Novel benzimidazole derivatives useful as selective androgen receptor modulators (sarms)

Abstract

The present invention is directed to novel benzimidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of hydrogen, C 1-4 alkyl, —C 1-4 alkyl-OH, —C 1-4 alkyl-CN, —C 1-4 alkyl-NO 2 , —C 1-4 alkyl-N(R A R B ), —C 1-4 alkyl-CO 2 H, —(C 1-4 alkyl)-X—R 7 , —CH 2 -aryl and —CH 2 -heteroaryl; wherein the aryl or heteroaryl group (on the —CH 2 -aryl and —CH 2 -heteroaryl group) is optionally substituted with one or more substituents independently selected from halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, —C 1-4 alkyl-CN, —C 1-4 alkyl-OH, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S—C 1-4 alkyl, —S-(halogen substituted C 1-4 alkyl), —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl, —O-aralkyl, —C(O)O—C 1-4 alkyl, —CO 2 H, —C(O)H, heteroaryl or heterocycloalkyl; 
         wherein R A  and R B  are independently selected from hydrogen or C 1-4 alkyl; alternatively, R A  and R B  are taken together with the nitrogen atom to which they are bound to form a five to seven membered aromatic, partially unsaturated or saturated ring structure, optionally containing one to two additional heteroatoms selected from O, S or N; and wherein the ring structure is optionally substituted with C 1-4 alkyl; 
         wherein X is selected from the group consisting of —S—, —SO—, SO 2 —, —O—SO 2 —, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR C —, —NR C —C(O)—, —C(O)—NR C —, —NR C —SO 2 — and —SO 2 —NR C —; wherein R C  is selected from hydrogen or C 1-4 alkyl; 
         wherein R 7  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 2-4 alkenyl, aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —(C 1-4 alkyl), —SO 2 —N(R D ) 2 , aryl, heteroaryl or heterocycloalkyl; wherein each R D  is independently selected from hydrogen or C 1-4 alkyl; 
         provided that when X is O or NR C , then R 6  is other than C 2-4 alkenyl; 
         R 2  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —O—C 1-4 alkyl, —S—C 1-4 alkyl, —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl and —NR E —C(O)—C 1-4 alkyl; wherein R E  is selected from hydrogen or C 1-4 alkyl; 
         R 3  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —O—C 1-4 alkyl, —S—C 1-4 alkyl, —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl and —NR F —C(O)—C 1-4 alkyl; wherein R F  is selected from hydrogen or C 1-4 alkyl; 
         provided that at least one of R 2  or R 3  is other than hydrogen; 
         a is an integer from 0 to 1; 
         R 10  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl and —O—C(O)—R 8 ; 
         wherein R 8  is selected from the group consisting of C 1-4 alkyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, aryl, aralkyl, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino; 
         R 11  is selected from the group consisting of hydrogen and halogen; 
         alternatively, R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, C═N(OH) or —C═N(O—C 1-4 alkyl); 
         R 12  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, —C 1-4 alkyl-OH, —C 1-4 alkyl-CN, —C 1-4 alkyl-NO 2 , —C 1-4 alkyl-N(R G R H ), C 1-4 alkyl-CO 2 H, —(C 1-4 alkyl)-Y—R 9 , —CH 2 -aryl and —CH 2 -heteroaryl; wherein the aryl or heteroaryl (on the —CH 2 -aryl or —CH 2 -heteroaryl group) is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —C 1-4 alkyl or —SO 2 —N(R J ) 2 ; wherein each R J  is independently selected from hydrogen or C 1-4 alkyl; 
         wherein R G  and R H  are independently selected from hydrogen or C 1-4 alkyl; alternatively, R G  and R H  are taken together with the nitrogen atom to which they are bound to form a five to seven membered aromatic, partially unsaturated or saturated ring structure, optionally containing one to two additional heteroatoms selected from O, S or N; and wherein the ring structure is optionally substituted with C 1-4 alkyl; 
         wherein Y is selected from the group consisting of —S—, —SO—, SO 2 —, —O—SO 2 —, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR K —, —NR K —C(O)—, —C(O)—NR K , —NR K —SO 2 — and —SO 2 —NR K —; wherein R K  is selected from hydrogen or C 1-4 alkyl; 
