Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders

Abstract

The present invention provides compounds useful, for example, for treating metabolic disorders in a subject. Such compounds have the general formula I: where the definitions of the variables Q, L 1 , L 2 , M, X, L 3 , and A are provided herein. The present invention also provides compositions that include, and methods for using, the compounds in preparing medicaments and for treating metabolic disorders such as, for example, type II diabetes.

1 . A compound having the formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
 Q is hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 L 1  is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k , N(R a ), C(O)—(C 5 -C 7 )heterocycloalkylene, (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , or C(O)N(R b ); 
 
     
       
         
         
             
             
         
       
       represents a cyclohexane ring or a benzo-fused (C 5 -C 8 )cycloalkane ring; 
       L 2  is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -C 4 )alkylene-C(O)N(R b ), (C 1 -C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , (C 2 -C 4 )alkenylene-SO 2 N(R b ), or (C 2 -C 4 )alkenylene-N(R b )SO 2 ; 
       M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, aryl(C 1 -C 4 )alkylene, or heteroaryl(C 1 -C 4 )alkylene; 
       X is CR 1 R 1′ , N(R 1″ ), O, or S(O) k ; 
       L 3  is a (C 1 -C 5 )alkylene or (C 2 -C 5 )heteroalkylene; 
       A is —CO 2 H, tetrazol-5-yl, —SO 3 H, —PO 3 H 2 , —SO 2 NH 2 , —C(O)NHSO 2 CH 3 , —CHO, thiazolidinedionyl, hydroxyphenyl, or pyridyl; 
       R a  is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 3 ) alkyl, or (C 2 -C 6 )heteroalkyl; 
       R b  is hydrogen, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
       R 1  is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or —C(O)NR 2 R 3 ; 
       R 1′  is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; 
       R 1″  is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl; 
       R 2  and R 3  are independently selected from hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )heterocycloalkyl; 
       optionally, R 2  and R 3  are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S; and 
       the subscript k is 0, 1, or 2 
     
   
   
       2 . The compound of  claim 1 , wherein L 1  is a bond, Q is H or aryl, 
     
       
         
         
             
             
         
       
     
     represents a substituted benzo-fused (C 5 -C 8 )cycloalkane ring or an unsubstituted benzo-fused (C 5 -C 8 )cycloalkane ring, L 2  is O, oxymethylene, or oxyethylene, M is benzene and X is para to L 2 , X is CR 1 R 1′ , R 1  is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or —C(O)NR 2 R 3 , R 1′  is H, L 3  is methylene, and A is CO 2 H, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. 
   
   
       3 . The compound of  claim 2 , wherein the compound is a pharmaceutically acceptable salt or solvate. 
   
   
       4 . The compound of  claim 2 , wherein the compound is a prodrug. 
   
   
       5 . The compound of  claim 4 , wherein the prodrug is an ester. 
   
   
       6 . The compound of  claim 1 , wherein the compound has the formula (II): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein
 Q is selected from hydrogen, aryl, or heteroaryl; 
 
     
       
         
         
             
             
         
       
       represents a cyclohexane ring or a benzo-fused (C 5 -C 8 )cycloalkane ring; 
       L 2  is selected from O or S(O) k ; 
       R 1  is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or —C(O)NR 2 R 3 ; 
       R 2  and R 3  are independently selected from hydrogen or (C 1 -C 4 )alkyl; 
       R 4  is independently selected from substituted (C 1 -C 6 )alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO 2 NR″R′″, —NR″CO 2 R′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —SiR′R″R′″, —S(O)R′, —SO 2 R′, —SO 2 NR′R″, —NR″SO 2 R, —CN, or —NO 2 , wherein R′, R″ and R′″ are each independently selected from hydrogen, unsubstituted (C 1 -C 8 )alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C 1 -C 4 )alkyl, or aryl-(C 1 -C 4 )alkyl groups; 
       R 5  is independently selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro; 
       the subscript k is 0, 1 or 2; 
       the subscript n is 0, 1 or 2; and 
       the subscript p is 0, 1, 2, 3 or 4. 
     
   
   
       7 . The compound of  claim 6 , wherein R 4  is independently selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro. 
   
   
       8 . The compound of  claim 6 , wherein the compound has the formula (IIIa) or (IIIb): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
   
   
       9 . The compound of  claim 6 , wherein 
     
       
         
         
             
             
         
       
     
     is a benzo-fused (C 5 -C 8 )cycloalkane ring selected from dihydroindene, tetrahydronaphthalene, tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene. 
   
   
       10 . The compound of  claim 6 , wherein the compound has the formula (IV): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein
 the subscript m is 1, 2, 3 or 4. 
 
   
   
       11 . The compound of  claim 10 , wherein the subscript m is 1 or 2. 
   
   
       12 . The compound of  claim 10 , wherein Q is hydrogen; L 2  is oxygen; the subscript n is 1 or 2; R 4  is independently selected from methyl, halogen, or (C 1 -C 6 )alkoxy; and R 1  is (C 2 -C 3 )alkynyl. 
   
   
       13 . The compound of  claim 6 , wherein the compound has the formula (VII): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. 
   
   
       14 . The compound of  claim 2 , wherein R 1  is selected from prop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl, thiophenyl, triazolyl, or —C(O)NR 2 R 3 . 
   
   
       15 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of  claim 1 . 
   
   
       16 . A method for treating type II diabetes, the method comprising:
 administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1 .   
   
   
       17 . A compound having the formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
 Q is hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 L 1  is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k , N(R a ), C(O)—(C 5 -C 7 )heterocycloalkylene, (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , or C(O)N(R b ); 
 
     
       
         
         
             
             
         
       
       represents a cyclohexane ring or a benzo-fused (C 5 -C 8 )cycloalkane ring; 
       L 2  is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -C 4 )alkylene-C(O)N(R b ), (C 1 -C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , (C 2 -C 4 )alkenylene-SO 2 N(R b ), or (C 2 -C 4 )alkenylene-N(R b )SO 2 ; 
       M is a benzene ring, and R 1  is combined with M to form a 5-, 6-, or 7-membered benzo-fused cycloalkane ring comprising 0, 1, or 2 heteroatoms selected from N, O, and S; 
       X is CR 1 R 1′ ; 
       L 3  is a bond, (C 1 -C 5 )alkylene or (C 2 -C 5 )heteroalkylene; 
       A is —CO 2 H, tetrazol-5-yl, —SO 3 H, —PO 3 H 2 , —SO 2 NH 2 , —C(O)NHSO 2 CH 3 , —CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl; 
       R a  is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 3 ) alkyl, or (C 2 -C 6 )heteroalkyl; 
       R b  is hydrogen, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
       R 1′  is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; 
       R 1″  is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl; and 
       the subscript k is 0, 1 or 2. 
     
   
   
       18 . The compound of  claim 17 , wherein Q is hydrogen, aryl, or heteroaryl; L 1  is a bond; L 2  is O or S(O) k ; L 3  is a (C 1 -C 3 )alkylene; and A is —CO 2 H. 
   
   
       19 . The compound of  claim 17 , wherein M is combined with R 1  to form a benzo-fused cycloalkane ring having a formula selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     wherein, the dotted lines indicate sites of attachment to L 2  and L 3 . 
   
   
       20 . The compound of  claim 17 , wherein M-X-L 3 -A is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     wherein the dotted line indicates the site of attachment to L 2 . 
   
   
       21 . The compound of  claim 17 , wherein the compound has the formula (VIII) or (IX) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein:
 Q is selected from hydrogen, aryl, or heteroaryl; 
 L 2  is selected from O or S(O) k ; 
 R 4  is independently selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro; 
 the subscript m is 1, 2, 3 or 4; and 
 the subscript n is 0, 1 or 2. 
 
   
   
       22 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of  claim 17 . 
   
   
       23 . A method for treating type II diabetes, the method comprising:
 administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 17 .   
   
