Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases

Abstract

The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

1 - 64 . (canceled) 
     
     
         65 . A compound of Formula 1-C or 1-D 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar 1  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein * indicates the bond of attachment of Ar 1  to the 5-membered ring of Formula 1-C or 1-D; 
         Ar 2  is absent; 
         Ar 3  is absent; 
         R 1  is carboxy, cyano, or a carbonyl group which is optionally substituted with a C 1 -C 4  alkoxy group, 
         or a pharmaceutically acceptable salt, hydrate or solvate, clathrate, racemate, stereoisomer or polymorph thereof. 
       
     
     
         66 . The compound of  claim 65 , wherein the compound of Formula 1-C is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof. 
     
     
         67 . The compound of  claim 65 , wherein the compound of Formula 1-D is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof. 
     
     
         68 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, clathrate, polymorph, racemate or stereoisomer thereof. 
     
     
         69 . A method for preventing or treating a disease associated with a gene having a nonsense mutation encoding a premature stop codon in mRNA in a patient in need thereof, comprising administering to said patient a compound of Formula 1-C or 1-D 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar 1  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein * indicates the bond of attachment of Ar 1  to the 5-membered ring of Formula 1-C or 1-D; 
         Ar 2  is absent; 
         Ar 3  is absent; 
         R 1  is carboxy, cyano, or a carbonyl group which is optionally substituted with a C 1 -C 4  alkoxy group, 
         or a pharmaceutically acceptable salt, hydrate or solvate, clathrate, racemate, stereoisomer or polymorph thereof, 
         wherein the premature stop codon results in either or both premature mRNA translation termination or nonsense-mediated mRNA decay, and wherein the disease is selected from cancer, a lysosomal storage disorder, an autoimmune disease, a blood disease, a collagen disease, diabetes, a cardiovascular disease, a pulmonary disease, an inflammatory disease, a central nervous system disease, heart disease, kidney disease, a muscular dystrophy, macular degeneration, retinitis pigmentosa, amyloidosis, giantism, dwarfism, hypothyroidism, hyperthyroidism, aging or obesity. 
       
     
     
         70 . The method of  claim 69 , wherein the autoimmune disease is immunodeficiency, severe combined immunodeficiency, rheumatoid arthritis or graft versus host disease; wherein the blood disease is familial polycythemia, hemophilia, Von Willebrand disease, ataxia-telangiectasia or β-thalassemia; wherein the collagen disease is epidermolysis bullosa, Marfan syndrome, osteogenesis imperfecta or cirrhosis; wherein the inflammatory disease is arthritis, rheumatoid arthritis or osteoarthritis; wherein the central nervous system disease is multiple sclerosis, classical late infantile neuronal ceroid lipofuscinosis, Alzheimer's disease or Tay Sachs disease; wherein the lysosomal storage disorder is tuberous sclerosis, Niemann Pick disease, mucopolysaccharidosis type VII, metachromatic leukodystrophy, Sandhoff disease, mucopolysaccharidosis type IIIA or mucopolysaccharidosis type VI; wherein the kidney disease is kidney stones; wherein the cardiovascular disease is familial hypercholesterolemia or atherosclerosis; wherein the pulmonary disease is cystic fibrosis; and, wherein the muscular dystrophy is Duchenne muscular dystrophy. 
     
     
         71 . The method of  claim 69 , wherein the disease is cancer associated with a genetic or a somatic nonsense mutation in a tumor suppressor gene in a human subject in need thereof. 
     
     
         72 . The method of  claim 71 , wherein the tumor suppressor gene is selected from the group consisting of PTEN, BRCA1, BRCA2, Rb, and p53. 
     
     
         73 . The method of  claim 71 , wherein the cancer is of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenals. 
     
     
         74 . The method of  claim 71 , wherein the cancer is a solid tumor cancer selected from sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma or retinoblastoma. 
     
     
         75 . The method of  claim 71 , wherein the cancer is a blood-born tumor selected from acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma. 
     
     
         76 . The method of  claim 69 , for inhibiting the growth of a cancer cell or for selectively producing a protein in a mammal by the suppression of a genetic or somatic nonsense mutation. 
     
     
         77 . The method of  claim 69 , wherein the compound of Formula 1-C is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof. 
     
     
         78 . The method of  claim 69 , wherein the compound of Formula 1-D is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof. 
     
     
         79 . A method for preventing or treating a disease associated with a gene having a nonsense mutation encoding a premature stop codon in mRNA in a patient in need thereof, comprising administering to said patient a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof,
 wherein the premature stop codon results in either or both premature mRNA translation termination or nonsense-mediated mRNA decay, and wherein the disease is selected from cancer, a lysosomal storage disorder, an autoimmune disease, a blood disease, a collagen disease, diabetes, a cardiovascular disease, a pulmonary disease, an inflammatory disease, a central nervous system disease, heart disease, kidney disease, a muscular dystrophy, macular degeneration, retinitis pigmentosa, amyloidosis, giantism, dwarfism, hypothyroidism, hyperthyroidism, aging or obesity. 
 
     
     
         80 . The method of  claim 79 , wherein the autoimmune disease is immunodeficiency, severe combined immunodeficiency, rheumatoid arthritis or graft versus host disease; wherein the blood disease is familial polycythemia, hemophilia, Von Willebrand disease, ataxia-telangiectasia or β-thalassemia; wherein the collagen disease is epidermolysis bullosa, Marfan syndrome, osteogenesis imperfecta or cirrhosis; wherein the inflammatory disease is arthritis, rheumatoid arthritis or osteoarthritis; wherein the central nervous system disease is multiple sclerosis, classical late infantile neuronal ceroid lipofuscinosis, Alzheimer's disease or Tay Sachs disease; wherein the lysosomal storage disorder is tuberous sclerosis, Niemann Pick disease, mucopolysaccharidosis type VII, metachromatic leukodystrophy, Sandhoff disease, mucopolysaccharidosis type IIIA or mucopolysaccharidosis type VI; wherein the kidney disease is kidney stones; wherein the cardiovascular disease is familial hypercholesterolemia or atherosclerosis; wherein the pulmonary disease is cystic fibrosis; and, wherein the muscular dystrophy is Duchenne muscular dystrophy. 
     
     
         81 . The method of  claim 79 , wherein the disease is cancer associated with a genetic or a somatic nonsense mutation in a tumor suppressor gene in a human subject in need thereof. 
     
     
         82 . The method of  claim 81 , wherein the tumor suppressor gene is selected from the group consisting of PTEN, BRCA1, BRCA2, Rb, and p53. 
     
     
         83 . The method of  claim 81 , wherein the cancer is of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenals. 
     
     
         84 . The method of  claim 81 , wherein the cancer is a solid tumor cancer selected from sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma or retinoblastoma. 
     
     
         85 . The method of  claim 81 , wherein the cancer is a blood-born tumor selected from acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma.