2-substituted-ethynylthiazole derivatives and uses of same

Abstract

The present invention provides 2-substituted-ethynylthiazole derivatives of formula (I): wherein R 1 , R 2 and X are as defined herein, or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and methods of using same.

1 ) A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         X is CH 2 NR 3 R 4 , —CH(OH)R 5 , —CO 2 R 3 , —COR 3 , or —C(OH)R 5 R 6 , wherein:
 R 3  is hydrogen or C 1 -C 6 alkyl; 
 R 4  is C 1 -C 6 alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, arylalkyl, or aryl, each of which is optionally mono-, di-, or tri-substituted independently with C 1 -C 6 alkyl, halogen, cycloalkyl, and aryl; or 
 R 3  and R 4  taken together with the N to which they are attached to form a 4 to 10 membered heterocyclyl, which optionally contains at least one additional heteroatom and optionally is mono-, di-, or tri-substituted independently with C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 cycloalkyl, CO 2 C 1 -C 6 alkyl, hydroxyalkyl, —CN, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , —NHCOC 1 -C 6 alkyl, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-C 1 -C 6 alkyl, ═O, and halogen; 
 R 5  is C 1 -C 3 alkyl, CF 3 , CHF 2 , cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or heterocyclyl that is attached via a carbon having from 1 to 3 substitutions, which are selected from a group consisting of C 1 -C 6 alkyl, halogen, cycloalkyl, aryl, hydroxy, C 1 -C 6 alkoxy, hydroxyalkyl, —CN, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , acyl, heteroaryl, heterocyclyl, and carbonyl; and 
 R 6  is hydrogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , or C 3 -C 6 cycloalkyl; 
 
         R 1  is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or heteroaryl, which is optionally mono-, or di-substituted independently with C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, CF 3 , CHF 2 , CN and halogen; 
         R 2  is hydrogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , or halogen; 
         with the proviso that X and R 2  are attached either to the fourth or fifth carbon of the thiazole ring and when X is attached to the fourth carbon, R 2  is attached to the fifth carbon and vice versa; or 
         a pharmaceutically-acceptable salt thereof. 
       
     
     
         2 ) (canceled) 
     
     
         3 ) (canceled) 
     
     
         4 ) The compound of  claim 1 , wherein R 1  is an alkyl, cycloalkyl, aryl or heteroaryl. 
     
     
         5 ) The compound of  claim 4 , wherein R 1  is a cyclohexyl, phenyl, thienyl, furyl, pyrazinyl, pyrimidyl, pyridyl, thiazolyl, or a moiety as shown below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 ) The compound of  claim 1 , wherein R 2  is hydrogen or fluorine. 
     
     
         7 ) The compound of  claim 1 , wherein the heterocyclyl formed by R 3  and R 4  together with the N to which they are attached is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl, or a bicyclo- or spirocyclo-moiety as follows: 
       
         
           
           
               
               
           
         
       
     
     
