6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same

Abstract

The present embodiments are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for modulating the activity of delta opioid receptor, biased and/or unbiased, and/or methods for treating pain, migraines, headaches, depression, Parkinsons Disease, anxiety, and/or overactive bladder, and other disorders and conditions described herein or any combination thereof.

1 - 175 . (canceled) 
     
     
         176 . A compound having Formula I, I-1, I-a, Ia-1 or I-b, Ib-1, or Ib-2 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         BB is 
       
       
         
           
           
               
               
           
         
         Z is C, S, N, S(O) 2  or O; 
         R 35  is a protecting group, C(═O)OR 81b , H, or optionally substituted aryl, C 1 -C 6  haloalkyl, —R 63 R 64 , —NR 63 R 64 , C 1 -C 6  branched or unbranched alkyl, C 2 -C 6  alkenyl, C 2 -C 6  haloalkenyl —(CH 2 ) n R 65 , heterocycle, C 1 -C 6  ester, cycloalkyl, C 1 -C 6  alkoxy, pyrrolinyl, morpholinyl, C 3 -C 6  cyclic ether, or piperidyl; 
         R 36  is H, halo, or optionally substituted C 1 -C 6  haloalkyl, —SO 2 C 1 -C 6 alkyl, —OCF 3 , C 1 -C 6  alkyl, or —OR 75 ; wherein R 75  is H or optionally substituted C 1 -C 6  alkyl; 
         R 37  is H, halo, —SO 2 C 1 -C 6 alkyl, —OCF 3 , optionally substituted C 1 -C 6  haloalkyl sulfonamide, or cyclic sulfonamide, or —(CH 2 ) q —R 38 , —NH—(CH 2 ) q —R 38 , —S—(CH 2 ) q —R 38 , —C(═O)R 38 , —O—(CH 2 ) q —R 38 , 
       
       
         
           
           
               
               
           
         
         R 38  is H, C 1 -C 6  alkyl, halo, C 1 -C 6  haloalkyl, —C(═O)C 1 -C 6  alkyl, —OR 66 , S(O) 2 R 67 , 
       
       
         
           
           
               
               
           
         
       
       or optionally substituted cycloalkyl, —(CH 2 ) p R 65 , or heterocycle;
 or R 37  is —(CH 2 ) q —R 38  or R 36  and R 37  form a heterocycle that is fused to the phenyl ring; 
 R 41  is absent, H, or C 1 -C 6  alkyl provided that when Z is S, O or S(O) 2 , R 41  is absent; or when Z is C, the bond connecting Z to the adjacent carbon is a double bond and R 41  is H, 
 R 34  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 R 39  is H or C 1 -C 6  alkyl; 
 R 40  is H, C 1 -C 6  alkyl, halo, or alkoxy; 
 R 42  is absent, H, C 1 -C 6  alkyl, a member of a carbocycle that includes the atom to which it is attached, ═O; 
 X a  is C or O, provided that when X a  is O, R 42  is absent; 
 X b  is S or O; 
 X c  is C or N; 
 R 47  is H or C 1 -C 6  alkyl; 
 each R 49  is, independently, H or C 1 -C 6  alkyl; 
 R 50  is H or C 1 -C 6  alkyl; 
 R 51  is H or C 1 -C 6  alkyl; 
 R 52  is H or C 1 -C 6  alkyl; 
 R 53  is H or C 1 -C 6  alkyl; 
 R 55  is H or C 1 -C 6  alkyl; 
 R 56  is H or C 1 -C 6  alkyl; 
 R 57  is H or C 1 -C 6  alkyl; 
 R 58  is absent or H; 
 R 59  is H or OH; 
 R 60  is H or N(R 54 ) 2 ; 
 each R 54  is, independently, H or C 1 -C 6  alkyl; 
 R 61  is H, C 1 -C 6  alkyl, optionally substituted C 1 -C 6  haloalkyl, gem-dimethyl, cyclopropyl spirocycle, or CF 3 ; 
 R 62  is absent, H, or C 1 -C 6  alkyl; 
 each R 63  and R 64  are, independently, H, or optionally substituted aryl, C 1 -C 6  haloalkyl, C 1 -C 6  branched or unbranched alkyl, C 2 -C 6  alkenyl, —(CH 2 ) v R 65 , cycloalkyl, —OH, alkoxy, pyrrolinyl, morpholinyl, or piperidyl; or R 63  and R 64  together form a 5-10 membered optionally substituted heterocycle or a 5-10 membered optionally substituted heteroaryl with the atom to which R 63  and R 64  are bonded to; 
 each R 65  is, independently, H, —C(═O)R 65A , —OH, or optionally substituted C 1 -C 6  haloalkyl, nitrogen, C 1 -C 6  branched or unbranched alkyl, aryl, heteroaryl, C 2 -C 6  alkenyl, cycloalkyl, heterocycle, alkoxy, pyrrolyl, pyrrolinyl, phenyl, pyrrolidinyl, imidazolidinyl, morpholinyl, or piperidyl; 
 R 65A  is phenyl or C 1 -C 6  branched or unbranched alkyl; 
 R 66  is H, —OH, or optionally substituted aryl, C 1 -C 6  haloalkyl, —R 63 R 64 , —NR 63 R 64 , C 1 -C 6  branched or unbranched alkyl, C 2 -C 6  alkenyl, —(CH 2 ) w R 65 , cycloalkyl, alkoxy, pyrrolinyl, morpholinyl, or piperidyl; 
 R 67  is optionally substituted C 1 -C 6  branched or unbranched alkyl or C 1 -C 6  haloalkyl; 
 R 81a  and R 82a  are each independently H or optionally substituted C 1 -C 6  alkyl; 
 R 81b  is H or optionally substituted branched or unbranched C 1 -C 6  alkyl; 
 z is 1 or 2, 
 each n, p, v, w, and q is, independently, an integer from 0-6; 
 wherein “optionally substituted” refers to an optional substituent selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 5 -C 6  aryl, C 1 -C 6  alkoxy, C 3 -C 5  heteroaryl, C 3 -C 6  cycloalkyl, C 5 -C 6  aryloxy, —CN, —OH, oxo, halo, haloalkyl, —NO 2 , —CO 2 H, —NH 2 , —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl) 2 , —NH(C 6  aryl), —N(C 1 -C 6  aryl) 2 , —CHO, —CO(C 1 -C 6  alkyl), —CO((C 5 -C 6  aryl), —CO 2 (C 1 -C 6  alkyl), and —CO 2 (C 5 -C 6  aryl). 
 
