Biphenyl Vasopressin Agonists

Abstract

A compound of the formulae (I) or (II): wherein: Y is a moiety selected from NR or —(CH 2 ) n ; wherein R is hydrogen or (C 1 -C 6 ) lower alkyl, and n is 1; represents: (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 -C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 -C 6 ) lower alkoxy, (C 1 -C 6 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 -C 6 ) lower alkyl], —CON[(C 1 -C 6 ) lower alkyl] 2 ; or (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen or (C 1 -C 6 ) lower alkoxy; represents: (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 -C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 -C 6 ) lower alkoxy, or (C 1 -C 6 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 -C 6 ) lower alkyl], —CON[(C 1 -C 6 ) lower alkyl] 2 ; or (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, (C 1 -C 6 ) lower alkoxy, or halogen; or (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen, or (C 1 -C 6 ) lower alkoxy; represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen, or (C 1 -C 6 ) lower alkoxy; R 1 is a moiety of the formula and R 2 , R 3 , R 7 , R 8 and R 9 are, independently, selected from a group consisting of hydrogen, (C 1 -C 3 ) lower alkyl, OCH 3 , halogen, CF 3 , —SCH 3 , OCF 3 , SCF 3 , or CN; or a pharmaceutically acceptable salt, or pro-drug form thereof.

1 . A compound of the formulae (I) or (II): 
     
       
         
         
             
             
         
       
     
     wherein:
 Y is a moiety selected from NR or —(CH 2 ) n ; 
 wherein R is hydrogen or (C 1 -C 6 ) lower alkyl, 
 and n is 1; 
 
     
       
         
         
             
             
         
       
     
     represents:
 (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 -C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 -C 6 ) lower alkoxy, (C 1 -C 10 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 -C 6 ) lower alkyl], —CON[(C 1 -C 6 ) lower alkyl] 2 ; or 
 (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen or (C 1 -C 6 ) lower alkoxy; 
 
     
       
         
         
             
             
         
       
     
     represents:
 (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C 1 -C 6 ) lower alkyl, halogen, cyano, CF 3 , hydroxy, (C 1 -C 6 ) lower alkoxy, or (C 1 -C 6 ) lower alkoxy carbonyl, carboxy, —CONH 2 , —CONH[(C 1 -C 6 ) lower alkyl], —CON[(C 1 -C 6 ) lower alkyl] 2 ; or 
 (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, (C 1 -C 6 ) lower alkoxy, or halogen; or 
 (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen, or (C 1 -C 6 ) lower alkoxy; 
 
     
       
         
         
             
             
         
       
     
     represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur atom, optionally substituted by (C 1 -C 6 ) lower alkyl, halogen, or (C 1 -C 6 ) lower alkoxy;
 R 1  is a moiety of the formula 
 
     
       
         
         
             
             
         
       
     
     and R 2 , R 3 , R 7 , R 8  and R 9  are, independently, selected from a group consisting of hydrogen, (C 1 -C 3 ) lower alkyl, OCH 3 , halogen, CF 3 , —SCH 3 , OCF 3 , SCF 3 , or CN; 
     or a pharmaceutically acceptable salt, or pro-drug form thereof. 
   
   
       2 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 3  and R 5  are independently selected from H, C 1 -C 6  alkyl, halogen, cyano, CF 3 , hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy carbonyl, carboxy, —CONH 2 , —CONH[C 1 -C 6  alkyl], —CON[C 1 -C 6  alkyl] 2 ; 
 R 2 , R 7 , R 8  and R 9  are each, independently, selected from the group of hydrogen, C 1 -C 3  alkyl, OCH 3 , halogen, CF 3 , SCH 3 , OCF 3 , SCF 3 , or CN; and 
 R 10  is a group selected from C 1 -C 6  alkyl, halogen, or C 1 -C 6  alkoxy; 
 
     or a pharmaceutically acceptable salt or prodrug form thereof. 
   
   
       3 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R is hydrogen or C 1 -C 6  alkyl; 
 R 3  and R 5  are independently selected from H, C 1 -C 6  alkyl, halogen, cyano, CF 3 , hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy carbonyl, carboxy, —CONH 2 , —CONH[C 1 -C 6  alkyl], —CON[C 1 -C 6  alkyl] 2 ; 
 R 2 , R 7 , R 8  and R 9  are each, independently, selected from the group of hydrogen, C 1 -C 3  alkyl, OCH 3 , halogen, CF 3 , SCH 3 , OCF 3 , SCF 3 , or CN; and 
 R 10  is a group selected from C 1 -C 6  alkyl, halogen, or C 1 -C 6  alkoxy; 
 
     or a pharmaceutically acceptable salt or prodrug form thereof. 
   
