Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders

Abstract

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.

1 . A compound having the Formula I: 
       
         
           
           
               
               
           
         
       
       wherein,
 X, Y and Z are each independently selected from the group consisting of O, N, N(R 3 ), S and C(R 3 ) and at least one of X, Y and Z is selected from O, N, N(R 3 ) and S; 
 the subscript r is an integer of from 0 to 3; 
 the subscript s is an integer of from 0 to 3, and the sum of r+s is <4; 
 the subscript q is an integer of from 0 to 4; 
 A is C(R 4 ) or N; 
 L is —(CH 2 ) n — wherein n is an integer of from 2 to 4 and at least one CH 2  is replaced by O, N(R 5 ), S, S(O) or S(O) 2 , and any remaining CH 2  is optionally substituted with one or two members selected from halogen, C 1-4  alkyl and C 1-4  haloalkyl; 
 Ar is a 5- to 10-membered aryl or heteroaryl group, optionally substituted with from one to five R 6  substituents; 
 R 1  is a member selected from the group consisting of C 1-10 alkyl, C 1-10 haloalkyl, C 3-7 cycloalkyl, C 2-10  alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo group and said aryl and heteroaryl group is optionally substituted with from one to four substituents independently selected from halo, C 1-10  alkyl, C 1-10  haloalkyl, C 3-7  cycloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, CN, NO 2 , —OR a , —NR a R b , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b ; and X 1  is selected from the group consisting of a bond, —C(O)— and —C(O)—(CH 2 ) 1-4 — wherein the aliphatic portions of X 1  are optionally substituted with one to three members selected from halogen, C 1-4  alkyl and C 1-4  haloalkyl; 
 each R 2  is a member independently selected from the group consisting of halo, C 1-8  alkyl, C 1-8 haloalkyl, C 3-7  cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SO 2 R a  and —SO 2 NR a R b ; 
 R 3  is a member selected from the group consisting of hydrogen, halogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, aryl and OR a ; 
 R 4  is a member selected from the group consisting of H, halo, C 1-6  alkyl, OR a  and CN; 
 R 5  is a member selected from the group consisting of —R a , —COR a  and —SO 2 R a ; 
 each R 6  is independently selected from the group consisting of halo, C 1-10  alkyl, C 1-10  haloalkyl, C 3-7  cycloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, CN, NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from the group consisting of halo, oxo, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, CN, NO 2 , —OR a , —NR a R b , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b  and wherein the subscript m is an integer of from 0 to 2; 
 and each R a  and R b  is independently selected from the group consisting of hydrogen, C 1-10  alkyl, C 1-10  haloalkyl, C 3-10  cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a  and R b  is optionally substituted with from one to three members selected from the group consisting of —OR n , —OC(O)N(R n ) 2 , —SR, —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R, —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2  and —NR n S(O) 2 N(R n ) 2 , wherein each R n  is independently hydrogen or an unsubstituted C 1-6  alkyl; 
 and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2  and —NR m S(O) 2 N(R m ) 2 , wherein each R m  is independently hydrogen or an unsubstituted C 1-6  alkyl; 
 and pharmaceutically acceptable salts and esters thereof; 
 wherein the molecular weight of said compound is less than 1200. 
 
     
     
         2 . A compound of  claim 1 , wherein two of X, Y and Z are independently selected from the group consisting of O, N, N(R 3 ) and S. 
     
     
         3 . A compound of  claim 1 , wherein each of X, Y and Z are independently selected from the group consisting of O, N, N(R 3 ) and S. 
     
     
         4 . A compound of  claim 1 , wherein the ring having X, Y and Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound of  claim 1 , wherein A is CR 4 . 
     
     
         6 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0 and Ar is phenyl or naphthyl, optionally substituted with from 1 to 5 R 6  substituents. 
     
     
         7 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring, optionally substituted with from 1 to 3 R 6  substituents. 
     
     
         8 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, triazolyl, pyrrolyl, isoxazolyl, isothiazolyl, and pyrazolyl, each of which is optionally substituted with from 1 to 3 R 6  substituents. 
     
