Trpm8 antagonists and their use in treatments

Abstract

Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

What is claimed is: 
     
         1 . A method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders in a subject, the method comprising: administering to the subject a compound of Formula I or a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof or a mixture thereof, wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 m is 0, 1, 2 or 3; 
 n is 0 or 1; 
 X 1  is C(R 4 ) or N; 
 X 2  is CH or N; 
 Y is NH, NR 1a , or O; 
 Z is O or S; 
 R 1  is C 1-6 alk, —(C═O)—O—C 1-6 alk, or a direct-bonded, C 1-6 alk-linked, C 1-2 alkO-linked, —C(═O)—O linked, —C(═O)— linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, the C 1-6 alk, the C 1-6 alk of the C 1-6 alk-link, and the monocyclic or bicyclic ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, C 1-6 alk, C 1-6 alkOH, C 1-6 alk-C(═O)R a , C 1-6 alk-C(═O)OR a , C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , ═S, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R a , —S(═O) 2 N(R a )C(═O)OR a , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a  and —NR a C 2-6 alkOR a , wherein the ring is additionally substituted by 0 or 1 directly bonded, SO 2  linked, C(═O) linked or CH 2  linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, and substituted by 0, 1, 2 or 3 groups selected from halo, C 1-6 alk, C 1-4 haloalk, cyano, oxo, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R a , —NR a R a , and —N(R a )C(═O)R a ; or R 1a  and R 1 , together with the N atom to which they are attached, form a saturated, partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclic or a 9- or 10-membered bicylic ring containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, wherein the ring formed by R 1a  and R 1  is substituted with 0, 1, or 2 substituents independently selected from halo, oxo, C 1-6 alk, C 1-6 alkOH, C 1-6 alk-C(═O)R a , C 1-6 alk-C(═O)OR a , C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , or —C(═O)NR a R a ; 
 R 2  is H, halo, cyano, R c , —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a  and —NR a C 2-6 alkOR a ; or R 2  is C 1-6 alk substituted by 0, 1, 2 or 3 substituents selected from C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a  and —NR a C 2-6 alkOR a , or R 2  is C 1-6 alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from R c ; 
 R 3  is H, C 1-8 alk, C 1-8 alkOH, C 1-4 haloalk, halo, cyano, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a  or —NR a C 2-6 alkOR a ; 
 R 4  is independently, at each instance, H, C 1-6 alk, —C 1-3 haloalk, —OC 1-6 alk, —OC 1-3 haloalk, —N(C 1-6 alk)C 1-6 alk, —NHC 1-6 alk, —NC(═O)C 1-6 alk, —N(C 1-6 alk)C 1-6 alk, F, Cl, Br, CN, OH or NH 2 ; or R 3  and R 4  together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5  substituents; 
 R 5  is independently, in each instance, Cl, Br, F, CH 3 , CF 3 , or OR a ; 
 R 6  is F, CF 3 , C 1-6 alk, or OR a ; 
 R a  is independently, at each instance, H or R b ; 
 R b  is independently, at each instance, phenyl, benzyl or C 1-6 alk, the phenyl, benzyl and C 1-6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C 1-4 alk, C 1-3 haloalk, —OC 1-4 alk, —OH, —NH 2 , —OC 1-4 alk, —OC 1-4 haloalk, —NHC 1-4 alk, and —N(C 1-4 alk)C 1-4 alk; and 
 R c  is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the C 1-6 alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from C 1-8 alk, C 1-4 haloalk, halo and cyano.