     
     
         177 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, having Formula II, III, IV, V, VI, VII, or VIIa: 
       
         
           
           
               
               
           
         
       
     
     
         178 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein R 62  is H. 
     
     
         179 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein each R 61  is methyl or gem-dimethyl. 
     
     
         180 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein Z is O or S(O) 2 . 
     
     
         181 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein either:
 (i) R 37  is alkoxy, halo, or optionally substituted sulfonamide or cyclic sulfonamide; or   (ii) R 36  and R 37  form a heterocycle that is fused to the phenyl ring; or   (iii) R 37  is absent.   
     
     
         182 . The compound of  claim 181 , wherein the fused ring structure is an optionally substituted benzofuran or benzopyran or wherein the fused ring has a formula of: 
       
         
           
           
               
               
           
         
       
     
     
         183 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, having Formula VIV, VV, VVI, VVII, or VIII: 
       
         
           
           
               
               
           
         
       
     
     
         184 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1-4. 
     
     
         185 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein either:
 (i) R 38  is absent or H; or   (ii) R 38  is C 1 -C 6  haloalkyl; or   (iii) R 38  is —C(═O)C 1 -C 6  alkyl; or   (iv) R 38  is —OR 66 , —S(O) 2 R 67 , or optionally substituted cycloalkyl, —(CH 2 ) p R 65 , or heterocycle, or   
       
         
           
           
               
               
           
         
       
     
     
         186 . The compound of  claim 176 , or a pharmaceutically acceptable salt thereof, wherein R 35  is optionally substituted C 1 -C 6  branched or unbranched alkyl, —CH 2 R 76  or —CH 2 CH 2 R 76 , wherein R 76  is optionally substituted aryl, ketone, cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  haloalkenyl, or heteroaryl; 
     
     
         187 . The compound of  claim 186 , wherein either:
 (i) R 76  is cyclopropyl; or   (ii) R 76  is difluorocyclopropyl; or   (iii) R 76  is 2,2-difluorocyclopropyl; or   (iv) R 76  is —CH═CF 2 .   
     
     
         188 . A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of claim  1 . 
     
     
         189 . A method of treating or preventing pain, neuropathic pain, including diabetic peripheral neuropathy and chemotherapy induced neuropathic pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, or PTSD in a subject comprising administering to the subject one or more compounds, or a pharmaceutically acceptable salt thereof, of claim  1 . 
     
     
         190 . A method of treating or preventing pain, neuropathic pain, including diabetic peripheral neuropathy and chemotherapy induced neuropathic pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreasing nociceptive sensitization, pain in an opioid exposed subject, or PTSD in a subject comprising administering to the subject a pharmaceutical composition according to  claim 188 . 
     
     
         191 . A method of treating or preventing a migraine in a subject comprising administering to the subject one or more compounds, or a pharmaceutically acceptable salt thereof, of  claim 176 . 
     
     
         192 . A method of treating or preventing a migraine in a subject comprising administering to the subject a pharmaceutical composition according to  claim 188 . 
     
     
         193 . The compound of  claim 176 , wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
     
     
         194 . The pharmaceutical composition of  claim 188 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.