Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof

Abstract

The invention is directed to a class of compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula I: as defined in the specification. The invention is also directed to compositions containing and uses of the compounds of formula I.

1 . A compound of formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein each R 1  and each R 2  and each R 7  is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —S(O) w R 8 , —SO 2 —N(R 8 ) 2 , (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl, and (C 3 -C 10 )cycloalkyl; wherein said (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl, or (C 3 -C 10 )cycloalkyl are each independently optionally substituted with one, two, three or four R 9 ; 
         w is 0, 1 or 2; 
         m is zero, one, two or three; 
         n is zero, one, two or three; 
         p is zero, one, two or three; 
         q is zero, one, two or three; 
         s is one and t is one; or one of s or t is one and the other of s or t is two; 
         R 3  is hydrogen or (C 1 -C 6 )alkyl; 
         each R 4  is independently selected from hydrogen, or (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl may be optionally substituted with one, two, three or four halogen, —CN, or —OR 9 ; 
         or two R 4  groups on the same carbon atom may be taken together to form an oxo (═O) radical or a (C 3 -C 6 )spirocycloalkyl; 
         R 5  is hydrogen, or (C 1 -C 6 )alkyl; 
         R 6  is (C 1 -C 6 )alkyl-(C═O)—, [(C 1 -C 6 )alkyl] 2 N—(C═O)—, (C 1 -C 6 )alkyl-SO 2 —, (C 3 -C 10 )cycloalkyl-SO 2 —, or [(C 1 -C 6 )alkyl] 2 N—SO 2 —; wherein said (C 1 -C 6 )alkyl moieties of said [(C 1 -C 6 )alkyl] 2 N—(C═O)— and [(C 1 -C 6 )alkyl] 2 N—SO 2 — may optionally be taken together with the nitrogen atom to which they are attached to form a four to six membered heterocyclic ring; 
         R 8  is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl, and (C 3 -C 10 )cycloalkyl; wherein said (C 1 -C 6 )alkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, —CN, perfluoro(C 1 -C 6 )alkyl, hydroxy, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkoxy, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, formyl, (C 1 -C 6 )alkyl-(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl]-(NH)—(C═O)—, [(C 1 -C 6 )alkyl] 2 N—(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, H(C═O)—NH—, (C 1 -C 6 )alkyl(C═O)—NH—, (C 1 -C 6 )alkyl(C═O)—[N((C 1 -C 6 )alkyl)]-, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO 2 —NH—, (C 1 -C 6 )alkyl-SO 2 —[N((C 1 -C 6 )alkyl)]-, H 2 N—SO 2 —, [(C 1 -C 6 )alkyl]-NH—SO 2 —, and [(C 1 -C 6 )alkyl] 2 N—SO 2 —; wherein said (C 1 -C 6 )alkyl may be additionally optionally substituted with an optionally substituted (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl, or (C 3 -C 10 )cycloalkyl; wherein said optional substituents may be independently selected from one, two, three or four radicals independently selected from halogen, hydroxyl, —CF 3 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and amino; wherein each of said R 8  (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl or (C 3 -C 10 )cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, —CF 3 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy and amino; 
         each R 9  is independently selected from the group consisting of halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 10 , —O—(C═O)—R 10 , —(NR 10 )—(C═O)—R 10 , —(C═O)—OR 10 , —(C═O)—N(R 10 ) 2 , —OR 10 , —O—(C═O)—OR 10 , —O—(C═O)—N(R 10 ) 2 , —NO 2 , —N(R 10 ) 2 , —(NR 10 )—SO 2 —R 10 , —S(O) u R 10 , —SO 2 —N(R 10 ) 2 ; 
         R 10  is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl and (C 3 -C 10 )cycloalkyl; wherein said (C 1 -C 6 )alkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, —CN, perfluoro(C 1 -C 6 )alkyl, hydroxy, amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkoxy, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, formyl, (C 1 -C 6 )alkyl-(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl]-(NH)—(C═O)—, [(C 1 -C 6 )alkyl] 2 N—(C═O)—, (C 1 -C 6 )alkyl-(C═O)—O—, H(C═O)—NH—, (C 1 -C 6 )alkyl(C═O)—NH—, (C 1 -C 6 )alkyl(C═O)—[N((C 1 -C 6 )alkyl)]-, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO 2 —NH—, (C 1 -C 6 )alkyl-SO 2 —[N((C 1 -C 6 )alkyl)]-, H 2 N—SO 2 —, [(C 1 -C 6 )alkyl]-NH—SO 2 —, and [(C 1 -C 6 )alkyl] 2 N—SO 2 —; wherein said (C 1 -C 6 )alkyl may also be additionally optionally substituted with an optionally substituted (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl or (C 3 -C 10 )cycloalkyl; wherein said optional substituents may be independently selected from one, two, three or four radicals independently selected from halogen, hydroxyl, —CF 3 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and amino; wherein each of said R 10  (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heterocycloalkyl, or (C 3 -C 10 )cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, —CF 3 , —CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and amino; 
         R 11  is hydrogen or (C 1 -C 6 )alkyl; 
         ring “A” is (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 4 -C 10 )cycloalkyl, or (C 1 -C 9 )heterocycloalkyl; wherein two of said R 1  substituents on said (C 4 -C 10 )cycloalkyl and (C 1 -C 9 )heterocycloalkyl may optionally be attached to the same carbon atom and may optionally be taken together to be oxo; 
         ring “B” is (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 4 -C 10 )cycloalkyl, or (C 1 -C 9 )heterocycloalkyl; 
         “X” is —O— or >C(R 4 ) 2 ; 
         “Y” is absent, >NR 11 , —(NR 11 )—(C═O)—, >C═O, —O— or >C(R 7 ) 2 ; and 
         “Z” is —O—, —S—, —(S═O)—, or —(SO 2 )—. 
       
