Compounds useful for treating disorders related to trpa1

Abstract

Compounds and compositions for treating disorders related to TRPA1 are described herein.

1 - 13 . (canceled) 
     
     
         14 . A method of pain in a subject in need thereof, the method comprising administering to a subject an effective amount of a compound of Formula I, or a salt thereof: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each of A, B, C, and D is independently CR 1  or N, provided that no more than 2 of A, B, C, and D are N; 
 each of X and Y is independently NR, O or S; 
 each R 1  is independently H, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted heterocyclyl, hydroxyl, optionally substituted C 1-6  alkoxy, optionally substituted C 1-6  alkenyloxy, cyano, halo, acyl, amino, optionally substituted alkylamino, aminoalkyl, amido, acylamino, alkylurea, alkylcarbamoyl, carboxyl, optionally substituted alkylcarboxyl, thioyl, optionally substituted alkylthio, SO 3 H, alkylsulfinyl, optionally substituted alkylsulfonyl, or nitro; 
 R is H, optionally substituted C 1-6  alkyl, OH, OR′, CN, NO 2 , or SO 2 R′; 
 R′ is H or C 1-6  alkyl; 
 R 2  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 
 each of R 3  and R 4  is independently H, optionally substituted C 1-6  alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, COR 10 , CO 2 R 10 , CH 2 CO 2 R 10 , or CONHR 10 , and 
 R 10  is H or optionally substituted C 1-6  alkyl. 
 
     
     
         15 . The method of  claim 14 , wherein the pain is selected from diabetic neuropathy, breast pain, psoriasis, eczema, dermatitis, burn, post-herpetic neuralgia (shingles), nociceptive pain, peripheral neuropathic and central neuropathic pain, chronic pain, cancer pain, trauma induced pain, migraine pain, cerebrovascular and vascular pain, rheumatoid arthritis pain, musculoskeletal pain, orofacial and facial pain, lower back or pelvic pain, surgical incision related pain, inflammatory pain, non-inflammatory pain, visceral pain, psychogenic pain and soft tissue inflammatory pain, fibromyalgia-related pain, reflex sympathetic dystrophy, and pain resulting from kidney stones or urinary tract infection. 
     
     
         16 . The method of  claim 14 , wherein each of X and Y is independently O. 
     
     
         17 . The method of  claim 14 , wherein X is O and Y is S. 
     
     
         18 . The method of  claim 14 , wherein each R 1  is H. 
     
     
         19 . The method of  claim 14 , wherein each of R 3  and R 4  is-independently H. 
     
     
         20 . The method of  claim 14 , wherein R 2  is optionally substituted aryl. 
     
     
         21 . The method of  claim 20 , wherein aryl is substituted with hydroxyl, C 1-6  alkenyloxy, cyano, acyl, amino, optionally substituted alkylamino, amido, acylamino, carboxyl, or optionally substituted alkylcarboxyl. 
     
     
         22 . A method of treating a respiratory disorder, the method comprising administering to a subject an effective amount of a compound of Formula I, or a salt thereof: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each of A, B, C, and D is independently CR 1  or N, provided that no more than 2 of A, B, C, and D are N; 
 each of X and Y is independently NR, O or S; 
 each R l  is independently H, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted heterocyclyl, hydroxyl, optionally substituted C 1-6  alkoxy, optionally substituted C 1-6  alkenyloxy, cyano, halo, acyl, amino, optionally substituted alkylamino, aminoalkyl, amido, acylamino, alkylurea, alkylcarbamoyl, carboxyl, optionally substituted alkylcarboxyl, thioyl, optionally substituted alkylthio, SO 3 H, alkylsulfinyl, optionally substituted alkylsulfonyl, or nitro; 
 R is H, optionally substituted C 1-6  alkyl, OH, OR′, CN, NO 2 , or SO 2 R′; 
 R′ is H or C 1-6  alkyl; 
 R 2  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 
 each of R 3  and R 4  is independently H, optionally substituted C 1-6  alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, COR 10 , CO 2 R 10 , CH 2 CO 2 R 10 , or CONHR 10 , and 
 R 10  is H or optionally substituted C 1-6  alkyl. 
 