         wherein R 9  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 2-4 alkenyl, aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —(C 1-4 alkyl), —SO 2 —N(R L ) 2  or —NR M —C(O)—C 1-4 alkyl; wherein each R L  is independently selected from hydrogen or C 1-4 alkyl; and wherein R M  is selected from hydrogen or C 1-4 alkyl; 
         provided that when Y is O or NR K , then R 9  is other than C 2-4 alkenyl; 
         provided that when R 1  is —CH 2 -phenyl wherein the phenyl is substituted with —C(O)O—C 1-4 alkyl or —CO 2 H; R 2  is methyl; R 3  is methyl; a is 0; R 10  is hydrogen; and R 11  is hydrogen; then R 12  is other than —CH 2 -phenyl; 
         provided further that when R 1  is —CH 2 -phenyl wherein the phenyl is substituted with —C(O)O—C 1-4 alkyl or —CO 2 H; R 2  and R 3  are selected to be (H and fluoro), (fluoro and H), (methyl, methyl) or (H and trifluoromethyl); a is an integer form 0 to 1; R 10  is hydrogen; and R 11  is hydrogen; then R 12  is other than C 1-4 alkyl; 
         provided further that when R 1  is hydrogen or C 1-4 alkyl; a is 0; R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, one of R 2  or R 3  is hydrogen and the other of R 2  or R 3  is selected from halogen, C 1-4 alkyl, —O—C 1-4 alkyl or nitro, then R 12  is other than C 1-4 alkyl, C 1-4 alkyl substituted with one halogen or benzyl; 
         provided further that when R 1  is —CH 2 -phenyl; a is 0; R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, of R 2  is hydrogen; and R 3  is nitro, then R 12  is other than C 1-4 alkyl; 
         provided further that when R 1  is hydrogen; a is 0; R 2  is —O—C 1-4 alkyl, R 3  is —O—C 1-4 alkyl; and R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—; then R 12  is other than benzyl; 
         provided further that when R 1  is —C 1-4 alkyl-N(C 1-4 alkyl) 2 ; a is 0; R 2  is —O—C 1-4 alkyl; R 3  is —O—C 1-4 alkyl; and R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, then R 12  is other than benzyl, wherein the benzyl is substituted with a halogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of hydrogen, C 1-4 alkyl, —C 1-4 alkyl-OH, —C 1-4 alkyl-CN, —C 1-4 alkyl-NO 2 , —C 1-4 alkyl-N(R A R B ), —C 1-4 alkyl-CO 2 H, —(C 1-4 alkyl)-X—R 7 , —CH 2 -aryl and —CH 2 -heteroaryl; wherein the aryl or heteroaryl group (on the —CH 2 -aryl and —CH 2 -heteroaryl group) is optionally substituted with one or more substituents independently selected from halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4  alkoxy, —C 1-4 alkyl-CN, —C 1-4 alkyl-OH, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S—C 1-4 alkyl, —S-(halogen substituted C 1-4 alkyl), —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl, —O-aralkyl, —C(O)O—C 1-4 alkyl, —CO 2 H, —C(O)H, heteroaryl or heterocycloalkyl; 
         wherein R A  and R B  are independently selected from hydrogen or C 1-4 alkyl; alternatively, R A  and R B  are taken together with the nitrogen atom to which they are bound to form a five to seven membered aromatic, partially unsaturated or saturated ring structure, optionally containing one to two additional heteroatoms selected from O, S or N; and wherein the ring structure is optionally substituted with C 1-4 alkyl; 
         wherein X is selected from the group consisting of —S—, —SO—, SO 2 —, —O—SO 2-5 —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR C —, —NR C —C(O)—, —C(O)—NR C —, —NR C —SO 2 — and —SO 2 —NR C —; wherein R C  is selected from hydrogen or C 1-4 alkyl; 
         wherein R 7  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 2-4 alkenyl, aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4  alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —(C 1-4 alkyl), —SO 2 —N(R D ) 2 , aryl, heteroaryl or heterocycloalkyl; wherein each R D  is independently selected from hydrogen or C 1-4 alkyl; 
         provided that when X is O or NR C , then R 6  is other than C 2-4 alkenyl; 
         R 2  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —O—C 1-4 alkyl, —S—C 1-4 alkyl, —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl and —NR E —C(O)—C 1-4 alkyl; wherein R E  is selected from hydrogen or C 1-4 alkyl; 
         R 3  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —O—C 1-4 alkyl, —S—C 1-4 alkyl, —SO—C 1-4 alkyl, —SO 2 —C 1-4 alkyl and —NR F —C(O)—C 1-4 alkyl; wherein R F  is selected from hydrogen or C 1-4 alkyl; 
         provided that at least one of R 2  or R 3  is other than hydrogen; 
         a is an integer from 0 to 1; 
