3
IH-1
—SO 2 -phenyl
N
3-OCH 3 -phenyl
CH 3
IH-2
SO 2 -(4-CH 3 -phenyl)
N
3,4-(OCH 3 ) 2 -phenyl
CH 3
IH-2
SO 2 -(2-naphthyl)
N
3,4-(OCH 3 ) 2 -phenyl
CH 3
IJ-1
SO-butyl
N
phenyl
CH 3
IK-1
SO-phenyl
N
3-OCH 3 -phenyl
CH 3 .
12. A composition comprising a compound according to any one of claim 8 , 9 , 10 , or 11 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
13. A method of inhibiting JNK3, Lck, or Src kinase activity in a biological sample comprising the step of contacting said biological sample with:
a) a compound according to any one of claim 8 , 9 , 10 , or or 11 ; or
b) a composition according to claim 12 .
14. A method of treating or lessening the severity of a JNK3-, Lck-, or Src-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to claim 12 .
15. A method of treating or lessening the severity of an inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease, neurodegenerative disease, allergy, reperfusion/ischemia in stroke, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation or a condition associated with proinflammatory cytokines comprising the step of administering to said patient a composition according to claim 12 .
16. The method according to claim 15 , wherein said method is used to treat an inflammatory disease selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, or adult respiratory distress syndrome.
17. The method according to claim 15 , wherein said method is used to treat an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, or graft vs. host disease.
18. The method according to claim 15 , wherein said method is used to treat a destructive bone disorders selected from osteoarthritis, osteoporosis or multiple myeloma-related bone disorder.
19. The method according to claim 15 , wherein said method is used to treat a proliferative disease selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, or multiple myeloma.
20. The method according to claim 15 , wherein said method is used to treat neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.
21. The method according to claim 15 , wherein said method is used to treat ischemia/reperfusion in stroke or myocardial ischemia, renal ischemia, heart attacks, organ hypoxia or thrombin-induced platelet aggregation.
22. The method according to claim 15 , wherein said method is used to treat a condition associated with T-cell activation or pathologic immune responses.
23. The method according to claim 15 , wherein said method is used to treat an angiogenic disorder selected from solid tumors, ocular neovasculization, or infantile haemangiomas.
24. The method according to claim 14 , wherein said disease is selected from hypercalcemia, restenosis, hypercalcemia, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obtructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis, or allergic rhinitis.
25. The method according to claim 24 , wherein said disease is selected from hypercalcemia, osteoperosis, osteoarthritis, or sympomatic treatment of bone metastasis.
26. The method according to claim 14 , wherein said disease is selected from autoimmune diseases, allergies, rheumatoid arthritis, and leukemia.