     
     
         23 . The method of  claim 22 , wherein the respiratory condition is selected from chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, asthma, cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, tuberculosis, restrictive lung disease, asbestosis, radiation fibrosis, hypersensitivity pneumonitis, infant respiratory distress syndrome, idiopathic pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstial pneumonia sarcoidosis, eosinophilic pneumonia, lymphangioleiomyomatosis, pulmonary Langerhan's cell histiocytosis, pulmonary alveolar proteinosis, common cold, sinusitis, tonsillitis, pharyngitis laryngitis, pneumonia, small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell undifferentiated carcinoma, carcinoid, mesothelioma, metastatic cancer of the lung, metastatic germ cell cancer, metastatic renal cell carcinoma, pulmonary hamartoma, pulmonary sequestration, congenital cystic adenomatoid malformation (CCAM), emphysema, mesothelioma, thromboembolism, air embolism (iatrogenic), pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation, and damage to capillaries in the lung resulting in blood leaking into the alveoli. 
     
     
         24 . The method of  claim 22 , wherein each of X and Y is independently O. 
     
     
         25 . The method of  claim 22 , wherein X is O and Y is S. 
     
     
         26 . The method of  claim 22 , wherein each R 1  is H. 
     
     
         27 . The method of  claim 22 , wherein each of R 3  and R 4  is-independently H. 
     
     
         28 . The method of  claim 22 , wherein R 2  is optionally substituted aryl. 
     
     
         29 . The method of  claim 28 , wherein aryl is substituted with hydroxyl, C 1-6  alkenyloxy, cyano, acyl, amino, optionally substituted alkylamino, amido, acylamino, carboxyl, or optionally substituted alkylcarboxyl. 
     
     
         30 . A method for treating a dermatological disorder or condition in a subject, the method comprising administering an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each of A, B, C, and D is independently CR 1  or N, provided that no more than 2 of A, B, C, and D are N; 
 each of X and Y is independently NR, O or S; 
 each R 1  is independently H, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted heterocyclyl, hydroxyl, optionally substituted C 1-6  alkoxy, optionally substituted C 1-6  alkenyloxy, cyano, halo, acyl, amino, optionally substituted alkylamino, aminoalkyl, amido, acylamino, alkylurea, alkylcarbamoyl, carboxyl, optionally substituted alkylcarboxyl, thioyl, optionally substituted alkylthio, SO 3 H, alkylsulfinyl, optionally substituted alkylsulfonyl, or nitro; 
 R is H, optionally substituted C 1-6  alkyl, OH, OR′, CN, NO 2 , or SO 2 R′; 
 R′ is H or C 1-6  alkyl; 
 R 2  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 
 each of R 3  and R 4  is independently H, optionally substituted C 1-6  alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, COR 10 , CO 2 R 10 , CH 2 CO 2 R 10 , or CONHR 10 , and 
 R 10  is H or optionally substituted C 1-6  alkyl. 
 
     
     
         31 . The method of  claim 30 , wherein the dermatological disorder or condition is selected from psoriasis, basal cell carcinomas (BCC), squamous cell carcinomas (SCC), pruritus, dermatitis, allergy, dry skin, and eczema. 
     
     
         32 . The method of  claim 30 , wherein each of X and Y is independently O. 
     
     
         33 . The method of  claim 30 , wherein X is O and Y is S. 
     
     
         34 . The method of  claim 30 , wherein each R 1  is H. 
     
     
         35 . The method of  claim 30 , wherein each of R 3  and R 4  is-independently H. 
     
     
         36 . The method of  claim 30 , wherein R 2  is optionally substituted aryl. 
     
     
         37 . The method of  claim 36 , wherein aryl is substituted with hydroxyl, C 1-6  alkenyloxy, cyano, acyl, amino, optionally substituted alkylamino, amido, acylamino, carboxyl, or optionally substituted alkylcarboxyl.