Novel rapamycin derivatives

Abstract

and pharmaceutically acceptable salts, and compositions thereof, wherein the substituents are as defined herein. Also provided are methods of making compounds of formula (I), and methods involving the compounds or compositions for treating disorders and diseases described herein.

We claim: 
     
         1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting of hydroxy, 
       
       
         
           
           
               
               
           
         
       
       and
 R 2  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1, 2 or 3; 
 n is 1, 2 or 3; 
 o is 1, 2, 3, 4, 5 or 6; 
 p is 1, 2, 3, 4 or 5 
 q is 1, 2, 3, 4 or 5 wherein the sum of p and q is 2, 3, 4, 5 or 6; 
 r is 2, 3 or 4; 
 s is 2, 3 or 4 wherein the sum of r and s is 4, 5 or 6; 
 X is O, S, NR 6  or SO 2 ; 
 R 3  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkylC 0-6 alkyl or phenylC 0-6 alkyl; 
 R 4  is hydrogen; 
 R 5  is hydrogen, hydroxy or cyano; or R 4  and R 5  together form ═O; and 
 R 6  is hydrogen, C 1-6 alkyl, C 3-6 cycloalkylC 0-6 alkyl, phenylC 0-6 alkyl, C 1-6 alkyl-CO—, C 3-8 cycloalkylC 0-6 alkyl-CO—, C 1-6 alkyl-SO 2 — or C 3-8 cycloalkylC 0-6 alkyl-SO 2 —. 
 
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 1  is selected from the group consisting of hydroxy, 
 
       
         
           
           
               
               
           
         
       
       and
 R 2  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1, 2 or 3; 
 n is 1, 2 or 3; 
 o is 1, 2, 3, 4, 5 or 6; 
 p is 1, 2, 3, 4 or 5 
 q is 1, 2, 3, 4 or 5 wherein the sum of p and q is 2, 3, 4, 5 or 6; 
 r is 2, 3 or 4; 
 s is 2, 3 or 4 wherein the sum of r and s is 4, 5 or 6; 
 X is O, S, NR 6  or SO 2 ; 
 R 3  is hydrogen, C 1-6 alkyl, C 3-8 cycloalkylC 0-6 alkyl or phenylC 0-6 alkyl; 
 R 4  is hydrogen; 
 R 5  is hydrogen, hydroxy or cyano; or R 4  and R 5  together form ═O; and 
 R 6  is hydrogen, C 1-6 alkyl, C 3-8 cycloalkylC 0-6 alkyl, phenylC 0-6 alkyl, C 1-6 alkyl-CO—, C 3-8 cycloalkylC 0-6 alkyl-CO—, C 1-6 alkyl-SO 2 — or C 3-6 cycloalkylC 0-6 alkyl-SO 2 —. 
 
     
     
         3 . The compound according to  claim 1  or  2  or a pharmaceutically acceptable salt thereof, wherein R 1  is hydroxy. 
     
     
         4 . The compound according to any one of  claims 1  to  3  or a pharmaceutically acceptable salt thereof, wherein R 2  is 
       
         
           
           
               
               
           
         
         and n is 1, 2 or 3. 
       
     
     
         5 . The compound according to any one of  claims 1  to  4  or a pharmaceutically acceptable salt thereof, wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein said compound is selected from: 
       
         
           
                 
               
                     
                 
                   Structure 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to any one of  claims 1  to  5  or a pharmaceutically acceptable salt thereof, wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. 
     
     
         11 . A pharmaceutical combination comprising a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents. 
     
     
         12 . A method of treating a disorder or a disease mediated by the mTOR pathway in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 . 
     
     
         13 . A method of treating a disease or disorder in a subject, wherein the target tissue, cell or organ associated with the pathology of the disease or disorder has FKBP12 levels sufficient to inhibit mTORC1, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 . 
     
     
         14 . A method of treating a disease or disorder in a subject having, or previously determined as having, FKBP12 levels sufficient to inhibit mTORC1, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 . 
     
     
         15 . The method of any one of  claims 12  to  14 , wherein the disease or disorder is selected from sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (strokes), chronic kidney disease, diabetes-associated kidney disease, impaired hepatic function, liver fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility disability, cognitive decline, tendon stiffness, heart dysfunction such as cardiac hypertrophy and/or systolic and/or diastolic dysfunction and/or hypertension, heart dysfunction which results in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, immune-senescence leading to cancer due to a decrease in immune-surveillance, infections due to an decline in immune-function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of olfaction, arthritis, and type II diabetes including complications stemming from diabetes, such as kidney failure, blindness and neuropathy. 
     
     
         16 . The method of any one of  claims 12  to  14 , wherein the disorder is liver fibrosis. 
     
     
         17 . A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 , wherein the disorder or disease is selected from:
 Acute or chronic organ or tissue transplant rejection; 
 Transplant vasculopathies; 
 Smooth muscle cell proliferation and migration leading to vessel intimal thickening, blood vessel obstruction, obstructive coronary atherosclerosis, restenosis; 
 Autoimmune diseases and inflammatory conditions; 
 Treatment and prevention of asthma; 
 Multi-drug resistance (MDR); 
 Fungal infections; 
 Inflammation; 
 Infection; 
 Age-related diseases; 
 Neurodegenerative diseases; 
 Proliferative disorders, in particular cancer; 
 Seizures and seizure related disorders; and 
 Mitochondrial myopathy and mitochondrial stress. 
 
     
     
         18 . The method of  claim 17 , wherein the disorder is a disorder that includes the process of fibrosis and/or inflammation. 
     
     
         19 . The method of  claim 18 , wherein the disorder is selected from liver and kidney disorders. 
     
     
         20 . The method of  claim 19 , wherein the liver disorder is selected from: liver fibrosis, which occurs in end-stage liver disease; liver cirrhosis; liver failure due to toxicity; non-alcohol-associated hepatic steatosis or NASH; and alcohol-associated steatosis. 
     
     
         21 . The method of  claim 19 , wherein the kidney disorder is kidney fibrosis. 
     
     
         22 . The method of  claim 21 , wherein the kidney fibrosis occurs as a result of acute kidney injury. 
     
     
         23 . The method of  claim 19 , wherein the kidney disorder is chronic kidney disorder. 
     
     
         24 . The method of  claim 19 , wherein the kidney disorder is diabetic nephropathy. 
     
     
         25 . A method of treating an age-related disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of  claims 1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 , wherein the disorder or disease is selected from: sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease (strokes), chronic kidney disease, diabetes-associated kidney disease, impaired hepatic function, liver fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility disability, cognitive decline, tendon stiffness, heart dysfunction such as cardiac hypertrophy and/or systolic and/or diastolic dysfunction and/or hypertension, heart dysfunction which results in a decline in ejection fraction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, immune-senescence leading to cancer due to a decrease in immune-surveillance, infections due to an decline in immune-function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of olfaction, arthritis, and type II diabetes including complications stemming from diabetes, such as kidney failure, blindness and neuropathy. 
     
     
         26 . A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims  1  to  9  or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 10 , or the pharmaceutical combination of  claim 11 . 
     
     
         27 . The method of  claim 26 , further comprising a PD-1/PDL-1 inhibitor. 
     
     
         28 . The method of  claim 26  or  27 , wherein the cancer is selected from renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibro-sarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, multiple myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, rhabdomyosarcoma, sarcoma, lymphoma, and neck cancer.