   
       24 . A compound having the formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
 Q is hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 L 1  is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) k , N(R a ), C(O)—(C 5 -C 7 )heterocycloalkylene, (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , or C(O)N(R b ); 
 
     
       
         
         
             
             
         
       
       represents an optionally substituted (C 5 -C 8 )cycloalkane ring; 
       L 2  is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(O) k , N(R a ), C(O)N(R b ), SO 2 N(R b ), (C 1 -C 4 )alkylene-C(O)N(R b ), (C 1 -C 4 )alkylene-N(R b )C(O), (C 2 -C 4 )alkenylene-C(O)N(R b ), (C 2 -C 4 )alkenylene-N(R b )C(O), (C 1 -C 4 )alkylene-SO 2 N(R b ), (C 1 -C 4 )alkylene-N(R b )SO 2 , (C 2 -C 4 )alkenylene-SO 2 N(R b ), or (C 2 -C 4 )alkenylene-N(R b )SO 2 ; 
       M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, aryl(C 1 -C 4 )alkylene, or heteroaryl(C 1 -C 4 )alkylene; 
       X is CR 1 R 1′ , N(R 1″ ), O, or S(O) k ; 
       L 3  is a bond, (C 1 -C 5 )alkylene, or (C 2 -C 5 )heteroalkylene; 
       A is —CO 2 H, tetrazol-5-yl, —SO 3 H, —PO 3 H 2 , —SO 2 NH 2 , —C(O)NHSO 2 CH 3 , —CHO, thiazolidinedion-yl, hydroxyphenyl, or pyridyl; 
       R a  is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 3 ) alkyl, or (C 2 -C 6 )heteroalkyl; 
       R b  is hydrogen, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
       R 1  is cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or —C(O)NR 2 R 3 ; 
       R 1′  is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; 
       R 1″  is hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl; 
       R 2  and R 3  are independently selected from hydrogen, aryl, heteroaryl, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )heterocycloalkyl; 
       optionally, R 2  and R 3  are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached comprising from 0 to 2 additional heteroatoms selected from N, O, or S; and 
       the subscript k is 0, 1, or 2 
     
   
   
       25 . The compound of  claim 24 , wherein L 1  is a bond, Q is H or aryl, 
     
       
         
         
             
             
         
       
     
     represents an optionally substituted cyclopentane or cyclohexane ring, L 2  is O, oxymethylene, or oxyethylene, M is benzene and X is para to L 2 , X is CR 1 R 1′ , R 1  is cyano, aryl, heteroaryl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl, or —C(O)NR 2 R 3 , R 1′  is H, L 3  is methylene, and A is CO 2 H or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. 
   
   
       26 . The compound of  claim 25 , wherein the compound is a pharmaceutically acceptable salt or solvate. 
   
   
       27 . The compound of  claim 24 , wherein the compound has the formula (II): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein
 Q is selected from hydrogen, aryl, or heteroaryl; 
 
     
       
         
         
             
             
         
       
       represents a cycloalkane ring; 
       L 2  is selected from O or S(O) k ; 
       R 1  is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, or —C(O)NR 2 R 3 ; 
       optionally, R 1  is combined with the adjacent benzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selected from N, O or S; 
       R 2  and R 3  are independently selected from hydrogen or (C 1 -C 4 )alkyl; 
       R 4  is independently selected from the group consisting of substituted (C 1 -C 6 )alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO 2 NR″R′″, —NR″CO 2 R′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —SiR′R″R′″, —S(O)R′, —SO 2 R′, —SO 2 NR′R″, —NR″SO 2 R, —CN, and —NO 2 , where R′, R″ and R′″ are each independently selected from hydrogen, unsubstituted (C 1 -C 8 )alkyl or heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C 1 -C 4 )alkyl, or aryl-(C 1 -C 4 )alkyl groups; 
       R 5  is independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro; 
       the subscript k is 0, 1 or 2; 
       the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and 
       the subscript p is 0, 1, 2, 3 or 4. 
     
   
   
       28 . The compound of  claim 27 , wherein R 4  is independently selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro. 
   
   
       29 . The compound of  claim 27 , wherein the compound has having the formula (IIIa) or (IIIb): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1  is (C 2 -C 8 )alkynyl, aryl, heteroaryl, or —C(O)NR 2 R. 
   
   
       30 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of  claim 24 . 
   
   
       31 . A method for treating type II diabetes, the method comprising: administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 24 .