     
     
         2 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is of Formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is of Formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 3 , or a pharmaceutically acceptable salt thereof, wherein “Z” is —O—. 
     
     
         5 . A compound according to  claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is —O—. 
     
     
         6 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “A” is phenyl. 
     
     
         7 . A compound according to  claim 6 , or a pharmaceutically acceptable salt thereof, wherein ring “A” is phenyl; n is zero, one or two; R 1  is selected from the group consisting of hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —S(O) w R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         8 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “A” is (C 1 -C 9 )heteroaryl; n is zero, one or two; and wherein R 1  is selected from the group consisting of hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —S(O) w R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         9 . The compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “A” is (C 1 -C 9 )heterocycloalkyl; n is zero, one or two; and wherein R 1  is selected from the group consisting of oxo, hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —S(O) w R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         10 . The compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “A” is (C 4 -C 10 )cycloalkyl; n is zero, one or two; and wherein R 1  is selected from the group consisting of oxo, hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —S(O) w R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         11 . A compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1  is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano or halogen and is in the ortho or para position relative to Y. 
     
     
         12 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “B” is phenyl; n is zero or one; R 2  is hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         13 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “B” is (C 1 -C 9 )heteroaryl; n is zero or one; and wherein R 2  is hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         14 . (canceled) 
     
     
         15 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring “B” is (C 4 -C 10 )cycloalkyl; n is zero or one; and wherein R 2  is hydrogen, halogen, hydroxyl, —CF 3 , —CN, —(C═O)R 8 , —O—(C═O)—R 8 , —(NR 8 )—(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —OR 8 , —O—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NO 2 , —N(R 8 ) 2 , —(NR 8 )—SO 2 —R 8 , —SO 2 —N(R 8 ) 2 , and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with one, two, three or four R 9 . 
     
     
         16 . A compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 2  is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, cyano or halogen. 
     
     
         17 . A compound according to  claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen. 
     
     
         18 . A compound according to  claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 4  is hydrogen. 
     
     
         19 - 20 . (canceled) 
     
     
         21 . A compound according to  claim 18 , or a pharmaceutically acceptable salt thereof, wherein q is zero. 
     
