Heterocyclic boronic acid compounds

Abstract

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH 2 ; S; O; CF 2 or C(CH 3 ) 2 ; Z is H; halogen; hydroxyl; (C 1-6 )alkoxy; (C 1-12 )alkyl; (C 3-12 )cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CR i R ii , R 1 , R 2 , R 3 , R 4 and R 5 are as described herein.

1 . A pyrrolidine compound of formula I:  
       
         
           
           
               
               
           
         
       
       including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein: 
 n is 1 to 3;  
 X is CH 2 ; S; O; CF 2  or C(CH 3 ) 2 ;  
 Z is H; halogen; hydroxyl; (C 1-6 )alkoxy; (C 1-12 )alkyl; (C 3-12 )cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ;  
 R 7  is halogen; (C 1-10 )alkyl; (C 1-10 )alkoxy; (C 1-10 )alkylamino; (C 1-10 ) dialkylamino; benzyl; benzyloxy; hydroxyl(C 1-6 )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;  
 optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and  
 optionally, one of the bonds in the ring containing X is a double bond;  
 R 1  and R 2  independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and  
 CR i R ii  may be present or absent, and  
 when CR i R ii  is present, then 
 R i , R ii , R 3 , R 4  and R 5  are selected from (aa) or (bb):  
 (aa) R i , R ii , R 3  and R 4  are hydrogen; and R 5  is hydrogen, (C 1-12 )alkyl or (C 3-12 ) cycloalkyl;  
 (bb) R i , R ii R 3 , R 4  and R 5  are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,  
 
 or alternatively,  
 when CR i R ii  is absent, then R 3 , R 4  and R 5  are selected from (cc), (dd) or (ee): 
 (cc) R 3  and R 4  are hydrogen; and 
 R 5  is 
 a) hydrogen, provided that R 5  is not hydrogen when n is 1, X is CH 2 , and Z is H;  
 b) (C 1-12 )alkyl; (C 2-12 )alkenyl; (C 2-12 )alkynyl; (C 3-12 )cycloalkyl; or (C 3-12 )cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R 6 , and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;  
 R 6  is (C 1-6 )alkyl; (C 1-6 )alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C 1-6 )alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ; amino, where the amino group is optionally mono- or independently plurisubstituted with R 8 ; —SOR 8 ; —SO 2 R 8 ; —COR 8 ; —CO 2 R 8 , —CONHR 8 ; —CON(R 8 ) 2 ; —OR 8 ; or —S—R 8 ;  
 R 7  is halogen; (C 1-10 )alkyl; (C 1-10 )alkoxy; (C 1-10 )alkylamino; (C 1-10 ) dialkylamino; benzyl; benzyloxy; hydroxyl(C 1-6 )alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;  
 R 8  is (C 1-10 )alkyl; (C 2-10 )alkenyl; (C 2-10 )alkynyl; (C 3-10 )cycloalkyl; (C 5-10 )cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ;  
 c) aryl optionally fused to a (C 3-10 )cycloalkyl; or heteroaryl optionally fused to a (C 3-10 )cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ;  
 d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH 2 ) j  adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH 2 ) j  adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C 1-8 )alkyl, (C 1-8 )alkoxy, (C 1-8 )alkanoyloxy, or R 9 R 10 N—CO—O—, where R 9  and R 10  are independently (C 1-8 )alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C 1-8 )alkyl, (C 1-8 )alkoxy, halogen, or trifluoromethyl, or R 9  and R 10  together are (C 3-6 )alkylene;  
 e) R 11 (CH 2 ) p — where R 11  is 2-oxopyrrolidinyl; (C 1-6 )alkoxy; phenyl; phenoxy; (C 1-8 )cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C 1-6 )alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R 12 ; where the phenoxy group is optionally mono- or independently disubstituted with (C 1-4 )alkyl, (C 1-4 )alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C 1-8 )alkyl; and p is 0 to 3;  
 R 12  is halogen; trifluoromethyl; cyano; nitro; (C 1-6 )alkyl; (C 1-6 )alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C 1-6 )alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R 7 ;  
 f) (R 3 ) 2 CH(CH 2 ) q —, where R 13  is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R 2 ; and q is 0 to 3;  
 g) a group of the formula:  
                     
 where R 14  and R 15  are independently hydrogen; (C 1-8 )alkyl; (C 1-6 )alkylcarbonyl; (C 3-12 )cycloalkyl ring; (C 3-12 )cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C 1-6 )alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 14  and R 15  together form a (C 3-12 )cycloalkyl ring; and r is 2 to 6;  
 
 
 
 h) a group of the formula:  
                     
 where R 16  and R 17  are each independently hydrogen; (C 1-8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C 1-6 )alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or R 16  and R 17  together form a (C 3-12 )cycloalkyl ring; and s is 1 to 6;  
 i) a group of the formula:  
                     
 wherein R 18  and R 19  are independently hydrogen; (C 1-8 )alkyl; (C 1-6 )alkylcarbonyl; di-(C 1-6 )alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R 12 ; or wherein R 18  and R 19  together with the N form an (N, C 3-12 ) heterocycloalkyl ring containing the nitrogen atom; and each t is independently 0 to 6; and u is 0 to 3;  
 j) a group of the formula:  
   (phenyl-CH 2 —C(CH 3 ) 2 —),  
 where the phenyl group is optionally mono- or independently plurisubstituted with R 12 ;  
 ; or  
 k) a group of the formula:  
                     
 where R 21  is hydrogen; (C 1-8 )alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R 12 ; each t is independently 0 to 6; and u is 0 to 3; and,  
 wherein a bond containing a wavy line signifies a point of attachment;  
 (dd) R 3 , R 4  and R 5  are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl or aralkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z, R 3  and R 5  are H, R 4  is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z and R 5  are H, R 3  and R 4  are not both methyl; or,  
 (ee) R 3  is hydrogen, and R 4  and R 5  together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,  
 wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R 4  have the formula —(CR 22 R 23 ) m — wherein m is 2 to 6, and R 22  and R 23  are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino; and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH 2 , the ring containing X is saturated, and Z and R 3  are H, then R 4  and R 5  together are not —(CH 2 ) 2 — or —(CH 2 ) 3 —.  
 
     
     
         2 . A linear alkyl pyrrolidine compound of formula I according to  claim 1  wherein CR i  R ii  is absent, R 3 , R 4  and R 5  are as given in clauses (cc), (dd) and (ee), and the linear alkyl pyrrolidine compound has formula II:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A linear beta pyrrolidine compound of formula I according to  claim 1  wherein CR i  R ii  is present, R 3 , R 4  and R 5  are as given in clauses (aa) and (bb), and the linear beta pyrrolidine compound has formula III: