Compounds and methods

Abstract

Disclosed are compounds having the formula: wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , Y, A, Z, L and n are as defined herein, and methods of making and using the same.

What is claimed is: 
     
         1 . A compound according to the Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is halo(C 1 -C 4 )alkyl, wherein said halo(C 1 -C 4 )alkyl contains at least 2 halo atoms; 
 A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, 
 wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A  and —((C 1 -C 4 )alkyl)NR A R A ; 
 Z is —C(═O)NR X —, —NR X C(═O)NR X , —NR X C(═O)—, —SO 2 —, —SO 2 NR X —, —NR X SO 2 —, —NHCH(CF 3 )—, —CH(CF 3 )NH—, —CH(CF 3 )—, —(C 1 -C 4 )alkyl-, —NR X —, or —(C 1 -C 3 )alkyl-NR X —; 
 n is 1-4 and R 2  and R 3  are independently selected from H, fluoro, and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, wherein, when n is 1, R 2  is F and R 3  is H, then Z is —C(═O)NR X —, —NR X C(═O)NR X , —SO 2 NR X —, —NHCH(CF 3 )—, —CH(CF 3 )NH—, —CH(CF 3 )—, —(C 1 -C 4 )alkyl-, —NR X —, or —(C 1 -C 3 )alkyl-NR X —, 
 or n is 1-4 and R 2  is selected from —NR A R B , —(C 1 -C 4 )alkyl-NR A R B , —CONR A R B , —(C 1 -C 4 )alkyl-CONR A R B , —CO 2 H, —(C 1 -C 4 )alkyl-CO 2 H, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )alkoxy(C 1 -C 4 )alkyl-, and R 3  is selected from H and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, 
 wherein the aryl, cycloalkyl and each of the (C 1 -C 4 )alkyl moieties of said optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl- of any R 2  and R 3  are optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A , —((C 1 -C 4 )alkyl)NR A R A , and hydroxyl; 
 or n is 0-4 and R 2  and R 3  taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, aryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, —OR Y , —NR Y R Y , —C(═O)OR Y , —C(═O)NR Y R Y , —NR Y C(═O)R Y , —SO 2 NR Y R Y , —NR Y SO 2 R Y , —OC(═O)NR Y R Y , —NR Y C(═O)OR Y , and —NR Y C(═O)NR Y R Y ; and 
 L is 5-6 membered heteroaryl or phenyl which is substituted by R 4  and is optionally further substituted, 
 wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C 1 -C 4 )alkyl; 
 R 4  is H, (C 1 -C 4 )alkyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N(C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N(C 1 -C 4 )alkyl-, (C 1 -C 4 )haloalkoxy-, (C 1 -C 4 )alkylamino, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, 
 wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C 1 -C 4 )alkoxy, hydroxyl, —NR A R C  and —((C 1 -C 4 )alkyl)NR A R C ; 
 or L-R 4 , taken together, form a 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C 1 -C 4 )alkoxy, hydroxyl, —NR A R C  and —((C 1 -C 4 )alkyl)NR A R C ; 
 wherein each R A  is independently selected from H and (C 1 -C 4 )alkyl; 
 R B  is H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —C(═O)(C 1 -C 4 )alkyl, —C(═O)O(C 1 -C 4 )alkyl, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 )alkyl, —C(═O)N((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl), —SO 2 (C 1 -C 4 )alkyl, or R A  and R B  taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl; 
 R C  is H, (C 1 -C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A  and R C  taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl; 
 each R X  is independently selected from H, (C 1 -C 6 )alkyl, and optionally substituted (C 2 -C 6 )alkyl, where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl)NH—, or ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N—; and 
 each R Y  is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and —(C 1 -C 4 )alkylphenyl; 
 or a salt thereof. 
 
     
     
         2 . The compound or salt according to  claim 1 , wherein R 1  is CHF 2  or CF 3 . 
     
     
         3 . The compound or salt according to  claim 2 , wherein R 1  is CF 3 . 
     
     
         4 . The compound or salt according to  claim 1 , wherein A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A  and —((C 1 -C 4 )alkyl)NR A R A . 
     
     
         5 . The compound or salt according to  claim 1 , wherein A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group. 
     
     
         6 . The compound or salt according to  claim 1 , wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, —NR A R A  and —((C 1 -C 4 )alkyl)NR A R A , where each R A  is independently H or methyl; or
 A is naphthyl, optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A  and —((C 1 -C 4 )alkyl)NR A R A ; or 
 A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl; or 
 A is oxazolyl, pyrazolyl, or thienyl, optionally substituted by a methyl group or 
 A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, —NR A R A  and —((C 1 -C 4 )alkyl)NR A R A , where each R A  is independently H or methyl. 
 
     
     
         7 . The compound or salt according to  claim 1 , wherein Z is —C(═O)NH— or —CH 2 NH—. 
     
     
         8 . The compound or salt according to  claim 1 , wherein n is 0 or 1. 
     
     
         9 . The compound or salt according to  claim 8 , wherein both R 2  and R 3  are C 1-4 alkyl. 
     
     
         10 . The compound or salt according to  claim 8 , wherein both R 2  and R 3  are H or both R 2  and R 3  are methyl or R 2  is hydroxyl and R 3  is H or methyl. 
     
     
         11 . The compound or salt according to  claim 8 , wherein R 2  and R 3  taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C 1 -C 4 )alkyl, aryl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-. 
     
     
         12 . The compound or salt according to  claim 8 , wherein R 2  and R 3  taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, 1-ethyl-piperidinyl, tetrahydrofuranyl, piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, 1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1-methyl-azetidinyl, 1-benzyl-azetidinyl, or 1-cyclopropylmethyl-azetidinyl group. 
     
     
         13 . The compound or salt according to  claim 1 , wherein L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4  and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl. 
     
     
         14 . The compound or salt according to  claim 1 , wherein L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl which is substituted by a methyl group. 
     
     
         15 . The compound or salt according to  claim 13 , wherein R 4  is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano. 
     
     
         16 . The compound or salt according to  claim 1 , wherein L-R 4 , taken together, form a 1,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-. 
     
     
         17 . The compound or salt according to  claim 1 , wherein each R A  and R B  is independently selected from H and (C 1 -C 4 )alkyl. 
     
     
         18 . The compound or salt according to  claim 1 , wherein said salt is a pharmaceutically acceptable salt. 
     
     
         19 . A compound which is:
 N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,   N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,   3-(5-(2,2-difluoroacetyl)thiophen-2-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamide,   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,   or a pharmaceutically-acceptable salt thereof.   
     
     
         20 . A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to  claim 1  and one or more pharmaceutically-acceptable excipients.