Thienopyridone derivatives as kinase inhibitors
A series of thieno[2,3-b]pyridin-6(7H)-one derivatives, substituted in the 2-position by a carbonyl- or sulfonyl-linked pyrrolidin-3-yl, pyrrolidin-3-ylamino or related moiety, being inhibitors of p38 MAP kinase, are accordingly of use in medicine, for example in the treatment and/or prevention of immune or inflammatory disorders.
1 . A compound of formula (1):
wherein:
X is a covalent bond or the group —N(R)—;
Y is a linking group —C(O)— or —S(O) 2 —;
n is zero or the integer 1;
m is the integer 1, 2 or 3;
p is zero or the integer 1, 2, 3 or 4;
q is zero or the integer 1 or 2;
R is a hydrogen atom or a straight or branched C 1-6 alkyl group;
R d is —OH, -(Alk 2 )OH, —OR 1 , -(Alk 2 )OR 1 , —NR 2 R 3 , -(Alk 2 )NR 2 R 3 or a straight or branched C 1-6 alkyl group;
Alk 2 is a straight or branched C 1-4 alkylene chain;
R 1 is a straight or branched C 1-6 alkyl group
R 1 and R 3 which may be the same or different, are each independently a hydrogen atom or a straight or branched C 1-6 alkyl group;
L is a linking atom or group —O—, —S—, —S(O)—, —S(O 2 )—, —CH 2 —, —CH(R d )—, —C(R d ) 2 — or —NR y —;
R y is a hydrogen atom or a C 1-4 alkyl group;
Alk 1 is a straight or branched C 1-4 alkylene chain;
Cy 1 is an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group; and
Ar is an optionally substituted aromatic or heteroaromatic group;
or a salt, solvate, hydrate or N-oxide thereof.
2 . A compound as claimed in claim 1 wherein Y is —C(O)—.
3 . A compound as claimed in claim 1 wherein m is 1 or 2.
4 . A compound as claimed in claim 1 wherein q is zero or 1.
5 . A compound as claimed in claim 1 wherein L is —CH 2 —, —CH(R d )—, —NH— or —N(CH 3 ).
6 . A compound as claimed in claim 1 wherein Cy 1 is phenyl, fluorophenyl, chlorophenyl, methylphenyl or cyclopropyl.
7 . A compound as claimed in claim 1 wherein Ar is phenyl, difluorophenyl, (chloro)(fluoro)phenyl, (fluoro)(methyl)phenyl, chlorophenyl, cyanophenyl, methylphenyl or methylpyridinyl.
8 . A compound as claimed in claim 1 that is
3-[(2,4-Difluorophenyl)amino]-N-[(1R*,2S*)-2-hydroxycyclopentyl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-[(1R*,2R*)-2-hydroxycyclopentyl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-[(1S,2S)-2-hydroxycyclopentyl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-[(1R,2R)-2-hydroxycyclopentyl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
rac-3-[(2,4-Difluorophenyl)amino]-6-oxo-7-phenyl-N-(pyrrolidinyl-3-yl)-6,7-dihydrothieno[2,3-b]-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-6-oxo-7-phenyl-N-[(3R)-pyrrolidinyl-3-yl]-6,7-dihydrothieno[2,3-b]-2-carboxamide;
3-Anilino-7-phenyl-2-(piperidin-4-ylcarbonyl)thieno[2,3-b]pyridin-6(7H)-one, 3-[(4-Fluoro-3-methylphenyl)amino]-7-phenyl-2-(piperidin-4-ylcarbonyl)-thieno[2,3-b]pyridin-6(7H)-one;
N-(Azetidin-3-yl)-3-[(4-fluoro-3-methylphenyl)amino]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-6-oxo-7-phenyl-N-[(3S)-pyrrolidinyl-3-yl]-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-[(3S)-1-methylpyrrolidin-3-yl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-[(3R)-1-methylpyrrolidin-3-yl]-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-6-oxo-7-phenyl-N-(piperidin-4-yl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;
3-[(2,4-Difluorophenyl)amino]-N-(1-methylpiperidin-4-yl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide,
3-[(2,4-Difluorophenyl)amino]-7-phenyl-2-(piperidin-4-ylcarbonyl)-thieno[2,3-b]pyridin-6(7H)-one;
3-[(6-Methylpyridin-2-yl)amino]-7-phenyl-2-(piperidin-4-ylcarbonyl)-thieno[2,3-b]pyridin-6(7H)-one; or
3-[(4-Fluoro-3-methylphenyl)amino]-2-[(1-methylpiperidin-4-yl)carbonyl]-7-phenylthieno[2,3-b]pyridin-6(7H)-one.
9 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof, in association with a pharmaceutically acceptable carrier.
10 . (canceled)
11 . A method for the treatment or prevention of a disorder for which an inhibitor of p38 MAP kinase is indicated, which comprises administering to a patient in need of such treatment a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof.
12 . The method of claim 11 wherein the disorder is an autoimmune disease, inflammatory disease, destructive bone disorder, proliferative disorder, neurodegenerative disorder, viral disease, allergy, infectious disease, heart attack, angiogenic disorder, reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin-induced platelet aggregation, or a condition associated with prostaglandin endoperoxidase synthetase-2 (COX-2).
13 . The method of claim 12 wherein the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs host disease, or psoriasis.
14 . The method of claim 12 wherein the inflammatory disease is asthma, an allergy, respiratory distress syndrome, or acute or chronic pancreatitis.
15 . The method of claim 12 wherein the destructive bone disorder is osteoporosis, osteoarthritis, or multiple myeloma-related bone disorder.
16 . The method of claim 12 wherein the proliferative disorder is acute or chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma, or multiple myeloma.
17 . The method of claim 12 wherein the neurodegenerative disorder is Parkinson's disease, Alzheimer's disease, cerebral ischemia, or a neurodegenerative disease caused by traumatic injury.
18 . The method of claim 12 wherein the viral disease is hepatitis A infection, hepatitis B infection, hepatitis C infection, HIV infection, or CMV retinitis.
19 . The method of claim 12 wherein the infectious disease is septic shock, sepsis, or Shigellosis.
20 . The method of claim 12 wherein the condition associated with prostaglandin endoperoxidase synthetase-2 (COX-2) is edema, analgesia, neuromuscular pain, headache, dental pain, arthritis pain, or pain caused by cancer.
21 . The method of claim 12 wherein the disease or disorder associated with the production of TNF is rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, ARC or malignancy, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, HIV, CMV, influenza, herpes.
22 . The method of claim 12 wherein the disease or disorder associated with the production of TNF is infection by a veterinary virus selected from equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus, feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
23 . The method of claim 12 wherein the disease or disorder associated with the production of IL-1 is rheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, stroke, endotoxemia, toxic shock syndrome, inflammatory reaction induced by endotoxin, diabetes, pancreatic β-cell disease, Alzheimer's disease, tuberculosis, atherosclerosis, muscle degeneration, or cachexia.
24 . The method of claim 12 wherein the disease or disorder associated with the production of IL-8 is psoriasis; inflammatory bowel disease; asthma; cardiac, brain, or renal reperfusion injury; adult respiratory distress syndrome; thrombosis; or glomerulonephritis.
25 . The method of claim 12 wherein the disease or disorder associated with the production of IL-6 or IL-8 is an infection caused by human rhinovirus (HRV), an enterovirus, a coronavirus, an influenza virus, a parainfluenza virus, a respiratory syncytial virus, or an adenovirus.