   
       4 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 2 , R 7 , R 8  and R 9  are each, independently, selected from the group of hydrogen, C 1 -C 3  alkyl, OCH 3 , halogen, CF 3 , SCH 3 , OCF 3 , SCF 3 , or CN; and 
 R 11  and R 12  are independently selected from C 1 -C 6  alkyl, halogen, or C 1 -C 6  alkoxy. 
 
   
   
       5 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 2 , R 7 , R 8  and R 9  are each, independently, selected from the group of hydrogen, C 1 -C 3  alkyl, OCH 3 , halogen, CF 3 , SCH 3 , OCF 3 , SCF 3 , or CN; 
 R 10  is a group selected from C 1 -C 6  alkyl, halogen, or C 1 -C 6  alkoxy; and 
 R 13  is C 1 -C 6  alkyl, halogen or C 1 -C 6  alkoxy; 
 
     or a pharmaceutically acceptable salt or prodrug form thereof. 
   
   
       6 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R is hydrogen or C 1 -C 6  alkyl; 
 R 3 , R 5 , R 3′ , and R 5′  are independently selected from H, C 1 -C 6  alkyl, halogen, cyano, CF 3 , hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy carbonyl, carboxy, —CONH 2 , —CONH[C 1 -C 6  alkyl], —CON[C 1 -C 6  alkyl] 2 ; 
 R 2 , R 7 , R 8  and R 9  are each, independently, selected from the group of hydrogen, C 1 -C 3  alkyl, OCH 3 , halogen, CF 3 , SCH 3 , OCF 3 , SCF 3 , or CN; and 
 
     or a pharmaceutically acceptable salt or prodrug form thereof. 
   
   
       7 . A compound of  claim 1  which is (2′-methoxy-[1,1′-biphenyl]-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       8 . A compound of  claim 1  which is (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(3′-methyl-[1,1′-biphenyl]-4-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       9 . A compound of  claim 1  which is (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4′-methoxy-[1,1′-biphenyl]-4-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       10 . A compound of  claim 1  which is [1,1′-biphenyl]-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       11 . A compound of  claim 1  which is [1,1′-biphenyl]-4-yl-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       12 . A compound of  claim 1  which is [1,1′-biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       13 . A compound of  claim 1  which is [1,1′-biphenyl]-4-yl-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       14 . A compound of  claim 2  which is [1,1′-biphenyl]-4-yl-(5,6,7,8-tetrahydro-thieno[3,2-b]azepin-4-yl)methanone. 
   
   
       15 . A compound of  claim 1  which is (5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)(6-phenyl-pyridin-3-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       16 . A compound of  claim 1  which is (5H-11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(4′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       17 . A compound of  claim 1  which is [1,1′-biphenyl]-4-yl]-(4H, 10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       18 . A compound of  claim 1  which is [3-chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       19 . A compound of  claim 1  which is [3-chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       20 . A compound of  claim 1  which is [3-chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       21 . A compound of  claim 1  which is [2′-methyl-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       22 . A compound of  claim 1  which is [2′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       23 . A compound of  claim 1  which is [3′-methoxy-(1,1′-biphenyl)-4-yl]-(5-methyl-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       24 . A compound of  claim 1  which is [3-chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       25 . A compound of  claim 1  which is [3-chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       26 . A compound of  claim 1  which is 3-chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       27 . A compound of  claim 1  which is [2′-methyl-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-c][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       28 . A compound of  claim 1  which is [2′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       29 . A compound of  claim 1  which is [3′-methoxy-(1,1′-biphenyl)-4-yl]-(11-methyl-5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       30 . A compound of  claim 1  which is [3-chloro-2′-methyl-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       31 . A compound of  claim 1  which is [3-chloro-2′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       32 . A compound of  claim 1  which is [3-chloro-3′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       33 . A compound of  claim 1  which is [2′-methyl]-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       34 . A compound of  claim 1  which is [2′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       35 . A compound of  claim 1  which is [3′-methoxy-(1,1′-biphenyl)-4-yl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof. 
   
   
       36 . A method of treating disorders which are remedied or alleviated by vasopressin agonist activity in a mammal in need thereof, the method comprising administering to the mammal a pharmaceutically effective amount of a compound of  claim 1 . 
   
   
       37 . The method of  claim 36  wherein the disorder which is remedied or alleviated by vasopressin agonist activity is selected from the group of diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, or temporary delay of urination. 
   
   
       38 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier