Benzo-fused compounds for use in 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; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture 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 benzo-fused (C 5 -C 8 )cycloalkane ring comprising a benzene ring fused to a (C 5 -C 8 )cycloalkane ring, an optionally substituted heterobenzo-fused (C 5 -C 8 )cycloalkane ring comprising a six-membered heteroaryl ring comprising 1 or 2 N atoms fused to a (C 5 -C 8 )cycloalkane ring, or a heteroaryl-fused (C 5 -C 8 )cycloalkane ring comprising a five-membered heteroaryl ring comprising 1 or 2 heteroatoms fused to a (C 5 -C 8 )cycloalkane ring, wherein the benzene ring of the benzo-fused (C 5 -C 8 )cycloalkane ring, the heteroaryl ring of the heterobenzo-fused (C 5 -C 8 )cycloalkane ring, or the heteroaryl ring of the heteroaryl-fused (C 5 -C 8 )cycloalkane ring is bonded to L 2  or M, if L 2  is a bond; 
 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 , 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, heterocycloalkyl, (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, in each instance, independently selected from 0, 1, or 2, wherein, R 1  is a group other than a group of the following formula: 
 
     
       
         
         
             
             
         
       
     
   
   
       2 . The compound of  claim 1 , wherein   is a benzo-fused (C 5 -C 8 )cycloalkane ring. 
   
   
       3 . The compound of  claim 1 , wherein   is a heterobenzo-fused (C 5 -C 8 )cycloalkane ring, wherein the heteroaryl ring of the heterobenzo-fused (C 5 -C 8 )cycloalkane ring comprises 1 or 2 N atoms. 
   
   
       4 . The compound of  claim 1 , wherein the (C 5 -C 8 )cycloalkane ring comprises 0-3 heteroatoms selected from N, O, and S. 
   
   
       5 . The compound of  claim 1 , wherein the compound has the formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof, wherein
 Q is selected from hydrogen, aryl, or heteroaryl; 
 L 2  is selected from (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, or S(O) k ; 
 R 1  is selected from (C 2 -C 8 )alkynyl, aryl, heteroaryl, heterocycloalkyl, 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, —(C 2 -C 8 ) alkynyl, —(C 2 -C 5 )alkenyl, or —NO 2 , where R′, R″ and R′″ each independently refer to 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 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. 
 
   
   
       6 . The compound of  claim 5 , wherein R 4  independently is selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro. 
   
   
       7 . The compound of  claim 5 , wherein the compound has the formula IIIA or IIIB: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, or prodrug thereof or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof. 
   
   
       8 . The compound of  claim 1 , wherein the compound has the formula IV: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof, wherein
 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, —(C 2 -C 5 )alkynyl, —(C 2 -C 5 )alkenyl, or —NO 2 , where R′, R″ and R′″ each independently refer to 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; 
 one of R 6  and R 6′  is L 1  or Q, if L 1  is a bond, and the others of R 6  and R 6′  are independently selected from H, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro, wherein one of R 6  and one of R 6′  on adjacent or non-adjacent carbon atoms, or on the same carbon atom may join together to form a C 5 -C 8  cycloalkane ring, or two of R 6  or two of R 6′ , on adjacent or non-adjacent carbon atoms, may join together to form a C 5 -C 8  cycloalkane ring; 
 the subscript n′ is 0, 1, 2, or 3; and 
 the subscript m is 1, 2, 3, or 4. 
 
   
   
       9 . The compound of  claim 8 , wherein the compound has the formula V: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof. 
   
   
       10 . The compound of  claim 8 , wherein the compound has the formula VI: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixture thereof. 
   
   
       11 . The compound of  claim 8 , wherein the subscript m is 1 or 2. 
   
   
       12 . The compound of  claim 8 , wherein the subscript m is 1 or 2; the subscript n′ is 0; L 1  is a bond; L 2  is selected from —CH 2 —O—, substituted oxymethylene, or O; R 1  is selected from aryl, heteroaryl, heterocycloalkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )alkynyl; R 1′  is H; and A is —CO 2 H. 
   
   
       13 . The compound of  claim 8 , wherein Q is H; L 3  is CH 2 ; and L 2  is —CH 2 —O— or —CH(CH 3 )—O—. 
   
   
       14 . The compound of  claim 8 , wherein R 6  and R 6′  are independently selected from H and methyl and at least two of R 6  and R 6′  are methyl groups. 
   
   
       15 . The compound of  claim 8 , wherein R 6  and R 6′  are independently selected from H and methyl and at least four of R 6  and R 6′  are methyl groups. 
   
   
       16 . The compound of  claim 1 , wherein R 1  is selected from heteroaryl or heterocycloalkyl. 
   
   
       17 . The compound of  claim 16 , wherein R 1  is selected from a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. 
   
   
       18 . The compound of  claim 1 , wherein the compound has the formula of any one of XIa-XIm: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or a mixture thereof, wherein
 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, —(C 2 -C 5 )alkynyl, —(C 2 -C 5 )alkenyl, or —NO 2 , where R′, R″ and R′″ each independently refer to 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; 
 the subscript n′ is 0, 1, 2, or 3; and 
 R d  is selected from optionally substituted C 1 -C 6  alkyl or optionally substituted aryl. 
 
   
   
       19 . The compound of  claim 1 , wherein   is a heteroaryl-fused (C 5 -C 8 )cycloalkane ring and the heteroaryl of the heteroaryl-fused (C 5 -C 8 )cycloalkane ring is selected from thiophene, furan, pyrrole, oxazole, thiazole, or imidazole. 
   
   
       20 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier, diluent, or excipient, and the compound of  claim 1 . 
   
   
       21 . A method for treating a disease or condition, comprising: administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1 , wherein the disease or condition is a disease or condition responsive to the modulation of GPR40. 
   
   
       22 . A method of synthesizing a compound of formula XV, the compound of formula XV having the following structure: 
     
       
         
         
             
             
         
       
     
     the method comprising:
 (a) reacting a compound of formula XIII with a compound of formula XIV to produce the compound of formula XV, wherein the compounds of formula XIII and XIV have the following structures: 
 
     
       
         
         
             
             
         
       
     
     wherein,
 Alk is a straight or branched chain alkyl group having from 1 to 8 carbon atoms; 
 R 1  is selected from cyano, aryl, heteroaryl, heterocycloalkyl, (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 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; 
 R 5  is independently selected from (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro; 
 p is selected from 0, 1, 2, 3, or 4; 
 z is selected from 1, 2, or 3; 
 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, —(C 2 -C 5 )alkynyl, —(C 2 -C 5 )alkenyl, 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; 
 n′ is 0, 1, 2, or 3; 
 m is 1,2,3, or 4; 
 one of R 6  and R 6′  is L 1  or Q, if L 1  is a bond, and the others of R 6  and R 6′  are independently selected from H, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, cyano, or nitro, wherein one of R 6  and one of R 6′  on adjacent or non-adjacent carbon atoms, or on the same carbon atom may join together to form a C 5 -C 8  cycloalkane ring, or two of R 6  or two of R 6′ , on adjacent or non-adjacent carbon atoms, may join together to form a C 5 -C 8  cycloalkane ring; 
 L 1  is selected from 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 ); 
 R a  is selected from hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 3 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 R b  is selected from hydrogen, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 Q is selected from hydrogen, aryl, heteroaryl, (C 1 -C 6 )alkyl, or (C 2 -C 6 )heteroalkyl; 
 W is a leaving group; and 
 further wherein, the compounds of formula XIII and XV can be a mixture of compounds having the R and S stereochemistry at the carbon bonded to R 1 , can have the R stereochemistry at the carbon bonded to R 1 , or can have the S stereochemistry at the carbon bonded to R 1 . 
 
   
   
       23 . The method of  claim 22 , wherein W is selected from OH, a halogen, an OTs, an OMs, or an OTf wherein Ts is p-toluenesulfonyl, Ms is methanesulfonyl, and Tf is trifluoromethanesulfonyl. 
   
   
       24 . The method of  claim 22 , wherein Alk is methyl or ethyl. 
   
   
       25 . The method of  claim 22 , wherein m is 1 or 2.