US2021069182A1PendingUtilityA1

Ror-gamma modulators

69
Assignee: ESCALIER BIOSCIENCES B VPriority: Oct 27, 2016Filed: Nov 23, 2020Published: Mar 11, 2021
Est. expiryOct 27, 2036(~10.3 yrs left)· nominal 20-yr term from priority
A61P 17/10A61P 17/06A61P 17/02A61P 17/00A61K 31/496C07D 401/06A61K 31/495A61Q 19/08A61P 17/08A61K 9/0014
69
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Claims

Abstract

Described herein are retinoic acid related-related orphan nuclear receptor (ROR) modulators and methods of utilizing RORγ modulators in the treatment of dermal diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is phenyl, or a 5-membered or 6-membered heteroaryl ring; 
       
         
           
           
               
               
           
         
       
       is phenyl, or a 5-membered or 6-membered heteroaryl ring; 
       
         
           
           
               
               
           
         
       
       is phenyl, or a 5-membered or 6-membered heteroaryl ring;
 X is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; 
 R 1  is —C(═O)OR 6  or —C(═O)N(R 6 ) 2 ; 
 each R 2  is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; 
 each R 3 , each R 4 , and each R 5  are each independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 SO 2 R 8 , —SO 2 R 8 , or —SO 2 N(R 7 ) 2 ; 
 each R 6  is independently hydrogen, C 1 -C 6 alkyl, or —C 1 -C 6 alkyl-Y—R 9 ; 
 each Y is independently —O—, —S—, or —N(R 10 )—; 
 each R 7  is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; 
 each R 8  is independently C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl; 
 each R 9  is independently hydrogen or C 1 -C 6 alkyl; 
 each R 10  is independently hydrogen or C 1 -C 6 alkyl; 
 m is 0, 1, 2, 3, or 4; 
 n is 0, 1, 2, 3, or 4; 
 p is 0, 1, 2, 3, or 4; and 
 q is 0, 1, 2, or 3; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         2 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl or a 6-membered heteroaryl ring. 
     
     
         3 . The compound of  claim 2  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl. 
     
     
         4 . The compound of  claim 2  wherein 
       
         
           
           
               
               
           
         
       
       is a 6-membered heteroaryl ring. 
     
     
         5 . The compound of  claim 4  wherein 
       
         
           
           
               
               
           
         
       
       is pyridyl. 
     
     
         6 . The compound of any one of  claims 1 - 5  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl or a 6-membered heteroaryl ring. 
     
     
         7 . The compound of any one of  claims 1 - 5  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl. 
     
     
         8 . The compound of any one of  claims 1 - 5  wherein 
       
         
           
           
               
               
           
         
       
       is a 6-membered heteroaryl ring. 
     
     
         9 . The compound of any one of  claims 1 - 5  wherein 
       
         
           
           
               
               
           
         
       
       is pyridyl. 
     
     
         10 . The compound of any one of  claims 1 - 9  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl or a 6-membered heteroaryl ring. 
     
     
         11 . The compound of any one of  claims 1 - 9  wherein 
       
         
           
           
               
               
           
         
       
       is phenyl. 
     
     
         12 . The compound of any one of  claims 1 - 9  wherein 
       
         
           
           
               
               
           
         
       
       is a 6-membered heteroaryl ring. 
     
     
         13 . The compound of any one of  claims 1 - 9  wherein 
       
         
           
           
               
               
           
         
       
       is pyridyl. 
     
     
         14 . The compound of  claim 1  having the structure of Formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of any one of  claims 1 - 14  wherein R 1  is —C(═O)OR 6 . 
     
     
         16 . The compound of  claim 15  wherein R 6  is C 1 -C 6 alkyl. 
     
     
         17 . The compound of  claim 16  wherein R 1  is —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , or —C(═O)OCH(CH 3 ) 2 . 
     
     
         18 . The compound of  claim 16  wherein R 1  is —C(═O)OCH 3  or —C(═O)OCH 2 CH 3 . 
     
     
         19 . The compound of  claim 15  wherein R 6  is —C 1 -C 6 alkyl-Y—R 9 . 
     
     
         20 . The compound of  claim 19  wherein Y is —O—. 
     
     
         21 . The compound of  claim 20  wherein R 9  is hydrogen. 
     
     
         22 . The compound of  claim 21  wherein R 1  is —C(═O)OCH 2 CH 2 OH. 
     
     
         23 . The compound of  claim 20  wherein R 9  is C 1 -C 6 alkyl. 
     
     
         24 . The compound of  claim 23  wherein R 1  is —C(═O)OCH 2 CH 2 OCH 2 CH 3 . 
     
     
         25 . The compound of  claim 19  wherein Y is —N(R 10 )—. 
     
     
         26 . The compound of  claim 25  wherein R 9  is hydrogen. 
     
     
         27 . The compound of  claim 26  wherein R 1  is —C(═O)OCH 2 CH 2 NH 2 . 
     
     
         28 . The compound of any one of  claims 1 - 14  wherein R 1  is —C(═O)N(R 6 ) 2 . 
     
     
         29 . The compound of  claim 28  wherein R 6  is C 1 -C 6 alkyl. 
     
     
         30 . The compound of any one of  claims 1 - 29  wherein X is a bond. 
     
     
         31 . The compound of any one of  claims 1 - 29  wherein X is a C 1 -C 6 alkyl. 
     