     
         9 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0 and Ar is a 6-membered heteroaryl ring, optionally substituted with from 1 to 3 R 6  substituents. 
     
     
         10 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0 and Ar is selected from the group consisting of pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with from 1 to 3 R 6  substituents. 
     
     
         11 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0, and n is 2. 
     
     
         12 . A compound of  claim 1 , wherein r is 1, s is 0 or 1, q is 0, n is 2 and one CH 2  of L is replaced by O, S or N(R 5 ). 
     
     
         13 . A compound of  claim 1 , wherein r is 1; s is 0 or 1; q is 0; n is 2 and one CH 2  of L is replaced by O; A is selected from the group consisting of CH, C(CH 3 ), CF and C(OH); the ring having X, Y and Z as ring members is selected from the group consisting of thiazole, oxazole, thiadiazole and oxadiazole. 
     
     
         14 . A compound of  claim 13 , wherein Ar is phenyl, optionally substituted with from 1 to 3 R 6  substituents. 
     
     
         15 . A compound of  claim 14 , wherein R 1  is a 5- to 10-membered heteroaryl group, and is optionally substituted with from one to two substituents independently selected from halo, C 1-10  alkyl, C 1-10  haloalkyl, C 3-7  cycloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, CN, NO 2 , —OR a , —NR a R b , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b . 
     
     
         16 . A compound of  claim 15 , wherein R 1  is a pyridine or pyrimidine, and is optionally substituted with from one to two substituents independently selected from halo, C 1-10  alkyl, C 1-10  haloalkyl, C 3-7  cycloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteroaryl, CN, NO 2 , —OR a , —NR a R b , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b . 
     
     
         17 . A compound of  claim 14 , wherein R 1  is selected from the group consisting of —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b  and —SO 2 R a . 
     
     
         18 . A compound of  claim 17 , wherein Ar is substituted with from 1 to 2 R 6  substituents independently selected from the group consisting of halo, C 1-10  alkyl, C 1-10  haloalkyl, CN, NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group. 
     
     
         19 . A compound of  claim 18 , wherein each R 6  is independently selected from the group consisting of halo, —OR a , —NR a R b , —NR a COR b , —NR a CO 2 R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group. 
     
     
         20 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein,
 D is selected from the group consisting of O, S, and NR 8 ; 
 X, Y, and Z are independently selected from the group consisting of O, N, S, and CR 3  and at least one of X, Y, and Z is O, N, NR 8 , or S; 
 J, K, T, and U are each independently selected from the group consisting of C, and N; 
 the subscript p is an integer of from 0 to 4; 
 the subscript q is an integer of from 0 to 4; 
 R 1  is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10  alkenyl, C 2-10 alkynyl, aryl, heteroaryl, CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a  and R b  are combined to form a 4-, 5- or 6-membered ring, and X 1  is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1  are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl; 
 each R 2  is a member independently selected from the group consisting of halogen, C 1-5  alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a  and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2  is alkyl or substituted alkyl, the two R 2  members can optionally cyclize to form a ring; 
 R 3  is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl; 
 each R 7  is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10  substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, CN, NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4  alkyl, C 1-4  haloalkyl, C 3-7  cycloalkyl, CN, NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b  and wherein the subscript m is an integer of from 0 to 2, or optionally R a  and R b  are combined to form a 4-, 5- or 6-membered ring; 
 R 8  is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl; 
 and each R a  and R b  is independently selected from the group consisting of hydrogen, C 1-10  alkyl, C 1-10 haloalkyl, C 3-10  cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a  and R b  is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2  and —NR n S(O) 2 N(R n ) 2 , wherein each R n  is independently hydrogen or an unsubstituted C 1-6  alkyl; 
 and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2  and —NR m S(O) 2 N(R m ) 2 , wherein each R m  is independently hydrogen or an unsubstituted C 1-6  alkyl; 
 and pharmaceutically acceptable salts and esters thereof; 
 wherein the molecular weight of said compound is less than 1200. 
 
     
     
         21 .- 61 . (canceled)