     
         22 . A compound according to  claim 21 , or a pharmaceutically acceptable salt thereof, wherein Y is absent. 
     
     
         23 . A compound according to  claim 21 , or a pharmaceutically acceptable salt thereof, wherein Y is —O—. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . A compound according to  claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 6  is (C 1 -C 5 )alkyl-SO 2 —. 
     
     
         28 . A compound according to  claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 6  is (C 3 -C 5 )cycloalkyl-SO 2 —. 
     
     
         29 . (canceled) 
     
     
         30 . A compound that is:
 N-{1-[4-trans-({4-[(isopropylsulfonyl)amino]tetrahydrofuran-3-yl}oxy)phenyl]pyrrolidin-3-yl}acetamide;   N-[(3S,4S)-4-(biphenyl-4-yloxy)tetrahydrofuran-3-yl]propane-2-sulfonamide;   N-{(3S,4S)-4-[(2′-cyanobiphenyl-4-yl)oxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;   N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;   N-{(1S,2R)-2-[(2′-cyanobiphenyl-4-yl)oxy]cyclopentyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[4-(5-cyano-2-thienyl)phenoxy]cyclopentyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[(2′-cyanobiphenyl-4-yl)oxy]cyclohexyl}propane-2-sulfonamide;   cis-N-[4-(4-pyridin-3-ylphenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide;   cis-N-{4-[4-(2-thienyl) phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;   N-{(3S,4S)-4-[(2′-cyano-4′-fluoro biphenyl-4-yl)oxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;   N-{(3S,4S)-4-[(4′-fluoro biphenyl-4-yl)oxy]tetra hydrofuran-3-yl}propane-2-sulfonamide;   N-{(3S,4S)-4-[(2′-ethoxy-4′-fluoro biphenyl-4-yl)oxy]tetra hydrofuran-3-yl}propane-2-sulfonamide;   cis-N-[4-{[6-(5-cyano-2-thienyl)pyridin-3-yl]oxy}tetra hydrofuran-3-yl]propane-2-sulfonamide;   cis-N-{4-[4-(3-thienyl) phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;   2-cyano-4′-({(1R,2S)-2-[(isopropyl sulfonyl)amino]cyclopentyl}oxy) biphenyl-4-carboxylic acid;   N-{(1S,2R)-2-[(2′-cyano-2,4′-difluoro biphenyl-4-yl)oxy]cyclopentyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[(2′-ethoxy-2-fluoro biphenyl-4-yl)oxy]cyclopentyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[4-(5-cyano-2-thienyl)-3-fluoro phenoxy]cyclopentyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[(2′-cyano-2-fluoro biphenyl-4-yl)oxy]cyclohexyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[(2′-cyano-2,4′-difluoro biphenyl-4-yl)oxy]cyclohexyl}propane-2-sulfonamide;   N-{(1S,2R)-2-[4-(5-cyano-2-thienyl)-3-fluoro phenoxy]cyclohexyl}propane-2-sulfonamide;   N-[(1S,2R)-2-(4-pyrrolidin-1-ylphenoxy)cyclohexyl]propane-2-sulfonamide;   N-[(1S,2R)-2-({6-[2-(2,2,2-trifluoro ethoxy)phenyl]pyridin-3-yl}oxy)cyclohexyl]propane-2-sulfonamide;   N-[(1S,2R)-2-({6-[2-(trifluoro methoxy)phenyl]pyridin-3-yl}oxy)cyclohexyl]propane-2-sulfonamide; or   N-[(1S,2R)-2-{[6-(5-cyano-2-thienyl)pyridin-3-yl]oxy}cyclohexyl]propane-2-sulfonamide   or a pharmaceutically acceptable salt thereof.   
     
     
         31 . A method for the treatment or prevention in a mammal of a condition selected from the group consisting of acute neurological and psychiatric disorders, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, attention deficit disorder, and conduct disorder, comprising administering a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.