Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Abstract

Compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

1 . A compound of a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and isotopic variants thereof, stereoisomers and tautomers thereof, wherein: 
         CY is bicycloheteroaryl; 
         W represents O, CR 8a R 8b , or NR 8c ; 
         X represents N, O, CR 8a , CR 8a R 8b , or NR 8c ; 
         Y represents CR 8d R 8c ; 
         W′, X′, and Y′ each independently represent CR 8  or N; provided that all three of W′, X′ and Y′ can not be N at the same time; 
         R 3  represents hydrogen, halogen, hydroxy, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy or substituted or unsubstituted 3-8 membered cycloalkyl; 
         R 4  and R 5  each independently represent hydrogen or substituted or unsubstituted (C 1 -C 6 )alkyl; m is 0 or 1; 
         each R 7  is H, halogen, hydroxy, (C 1 -C 6 )acyl, cyano, substituted or unsubstituted (C 1 -C 6 )alkyl, or substituted or unsubstituted (C 1 -C 6 )alkoxy; or R 7  is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy; n is 1, 2, 3, 4 or 5; 
         each R 8  independently represents hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, or substituted or unsubstituted 3-8 membered cycloalkyl; 
         each R 8a , R 8b , R 8d , R 8e  and R 8f  independently represents hydrogen, halo, hydroxy, substituted or unsubstituted (C 1 -C 6 )alkyl, or substituted or unsubstituted 3-8 membered cycloalkyl; 
         R 8c  represents hydrogen, or substituted or unsubstituted (C 1 -C 6 )alkyl; and 
         the dotted bond represents a single or a double bond; 
         provided that:
 i) when the dotted bond is a double bond, then R 8f  is absent; 
 ii) when X is N or O; then R 8f  is hydrogen, or substituted or unsubstituted alkyl; 
 iii) when X is O; then W is O or NR 8c ; and 
 iv) when W is O; and the dotted bond is a single bond; then X is O or NR 8 . 
 
       
     
     
         2 . A compound according to  claim 1  wherein R 3 , R 4 , R 5 , R 7 , R 8 , R 8a , R 8b , R 8c , R 8d , R 8e  or R 8f  is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy (C 1 -C 6 )alkyl. 
     
     
         3 . A compound according to  claim 1 , wherein CY is quinolinyl, isoquinolinyl, indolyl, dihydroindolyl, benzofuranyl, benzothiophenyl, benzopyranyl, pyranopyridyl, benzimidazolyl, indazolyl, benzthiazolyl, benzoxazolyl, pyrazolopyridine, pyrazolooxazinyl, or thiazolopyridine. 
     
     
         4 . A compound according to  claim 1 , wherein the compound is according to formulae IIa, IIb, IIc, IId, IIe, IIf, IIg, or IIh: 
       
         
           
           
               
               
           
         
       
       wherein W, X, Y, W′, X′, Y′, R 3 , R 4 , R 5 , and R 8f  are as in  claim 1 ; R 7  is hydrogen, halogen, hydroxy, (C 1 -C 6 )acyl, (C 1 -C 6 )alkyl unsubstituted or substituted with one or more groups selected from halo, hydroxy and (C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkoxy unsubstituted or substituted with one or more groups selected from halo, hydroxy and (C 1 -C 6 )alkoxy; m is 0 or 1; n is 1, 2, 3 or 4; and the dotted bond represents a single or a double bond. 
     
     
         5 . A compound according to  claim 1 , wherein W and X each independently represent CR 8a R 8b ; and the dotted bond is a single bond. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A compound according to  claim 1 , wherein W represents CR 8a R 8b . 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
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         15 . A compound according to  claim 1 , wherein X′, and Y′ each independently represent CR 8 . 
     
     
         16 . (canceled) 
     
     
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         19 . (canceled) 
     
     
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         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
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         32 . A compound according to  claim 1 , wherein R 3  is 1-methyl-1-hydroxyethyl and R 8  is H, or R 3  is 1-methyl-1-trifluoromethylethyl and R 8  is H. 
     
     
         33 . (canceled) 
     
     
         34 . A compound according to  claim 1 , wherein R 8a  is hydrogen or Me. 
     
