Selective androgen receptor modulators

Abstract

This invention provides compounds of Formula (II), or (IIa) and or salts thereof, pharmaceutical compositions comprising a compound of Formula (II), or (IIa) and a pharmaceutically acceptable excipient, processes for making compounds of Formula (II), or (IIa) and intermediates useful in the preparation of same; and methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type II diabetes related disorders or diseases, anemia, depression, and renal disease) using compounds of Formula (I), (II) or (IIa).

1 . A compound according to Formula (II), or a pharmaceutically acceptable salt thereof;
 wherein the compound of Formula (II) is:   
       
         
           
           
               
               
           
         
         wherein:
 c is 0, 1, 2, or 3; and 
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3 alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 with the proviso that at least two of X, Y and Z are each independently halogen, NO 2  or CN; and provided that two of X, Y and Z are not both Br. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A compound according to  claim 1 , wherein:
 X, Y and Z are independently selected from hydrogen, chlorine, bromine, CF 3  and CN; with the proviso that at least two of X, Y and Z are each independently halogen, or CN; and provided that two of X, Y and Z are not both Br.   
     
     
         14 . A compound according to  claim 1 , wherein:
 each R a  is independently selected from chlorine, fluorine, bromine, CH 3  and benzyl.   
     
     
         15 . A compound according to  claim 1 , wherein:
 c is 0, or 1.   
     
     
         16 . A compound according to  claim 1 , wherein:
 X and Y are hydrogen;   Z is CN;   each R a  is independently selected from bromine and benzyl; and   c is 0 or 1.   
     
     
         17 . A compound according to  claim 1 , wherein:
 X and Y are hydrogen; Z is bromine;   Each R a  is independently selected from bromine and benzyl; and   c is 0 or 1.   
     
     
         18 . A compound according to  claim 1 , wherein:
 X and Y are chlorine;   Z is hydrogen;   each R a  is independently selected from bromine and benzyl; and   c is 0 or 1.   
     
     
         19 . A compound according to  claim 1 , wherein the compound of Formula (II) is a compound of Formula (IIa); or a pharmaceutically acceptable salt thereof;
 wherein the compound of Formula (IIa) is:   
       
         
           
           
               
               
           
         
         wherein: 
         c is 0, 1, 2, or 3; and 
         R a , X, Y and Z are as defined in  claim 1 ; 
         with the proviso that at least two of X, Y and Z are each independently halogen, NO 2  or CN; and provided that two of X, Y and Z are not both Br. 
       
     
     
         20 . A compound selected from the following:
 6 Bromo-9H-carbzol-1-ol, 8-Hydroxy-9H-carbazole-3-carbonitrile, 5,6-Dichloro-9H-carbazol-1-ol, 2-Bromo-6,7-dichloro-9H-carbazol-1-ol, 2-Benzyl-5,6-dichloro-9H-carbazol-1-ol, and 2-Benzyl-6,7-dichloro-9H-carbazol-1-ol, or a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         21 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         22 . A method of modulating an androgen receptor in a cell, comprising the administration of a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
           n is 0, 1, 2 or 3. 
         
       
     
     
         23 . A method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
           n is 0, 1, 2 or 3, and monitoring the effect of the compound on the cell. 
         
       
     
     
         24 . A method of treating sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget's disease, osteoarthritis, connective tissue disease or disorders, injury, burns, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
           n is 0, 1, 2 or 3. 
         
       
     
     
         25 . A method of treating prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
         
       
       n is 0, 1, 2 or 3. 
     
     
         26 . The use of a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
         
       
       n is 0, 1, 2 or 3, in the manufacture of a medicament for the treating sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, hypercholesterolemia, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget's disease, osteoarthritis, connective tissue disease or disorders, injury, bums, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity. 
     
     
         27 . The use of a compound according to  claim 1  or Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 X, Y and Z are independently selected from the group consisting of hydrogen, halogen, CN, C 1-4  alkyl, C 1-3  hydroxyalkyl, C 1-3  haloalkyl, NO 2 , NH 2 , C 1-3 alkyl and OH; with the proviso that at least one of X, Y and Z is not hydrogen; 
 each R a  is independently selected from halogen, OH, NH(CO)C 1-6  alkyl, C 1-4  alkyl (wherein said C 1-4 alkyl is optionally substituted with from 1-2 substituents each independently selected from CN, OH and OC 1-3  alkyl), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from halogen, C 1-3  alkyl, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ), C(O)—C 1-10  alkyl, SO 3 —, PO 3 —, SO 2 NR b R b′  and C(O)phenyl; 
 R b  is independently selected from C 1-4  alkyl (wherein said C 1-4  alkyl is optionally substituted with from 1-2 substituents each independently selected from the group consisting of CN, OH and OPh (wherein said Ph is optionally substituted with 1-2 substituents each independently selected from the group consisting of halogen, OH, CN and OC 1-3  alkyl)), C 1-5  haloalkyl, monocyclic aryl (wherein said monocyclic aryl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3  alkyl, C 1-5  haloalkyl, CN, halogen, OH and OC 1-3  alkyl), and benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents each independently selected from the group consisting of halogen, C 1-3  alkyl, CN, S(O) 0-2 C 1-3  alkyl, S(O) 0-2 phenyl, O—C 1-6  alkyl, and OCF 3 ); 
 A is a 2-5 membered carbon alkyl linker selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            and 
         
       
       n is 0, 1, 2 or 3, in the manufacture of a medicament for the treating prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer. 
     
     
         28 . (canceled) 
     
     
         29 . A compound useful for the production of an androgen receptor modulator, said compound having the Formula (IIa), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 c is 0, 1, 2, or 3; and 
 R a , X, Y, Z and care as defined in  claim 1   
 with the proviso that at least two of X, Y and Z are each independently halogen, NO 2  or CN; and provided that two of X, Y and Z are not both Br.