Small molecule modulators of hepatocyte growth factor (scatter factor) activity
The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R 1 , R 2 and B are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role.
1. An isolated compound having the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof;
wherein X is S; and
R is one or more substituents selected from the group consisting of halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d where n —0–2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkyl; an optionally substituted fused aromatic or non-aromatic 5–6 membered monocyclic ring optionally containing 1–3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
wherein each occurrence of R 8 is independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R b and R c is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro and N(R e ) 2; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R d is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6 alkyl optionally substatuted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and each occurrence of R e is independently hydrogen or C 1-6 alkyl.
2. The compound of claim 1 having the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof.
3. A HGF/SF mimetic pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent; and
a compound having the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof;
wherein X is S; and
R is one or more substituents selected from the group consisting of halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d where n —0–2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkyl; an optionally substituted fused aromatic or non-aromatic 5–6 membered monocyclic ring optionally containing 1–3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
wherein each occurrence of R a is independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R b and R c is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro and N(R e ) 2; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R d is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6 alkyl optionally substatuted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and each occurrence of R e is independently hydrogen or C 1-6 alkyl.
4. The composition of claim 3 wherein the compound has the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof.
5. A method for treating or lessening the severity of a disease, condition or disorder selected from fibrotic liver disease; hepatic ischemia-reperfusion injury; cerebral infarction: ischemic heart disease; renal disease; lung (pulmonary) fibrosis; liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, stones in the bile duct, cholangiopathies selected from primary biliary cirrhosis and sclerosing cholangitis, autoimmune hepatitis, and inherited metabolic disorders selected from Wilson's disease, hemochromatosis, and alpha-1antitrypsin deficiency: damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; idiopathic pulmonary fibrosis; wounds; ischemia/reperfusion injury in the brain, heart, liver and kidney; myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; vascular occlusion; liver fibrosis or cirrhosis; radiocontrast nephropathy: fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus;
wherein the method comprises administering to a patient in need thereof:
a compound and optionally a pharmaceutically acceptable carrier or diluent, where the compound has the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof:
wherein X is S; and
R is one or more substituents selected from the group consisting of hydrogen, halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d where n —0–2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkyl; an optionally substituted fused aromatic or non-aromatic 5–6 membered monocyclic ring optionally containing 1–3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
wherein each occurrence of R a is independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R b and R c is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro and N(R e ) 2; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, C 1-5 alkoxy, nitro, and N(R e ) 2 ;
each occurrence of R d is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6 alkyl optionally substatuted with one or more substituents independently selected from halogen, hydroxy, C 1-5 alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and each occurrence of R e is independently hydrogen or C 1-6 alkyl.