     
         35 . (canceled) 
     
     
         36 . A compound according to  claim 1 , wherein R 8c  is Me. 
     
     
         37 . (canceled) 
     
     
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         39 . A compound according to  claim 1 , wherein m is 1; and R 4  is hydrogen, or Me. 
     
     
         40 . (canceled) 
     
     
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         44 . A compound according to  claim 1 , selected from
 6-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (quinolin-4-ylmethyl)-amide;   6-Chloro-2H-chromene-3-carboxylic acid (quinolin-4-ylmethyl)-amide;   6-Bromo-2H-chromene-3-carboxylic acid (quinolin-4-ylmethyl)-amide;   6-Trifluoromethoxy-2H-chromene-3-carboxylic acid (quinolin-4-ylmethyl)-amide;   6-Chloro-2H-chromene-3-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   (S)-6-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   (R)-6-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   7-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (2-hydroxymethyl-thiazolo[5,4-b]pyridin-6-yl)-amide;   4-Methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide;   (S)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide;   (R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   (S)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid (2-hydroxymethyl-thiazolo[5,4-b]pyridin-6-yl)-amide;   (R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (2-hydroxymethyl-thiazolo[5,4-b]pyridin-6-yl)-amide;   (R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid (7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-amide;   (S)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid (7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)-ethyl]-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid quinolin-3-ylamide;   (S)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)-ethyl]-amide;   (R)-2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid (1-acetyl-2,3-dihydro-1H-indol-6-yl)-amide;   6-Methyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid (2-hydroxymethyl-thiazolo[5,4-b]pyridin-6-yl)-amide;   (S)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide; and   (R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide;   
       or a pharmaceutically acceptable salt thereof, and isotopic variants thereof, stereoisomers and tautomers thereof. 
     
     
         45 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
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         52 . A method for treating a disease or condition which comprises administering to a patient in need of a therapeutically acceptable amount of a compound of  claim 1 , wherein the disease is: pain including acute, inflammatory and neuropathic pain; chronic pain; dental pain; headache including migraine, cluster headache and tension headache; Parkinson's disease; Alzheimer's disease; multiple sclerosis; diseases and disorders mediated by or result in neuroinflammation, traumatic brain injury, stroke, or encephalitis; centrally-mediated neuropsychiatric diseases and disorders including depression, mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders including allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or result in inflammation including arthritis, rheumatoid arthritis and osteoarthritis; myocardial infarction; autoimmune diseases and disorders; uveitis and atherosclerosis; itch/pruritus, psoriasis; alopecia (hair loss); obesity; lipid disorders; cancer; high blood pressure; spinal cord injury; irritable bowel syndrome; overactive bladder; or renal disorders. 
     
     
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         59 . A method for preparing a compound of  claim 1  which comprises contacting an amine of the formula A and an acid of the formula B with 
       
         
           
           
               
               
           
         
         under conditions sufficient to form a compound according to  claim 1 ; and 
         wherein CY, W, X, Y, W′, X′, Y′, m, n, R 3 , R 4 , R 5 , R 7 , and R 8f  are as in  claim 1 . 
       
     
     
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         66 . A method for treating a disease or condition which comprises administering to a patient in need of a therapeutically acceptable amount of a pharmaceutical composition of  claim 45 , wherein the disease is: pain including acute, inflammatory and neuropathic pain; chronic pain; dental pain; headache including migraine, cluster headache and tension headache; Parkinson's disease; Alzheimer's disease; multiple sclerosis; diseases and disorders mediated by or result in neuroinflammation, traumatic brain injury, stroke, or encephalitis; centrally-mediated neuropsychiatric diseases and disorders including depression, mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders including allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or result in inflammation including arthritis, rheumatoid arthritis and osteoarthritis; myocardial infarction; autoimmune diseases and disorders; uveitis and atherosclerosis; itch/pruritus, psoriasis; alopecia (hair loss); obesity; lipid disorders; cancer; high blood pressure; spinal cord injury; irritable bowel syndrome; overactive bladder; or renal disorders. 
     
     
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