Bicyclic ror-gamma modulators

Abstract

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

What is claimed is: 
     
         1 . A compound of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
    is phenyl, or a 5-membered or 6-membered heteroaryl ring; 
    is phenyl, or a 5-membered or 6-membered heteroaryl ring; 
 Q is —(CH 2 ) n —, —CH 2 YCH 2 —, or —(CH 2 ) m Y—, wherein —(CH 2 ) n —, —CH 2 YCH 2 —, or —(CH 2 ) m Y— is attached to the ring carbon atoms at a and b, c and d, a and c, or b and d; 
 X is —N(R 3a )—, —C(R 3b )(R 3c )—, or —O—; 
 Y is —O—, —S—, or —N(R 3d )—; 
 Z is —(C(R 1 )(R 2 )) t —; 
 each R 1  and each R 2  are each independently hydrogen, halo, or C 1 -C 6 alkyl; 
 each R 3  is independently selected from halo and C 1 -C 6 alkyl; 
 R 3a  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, C 2 -C 9  heteroaryl, (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene-, —S(O) 2 R 10 , —C(O)R 10 , —C(O)OR 11 , or —C(O)N(R 11 ) 2 , wherein C 2 -C 9  heteroaryl and (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene- are optionally substituted with 1 to 3 groups independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl; 
 R 3b  is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, —N(R 11 )S(O) 2 R 10 , —S(O) 2 R 10 , —C(O)R 10 , —C(O)OR 11 , or —C(O)N(R 11 ) 2 ; 
 R 3c  is hydrogen, halo, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl; 
 R 3d  is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, —S(O) 2 R 8 , —C(O)R 8 , —C(O)OR 9 , and —C(O)N(R 9 ) 2 ; 
 each R 4  and each R 5  are each independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, C 1 -C 6 alkoxy, —N(R 7 ) 2 , —C(O)R 6 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 6 , —N(R 7 )SO 2 R 6 , —SO 2 R 6 , and —SO 2 N(R 7 ) 2 ; 
 each R 6  is independently C 1 -C 6 alkyl or C 1 -C 6  haloalkyl; 
 each R 7  is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl; 
 R 8  is C 1 -C 6 alkyl or C 1 -C 6  haloalkyl; 
 each R 9  is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl; 
 R th  is C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, C 3 -C 8 cycloalkyl, C 2 -C 9  heterocyclyl, phenyl, (phenyl)-C 1 -C 6 alkylene-, C 2 -C 9  heteroaryl, or (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene-, wherein the C 3 -C 8 cycloalkyl, C 2 -C 9  heterocyclyl, phenyl, (phenyl)-C 1 -C 6 alkylene-, C 2 -C 9  heteroaryl, or (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene- is optionally substituted with 1 to 3 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl; 
 each R H  is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl; 
 k is 0, 1, 2, 3, or 4; 
 m is 1 or 2; 
 n is 1, 2, 3, or 4; 
 p is 0, 1, 2, 3, or 4; 
 q is 0, 1, 2, 3, or 4; and 
 t is 0, 1, 2, or 3. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is phenyl or a 6-membered heteroaryl ring. 
     
     
         3 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is phenyl. 
     
     
         4 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is a 6-membered heteroaryl ring. 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is pyridyl. 
     
     
         6 . The compound of any one of  claims 1 - 5 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is phenyl or a 6-membered heteroaryl ring. 
     
     
         7 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is phenyl. 
     
     
         8 . The compound of any one of  claims 1 - 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is a 6-membered heteroaryl ring. 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein   is pyridyl. 
     
     
         10 . The compound of  claim 1  having the Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         11 . The compound of any one of  claims 1 - 10 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is —NR 3a — or —C(R 3b )(R 3c )—. 
     
     
         12 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is attached to the ring carbon atoms at a and b. 
     
     
         13 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is attached to the ring carbon atoms at c and d. 
     
     
         14 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is attached to the ring carbon atoms at a and c. 
     
     
         15 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is attached to the ring carbon atoms at b and d. 
     
     
         16 . The compound of  claim 10  having the Formula (IIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
       
     
     
         17 . The compound of  claim 10  having the Formula (IIb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
       
     
     
         18 . The compound of  claim 10  having the Formula (IIc): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
       
     
     
         19 . The compound of any one of  claims 1 - 18 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1  and each R 2  are hydrogen. 
     
     
         20 . The compound of any one of  claims 1 - 19 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1, 2, or 3. 
     
     
         21 . The compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1. 
     
     
         22 . The compound of any one of  claims 1 - 21 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is C 1 -C 6 alkyl, C 2 -C 9  heteroaryl, (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene-, —S(O) 2 R 10 , —C(O)OR 10 , —C(O)OR 11 , or —C(O)—C 1 -C 6 alkylene-OR 11 , wherein C 2 -C 9  heteroaryl and (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene- are optionally substituted with 1 or 2 groups each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         23 . The compound of any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is C 1 -C 6 alkyl, (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene-, —S(O) 2 R 10  , or —C(O)R 10 , wherein (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene- is optionally substituted with 1 or 2 groups each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         24 . The compound of any one of  claims 1 - 23 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is (C 2 -C 9 heteroaryl)-C 1 -C 6 alkylene- or —S(O) 2 R 10 , wherein (C 2 -C 9 heteroaryl)-C 1 -C 6 alkylene- is optionally substituted with 1 or 2 groups each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         25 . The compound of any one of  claims 1 - 24 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is —S(O) 2 R 10 . 
     