     
         32 . The compound of  claim 31  wherein X is a —CH 2 —. 
     
     
         33 . The compound of any one of  claims 1 - 32  wherein each R 3 , each R 4 , and each R 5  are each independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. 
     
     
         34 . The compound of any one of  claims 1 - 33  wherein m is 0 or 1, and n is 0 or 1. 
     
     
         35 . The compound of any one of  claims 1 - 33  wherein m is 0, and n is 0. 
     
     
         36 . The compound of any one of  claims 1 - 33  wherein m is 0, n is 0, and q is 0. 
     
     
         37 . The compound of any one of  claims 1 - 35  wherein p is 0 or 1, and q is 0. 
     
     
         38 . The compound of any one of  claims 1 - 35  wherein p is 1, R 4  is C 1 -C 6 alkyl, and q is 0. 
     
     
         39 . The compound of any one of  claims 1 - 33  wherein m is 0 or 1, n is 0 or 1, p is 0 or 1, and q is 0 or 1. 
     
     
         40 . The compound of any one of  claims 1 - 32  wherein m is 0, n is 0, p is 0, and q is 0. 
     
     
         41 . A compound having the structure of Formula (Ib): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is a bond, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; 
 R 1  is —C(═O)OR 6  or —C(═O)N(R 6 ) 2 ; 
 each R 2  is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; 
 each R 3  is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 SO 2 R 8 , —SO 2 R 8 , or —SO 2 N(R 7 ) 2 ; 
 R 4  is hydrogen or C 1 -C 6 alkyl; 
 each R 5  is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 SO 2 R 8 , —SO 2 R 8 , or —SO 2 N(R 7 ) 2 ; 
 each R 6  is independently hydrogen, C 1 -C 6 alkyl, or —C 1 -C 6 alkyl-Y—R 9 ; 
 each Y is independently —O—, —S—, or —N(R 10 )—; 
 each R 7  is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl; 
 each R 8  is independently C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl; 
 each R 9  is independently hydrogen or C 1 -C 6 alkyl; 
 each R 10  is independently hydrogen or C 1 -C 6 alkyl; 
 m is 0, 1, 2, 3, or 4; 
 n is 0, 1, 2, 3, or 4; and 
 q is 0, 1, 2, or 3; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         42 . The compound of  claim 41  wherein R 1  is —C(═O)OR 6 . 
     
     
         43 . The compound of  claim 42  wherein R 6  is C 1 -C 6 alkyl. 
     
     
         44 . The compound of  claim 43  wherein R 1  is —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , or —C(═O)OCH(CH 3 ) 2 . 
     
     
         45 . The compound of  claim 43  wherein R 1  is —C(═O)OCH 3  or —C(═O)OCH 2 CH 3 . 
     
     
         46 . The compound of  claim 42  wherein R 6  is —C 1 -C 6 alkyl-Y—R 9 . 
     
     
         47 . The compound of  claim 46  wherein Y is —O—. 
     
     
         48 . The compound of  claim 47  wherein R 9  is hydrogen. 
     
     
         49 . The compound of  claim 48  wherein R 1  is —C(═O)OCH 2 CH 2 OH. 
     
     
         50 . The compound of  claim 47  wherein R 9  is C 1 -C 6 alkyl. 
     
     
         51 . The compound of  claim 50  wherein R 1  is —C(═O)OCH 2 CH 2 OCH 2 CH 3 . 
     
     
         52 . The compound of  claim 46  wherein Y is —N(R 10 )—. 
     
     
         53 . The compound of  claim 52  wherein R 9  is hydrogen. 
     
     
         54 . The compound of  claim 53  wherein R 1  is —C(═O)OCH 2 CH 2 NH 2 . 
     
     
         55 . The compound of  claim 41  wherein R 1  is —C(═O)N(R 6 ) 2 . 
     
     
         56 . The compound of  claim 55  wherein R 6  is C 1 -C 6 alkyl. 
     
     
         57 . The compound of any one of  claims 41 - 56  wherein X is a bond. 
     
     
         58 . The compound of any one of  claims 41 - 56  wherein X is a C 1 -C 6 alkyl. 
     
     
         59 . The compound of  claim 58  wherein X is a —CH 2 —. 
     
     
         60 . The compound of any one of  claims 41 - 59  wherein each R 3  and each R 5  are each independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. 
     
     
         61 . The compound of any one of  claims 41 - 60  wherein m is 0 or 1, n is 0 or 1, and q is 0 or 1. 
     
     
         62 . The compound of any one of  claims 41 - 60  wherein m is 0, n is 0, and q is 0. 
     
     
         63 . The compound of any one of  claims 41 - 62  wherein R 4  is hydrogen. 
     
     
         64 . The compound of any one of  claims 41 - 62  wherein R 4  is C 1 -C 6 alkyl. 
     
     
         65 . The compound of any one of  claims 41 - 62  wherein R 4  is —CH 3 . 
     
     
         66 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         67 . A compound selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         68 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any one of  claims 1 - 67 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         69 . A method of treating a disease, disorder or condition in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of  claims 1 - 67 , or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder or condition is a dermal disease, disorder or condition is selected from the group consisting of skin aging, scarring, psoriasis, dermatitis, eczema, urticaria, rosacea, burns, and acne.

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