         R 10  is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl and —O—C(O)—R 8 ; 
         wherein R 8  is selected from the group consisting of C 1-4 alkyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, aryl, aralkyl, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4  alkoxy, cyano, nitro, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino; 
         R 11  is selected from the group consisting of hydrogen and halogen; 
         alternatively, R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, C═N(OH) or —C═N(O—C 1-4 alkyl); 
         R 12  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, —C 1-4 alkyl-OH, —C 1-4 alkyl-CN, —C 1-4 alkyl-NO 2 , —C 1-4 alkyl-N(R G R H ), C 1-4 alkyl-CO 2 H, —(C 1-4 alkyl)-Y—R 9 , —CH 2 -aryl and —CH 2 -heteroaryl; wherein the aryl or heteroaryl (on the —CH 2 -aryl or —CH 2 -heteroaryl group) is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —C 1-4 alkyl or —SO 2 —N(R J ) 2 ; wherein each R J  is independently selected from hydrogen or C 1-4 alkyl; 
         wherein R G  and R H  are independently selected from hydrogen or C 1-4 alkyl; alternatively, R G  and R H  are taken together with the nitrogen atom to which they are bound to form a five to seven membered aromatic, partially unsaturated or saturated ring structure, optionally containing one to two additional heteroatoms selected from O, S or N; and wherein the ring structure is optionally substituted with C 1-4 alkyl; 
         wherein Y is selected from the group consisting of —S—, —SO—, SO 2 —, —O—SO 2 —, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR K —, —NR K —C(O)—, —C(O)—NR K —, —NR K —SO 2 — and —SO 2 —NR K —; wherein R K  is selected from hydrogen or C 1-4 alkyl; 
         wherein R 9  is selected from the group consisting of C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 2-4 alkenyl, aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C 1-4 alkyl)-, heteroaryl, heteroaryl-(C 1-4 alkyl)-, heterocycloalkyl and heterocycloalkyl-(C 1-4 alkyl)-; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, —S(O) 0-2 —(C 1-4 alkyl), —SO 2 —N(R L ) 2  or —NR M —C(O)—C 1-4 alkyl; wherein each R L  is independently selected from hydrogen or C 1-4 alkyl; and wherein R M  is selected from hydrogen or C 1-4 alkyl; 
         provided that when Y is O or NR K , then R 9  is other than C 2-4 alkenyl; 
         provided that when R 1  is —CH 2 -phenyl wherein the phenyl is substituted with —C(O)O—C 1-4 alkyl or —CO 2 H; R 2  is methyl; R 3  is methyl; a is 0; R 10  is hydrogen; and R 11  is hydrogen; then R 12  is other than —CH 2 -phenyl; 
         provided further that when R 1  is —CH 2 -phenyl wherein the phenyl is substituted with —C(O)O—C 1-4 alkyl or —CO 2 H; R 2  and R 3  are selected to be (H and fluoro), (fluoro and H), (methyl, methyl) or (H and trifluoromethyl); a is an integer form 0 to 1; R 10  is hydrogen; and R 11  is hydrogen; then R 12  is other than C 1-4 alkyl; 
         provided further that when R 1  is hydrogen or C 1-4 alkyl; a is 0; R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, one of R 2  or R 3  is hydrogen and the other of R 2  or R 3  is selected from halogen, C 1-4 alkyl, —O—C 1-4 alkyl or nitro, then R 12  is other than C 1-4 alkyl, C 1-4 alkyl substituted with one halogen or benzyl; 
         provided further that when R 1  is —CH 2 -phenyl; a is 0; R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, of R 2  is hydrogen; and R 3  is nitro, then R 12  is other than C 1-4 alkyl; 
         provided further that when R 1  is hydrogen; a is 0; R 2  is —O—C 1-4 alkyl, R 3  is —O—C 1-4 alkyl; and R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—; then R 12  is other than benzyl; 
         provided further that when R 1  is —C 1-4 alkyl-N(C 1-4 alkyl) 2 ; a is 0; R 2  is —O—C 1-4 alkyl; R 3  is —O—C 1-4 alkyl; and R 10  and R 11  are taken together with the carbon atom to which they are abound to form —C(O)—, then R 12  is other than benzyl, wherein the benzyl is substituted with a halogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 16 . 
     
     
         19 . The use of a compound as in  claim 16  for the preparation of a medicament
 for treating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, for (j) male contraception, or for (k) male performance enhancement, in a subject in need thereof.