     
         26 . The compound of any one of  claims 1 - 25 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R l ° is C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, C 3 -C 8 cycloalkyl, C 2 -C 9  heterocyclyl, or (phenyl)-C 1 -C 6 alkylene-, wherein C 3 -C 8 cycloalkyl, C 2 -C 9  heterocyclyl, or (phenyl)-C 1 -C 6 alkylene- is optionally substituted with 1 or 2 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         27 . The compound of any one of  claims 1 - 26 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 10  is C 1 -C 6 alkyl. 
     
     
         28 . The compound of any one of  claims 1 - 27 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is —S(O) 2 CH 3 . 
     
     
         29 . The compound of any one of  claims 1 - 24 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is (C 2 -C 9  heteroaryl)-C 1 -C 6 alkylene- optionally substituted with 1 or 2 groups each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         30 . The compound of  claim 29 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3a  is (C 2 -C 9  heteroaryl)-CH 2  - optionally substituted with 1 or 2 groups each independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6  haloalkyl, and hydroxyl. 
     
     
         31 . The compound of any one of  claims 1 - 30 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is —CH 2 OCH 2 — or —(CH 2 ) n —. 
     
     
         32 . The compound of any one of  claims 1 - 31 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is —(CH 2 ) n —. 
     
     
         33 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. 
     
     
         34 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. 
     
     
         35 . The compound of any one of  claims 1 - 31 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Q is —CH 2 OCH 2 —. 
     
     
         36 . The compound of any one of  claims 1 - 35 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, 2, or 3. 
     
     
         37 . The compound of any one of  claims 1 - 36 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 4  is independently halo, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl. 
     
     
         38 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1. 
     
     
         39 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 2. 
     
     
         40 . The compound of any one of  claims 1 - 37 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 3. 
     
     
         41 . The compound of any one of  claims 1 - 36 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0. 
     
     
         42 . The compound of any one of  claims 1 - 41 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, or 2. 
     
     
         43 . The compound of any one of  claims 1 - 42 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 5  is independently halo, C 1 -C 6 alkyl, or C 1 -C 6  haloalkyl. 
     
     
         44 . The compound of any one of  claims 1 - 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1. 
     
     
         45 . The compound of any one of  claims 1 - 42 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0. 
     
     
         46 . The compound of any one of  claims 1 - 45 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein k is 0. 
     
     
         47 . The compound of  claim 1  selected from:
 2-(2′-ethyl-4′-(((1R,5S)-7-(methylsulfonyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-4′-(((1R,5S)-9-(methylsulfonyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-3′,5′-difluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-2,3′,5′-trifluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-3′,5′-difluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(3-chloro-4-(4-ethyl-6-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyridin-3-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-4′-((3-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-5′-fluoro-2′-isopropyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-6′-fluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-2,6′-difluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-6′-fluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-5′-fluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-4′-((3-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(5′-fluoro-2′-isopropyl-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(2-chloro-2′-isopropyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-isopropyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-2,3′,6′-trifluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-3′,6′-difluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-2-fluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2,2′-diethyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-ethyl-2′-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2-chloro-2′-ethyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-3′,5′-difluoro-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(6′-ethyl-2′,3′-difluoro-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-3′,6′-difluoro-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(4-(2-ethyl-6-((8-(methylsulfony)-3,8-diazabicyclo[3.2.1] octan-3-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(4-(4-ethyl-6-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2. 1] octan-3-yl)methyl)pyridin-3-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 
 2′-ethyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1] octan-3-yl)methyl)-[1,1′-biphenyl]-2-carboxamide; 
 2-(6-(2-ethyl-4-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1] octan-3-yl)methyl)phenyl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(4-(3-ethyl-5-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1] octan-3-yl)methyl)pyridin-2-yl)-3-methylphenyl)-1, 1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(3′-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1] octan-3-yl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(2′-ethyl-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1] octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)- 1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-isopropyl-2-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(4′-((8-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-4′-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-4′-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1 -(3-((2-ethyl-4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1 -one; 
 2-(2′-bromo-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-bromo-4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(4′-((8-ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 (3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(tetrahydro-2H-pyran-4-yl)methanone; 
 ethyl 3 -((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 
 1-(3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methoxypropan-1-one; 
 N-(3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3-azabicyclo[3.2.1]octan-8-yl)methanesulfonamide; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-(pyrimidin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(2′-chloro-4′-((8-((2-methylpyridin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-(pyridazin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(2′-ethyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-ethyl-4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1-(3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methoxyethan-1-one; 
 2-(2′-chloro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(2′-chloro-4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-fluoro-4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-((trifluoromethypsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-fluoro-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-((4-fluoropheny)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-((3-fluoropyridin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(4′-((8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 2-(4′-((8-(benzylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-((2-methylpyridin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-((2,2,2-trifluoroethyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-(propylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(4′-((8-(ethylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol; 
 4-((3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridin-2-ol; 
 1-(3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((5-(pyridin-4-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 2-(2,6-difluorophenyl)-1-(3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one; 
 (3-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(pyridin-4-yl)methanone; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((5-(pyridin-4-ylmethyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-(4-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2′-methyl-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(2′-methyl-4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; 
 1,1,1,3,3,3-hexafluoro-2-(4′-((3-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; and 
 1,1,1,3,3,3-hexafluoro-2-(4′-((8-(pyridin-4-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         48 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 47 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         49 . 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 - 47 , or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is selected from psoriasis, psoriatic arthritis, uveitis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, vitiligo, vesiculobullous dermatosis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lupus, lupus nephritis, multiple sclerosis, axial spodyloarthritides, hidraenitis suppurativa, Sjögren's syndrome, regional enteritis, Tolosa-Hunt syndrome, undifferentiated connective tissue disease, obesity, obesity-induced insulin resistance, atherosclerosis, and type II diabetes.