         8 ) The compound of  claim 1 , wherein the compound is:
 2-Phenylethynyl-thiazole-4-carboxylic acid benzylamide;   2-Phenylethynyl-thiazole-4-carboxylic acid o-tolylamide;   2-Phenylethynyl-thiazole-4-carboxylic acid (2-chloro-phenyl)-amide;   2-Phenylethynyl-thiazole-4-carboxylic acid phenylamide;   2-Phenylethynyl-thiazole-4-carboxylic acid m-tolylamide;   2-Phenylethynyl-thiazole-4-carboxylic acid (4-chloro-phenyl)-amide;   2-Phenylethynyl-thiazole-4-carboxylic acid p-tolylamide;   2-Phenylethynyl-thiazole-4-carboxylic acid cyclopropylmethyl-amide;   2-Phenylethynyl-thiazole-5-carboxylic acid (4-chloro-phenyl)-amide;   2-Phenylethynyl-thiazole-5-carboxylic acid phenylamide;   2-Phenylethynyl-thiazole-5-carboxylic acid cyclopropylmethyl-amide;   2-Phenylethynyl-thiazole-5-carboxylic acid m-tolylamide;   2-Phenylethynyl-thiazole-5-carboxylic acid p-tolylamide;   2-Phenylethynyl-thiazole-5-carboxylic acid o-tolylamide;   2-Phenylethynyl-thiazole-5-carboxylic acid benzylamide;   2-Phenylethynyl-thiazole-5-carbaldehyde;   1-(2-Phenylethynyl-thiazol-5-ylmethyl)-piperidine;   2-Phenylethynyl-5-pyrrolidin-1-ylmethyl-thiazole;   4-Methyl-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   4-(2-Phenylethynyl-thiazol-5-ylmethyl)-morpholine;   1-(2-Phenylethynyl-thiazol-5-ylmethyl)-piperidin-4-ol;   1-Methyl-4-(2-phenylethynyl-thiazol-5-ylmethyl)-piperazine;   Dimethyl-(2-phenylethynyl-thiazol-5-ylmethyl)-amine;   Diethyl-(2-phenylethynyl-thiazol-5-ylmethyl)-amine;   5-(3-Methoxy-azetidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-Azetidin-1-ylmethyl-2-phenylethynyl-thiazole;   5-((S)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-((R)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   2-(2-Phenylethynyl-thiazol-5-ylmethyl)-2-ara-bicyclo[2.2.1]heptane;   5-(3,3-Difluoro-azetidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-(3,3-Difluoro-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   2-Methyl-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   3,3-Difluoro-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   4,4-Difluoro-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   5-(3-Fluoro-azetidin-1-ylmethyl)-2-phenylethynyl-thiazole;   3-Fluoro-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   4-Fluoro-1-(2-phenylethynyl-thiazol-5-ylmethyl)-piperidine;   5-(2-Methyl-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-(2,2-Dimethyl-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-((S)-3-Fluoro-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   5-((R)-3-Fluoro-pyrrolidin-1-ylmethyl)-2-phenylethynyl-thiazole;   1-[1-(2-Phenylethynyl-thiazol-5-yl)-ethyl]-piperidine;   4-[1-(2-Phenylethynyl-thiazol-5-yl)-ethyl]-morpholine;   2-Phenylethynyl-5-(1-pyrrolidin-1-yl-ethyl)-thiazole;   Phenyl-(2-phenylethynyl-thiazol-5-yl)-methanol;   Cyclohexyl-(2-phenylethynyl-thiazol-5-yl)-methanol;   1-(2-Phenylethynyl-thiazol-5-yl)-ethanol;   Phenyl-(2-phenylethynyl-thiazol-5-yl)-methanone;   Cyclohexyl-(2-phenylethynyl-thiazol-5-yl)-methanone;   1-(2-Phenylethynyl-thiazol-5-yl)-ethanone;   1-Phenyl-1-(2-phenylethynyl-thiazol-5-yl)-ethanol;   1-Cyclohexyl-1-(2-phenylethynyl-thiazol-5-yl)-ethanol;   (4-Methyl-cyclohexyl)-(2-phenylethynyl-thiazol-5-yl)-methanone:   (4-Fluoro-cyclohexyl)-(2-phenylethynyl-thiazol-5-yl)-methanone;   (4-Hydroxy-cyclohexyl)-(2-phenylethynyl-thiazol-5-yl)-methanone;   [2-(3-Chloro-phenylethynyl)-thiazol-5-yl]-(4-hydroxy-cyclohexyl)-methanone; and   Cyclohexyl-[2-(6-methyl-pyridin-2-ylethynyl)-thiazol-5-yl]-methanone; or   
       a pharmaceutically acceptable salt thereof. 
     
     
         9 ) A pharmaceutical composition comprising at least one compound of  claim 1  and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         10 ) The pharmaceutical composition of  claim 9 , wherein the composition improves cognitive functioning in a human. 
     
     
         11 ) The pharmaceutical composition of  claim 9 , wherein the composition is for use in a human who has been diagnosed with a cognitive impairment. 
     
     
         12 ) The pharmaceutical composition of  claim 9 , wherein the composition is for use in a human who has first-episode schizophrenia 
     
     
         13 ) A method of improving cognitive functioning, comprising administering an effective amount of a compound of  claim 1  to a human in need thereof. 
     
     
         14 ) The method according to  claim 13 , wherein the human suffers from cognitive dysfunction. 
     
     
         15 ) The method of  claim 14 , wherein the cognitive dysfunction presents in connection with a disease or disorder selected from the group consisting of psychosis, schizophrenia, a disease involving a psychotic symptom, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, substance-induced psychotic disorder, an affective disorder, ADHD, or a combination thereof. 
     
     
         16 ) The method according to  claim 15 , wherein the affective disorder is depression, mania, or bipolar disorder. 
     
     
         17 ) The method according to  claim 15 , wherein the disease or disorder is schizophrenia. 
     
     
         18 ) The method according to  claim 15 , wherein the disease or disorder is ADHD. 
     
     
         19 ) The method according to  claim 15 , wherein the method further comprises reducing a cognitive symptom in a schizophrenic patient or ADHD patient. 
     
     
         20 ) A method of treating a disease or disorder, comprising administering an effective amount of a compound of  claim 1  to a human in need thereof, wherein the disease or disorder is schizophrenia, cognition, cognitive impairment associated with schizophrenia (CIAS), psychosis, depression, mania, bipolar disorder, ADHD, or a combination thereof. 
     
     
         21 . The compound of  claim 1 , wherein the compound is of formula (Ib), (Ic), (Id) or (Ie):