1,2,4-oxadiazole derivatives as liver x receptor agonists

Abstract

Provided herein are compounds and pharmaceutical compositions useful for treating meibomian gland dysfunction (MGD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (I′), or pharmaceutical composition described herein.

1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph, or stereoisomer thereof, 
         wherein: 
         R 1  is 
       
       
         
           
           
               
               
           
         
         
           C 1 -C 6 alkyl, 
           phenyl, or 
           5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, 
           wherein the phenyl and heteroaryl are optionally substituted with one R 10 , and the C 1 -C 6 alkyl is substituted with one or two —CF 3 ; 
         
         R 2  is —CF 3  or C1; 
         R 3a  is
 H, or 
 C 1 -C 6 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH and —N(R 12 ) 2 ; 
 
         R 3b  is
 H, or 
 C 1 -C 6 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH and —N(R 12 ) 2 ; 
 
         or R 3a  and R 3b  together with the carbon atom they are attached to may combine to form a C 3 -C 8 cycloalkyl, wherein the cycloalkyl is optionally substituted with one R 5 ; 
         or R 3a  and R 3b  together with the carbon atom they are attached to may combine to form a 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, wherein the heterocycloalkyl is optionally substituted with one R 5 ; 
         R 4  is C 1 -C 6 alkyl substituted with one or two groups independently selected from:
 R 6 , 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, and 
 C 3 -C 8 cycloalkyl, 
 wherein the heterocycloalkyl is optionally substituted with one or two substituents independently selected from —OH and C 1 -C 3 alkyl; 
 
         each R 5  is independently selected from:
 C(═O)R 8 , 
 C 1 -C 3 alkyl, 
 C 3 -C 8 cycloalkyl, and 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, 
 wherein the C 1 -C 3 alkyl is optionally substituted with one R 9 , and the heterocycloalkyl is optionally substituted with one C 1 -C 3 alkyl or —C(═O)R 8 ; 
 
         each R 6  is independently selected from —OH and C 1 -C 3 alkyl; 
         R 7  is
 C 1 -C 6  alkyl, 
 —N(R 12 ) 2 , 
 C 3 -C 8 cycloalkyl, or 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, 
 wherein the C 1 -C 6 alkyl is optionally substituted with one or more R 11 , and the C3-C 8  cycloalkyl is optionally substituted with one or more —OH; 
 
         R 8  is
 C 1 -C 6  alkyl, 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, or 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, 
 wherein the heterocycloalkyl is optionally substituted with one C 1 -C 6 alkyl, and the C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —C(═O)OH, N(R 12 ) 2 , and C 3 -C 8 cycloalkyl; 
 
         R 9  is
 phenyl, 
 C 3 -C 8 cycloalkyl, 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S, or 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, 
 wherein the heteroaryl is optionally substituted with —OH, the heterocycloalkyl is optionally substituted with C 1 -C 6 alkyl, and the phenyl is optionally substituted with one or two —OH; 
 
         R 10  is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; 
         each R 11  is independently selected from
 halogen, 
 C 1 -C 6 haloalkyl, 
 C 1 -C 6 alkoxy, 
 —N(R 13 ) 2 , 
 —OH, and 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 , O or S; 
 
         each R 12  is independently selected from H and C 1 -C 6 alkyl, and 
         each R 13  is independently selected from
 H, and 
 C 1 -C 6 alkyl, 
 wherein the alkyl is optionally substituted with —OH or C 1 -C 6 alkoxy. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1  or  2 , wherein R 3a  and R 3b  are each independently selected from the group consisting of: H, CH 3 , —(CH 2 ) 2 CH 3 , —CH 2 OH, and 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1  or  2 , wherein R 3a  and R 3b  together combine to form a group selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein the compound is a compound of Formula (Ia) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, wherein:
 X is NR 5 , CH 2 , or O; 
 n is 0 or 1, and 
 m is 0 or 1. 
 
     
     
         6 . The compound according to  claim 5 , wherein X is NR 5 , CH 2 , or O. 
     
     
         7 . The compound according to any one of  claims 5 - 6 , wherein X is CH 2 . 
     
     
         8 . The compound according to any one of  claims 5 - 6 , wherein X is O. 
     
     
         9 . The compound according to any one of  claims 5 - 6 , wherein X is NR 5 . 
     
     
         10 . The compound according to  claim 9 , wherein R 5  is selected from the group consisting of: H, CH 3 , —CH 2 CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to any one of  claims 5 - 10 , wherein n is 0 or 1. 
     
     
         12 . The compound according to any one of  claims 5 - 11 , wherein n is 0. 
     
     
         13 . The compound according to any one of  claims 5 - 11 , wherein n is 1. 
     
     
         14 . The compound according to any one of  claims 5 - 13 , wherein m is 0 or 1. 
     
     
         15 . The compound according to any one of  claims 5 - 14 , wherein m is 1. 
     
     
         16 . The compound according to  claim 1 , wherein the compound is a compound of Formula (Ie) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof. 
     
     
         17 . The compound according to  claim 5  or  16 , wherein R 7  is selected from the group consisting of: —CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to any one of  claims 1 - 17 , wherein R 2  is CF 3 . 
     
     
         19 . The compound according to any one of  claims 1 - 18 , wherein R 4  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound is selected from the group consisting of:
 5,5-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methyl-1-(2-morpholinoethyl)-5-propylimidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)imidazolidine-2,4-dione;   2-(4-(5-((4,4-dimethyl-2,5-dioxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenoxy)—N-isopropyl-N-methylbenzenesulfonamide;   1-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethylimidazolidine-2,4-dione;   3-((3-(4-(2-(tert-butyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-cyclobutyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-methyl-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   2-(4-(5-((8-cyclobutyl-1-(2-morpholinoethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenoxy)—N-isopropyl-N-methylbenzenesulfonamide;   8-cyclobutyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-1-(2-morpholinoethyl)-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-1-(2-morpholinoethyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-3-((3-(4-(2-(methylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(tert-butyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-cyclobutyl-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(2-((2,2,2-trifluoroethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-3-((3-(4-(2-(methylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-cyclobutyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(4-hydroxybenzyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(3,5-dihydroxybenzyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-(1-methylpiperidin-4-yl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-(1-methylpyrrolidin-3-yl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-ethyl-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-8-(pyridazin-3-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(cyclopropylmethyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(2-cyclopropylacetyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-8-(pyrimidine-5-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   1-(2-morpholinoethyl)-8-(pyrimidine-5-carbonyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(pyrimidine-5-carbonyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-(3-(dimethylamino)propanoyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-(1-methylpiperidine-4-carbonyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-8-(pyrimidine-4-carbonyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   8-butyryl-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-(pyrazine-2-carbonyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-(pyrimidine-5-carbonyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-3-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   3-((3-(4-(2-((3-hydroxycyclobutyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-((2-(pyrrolidin-1-yl)propyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;   7-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(2-morpholinoethyl)-5,7-diazaspiro[3.4]octane-6,8-dione;   5-(hydroxymethyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   8-cyclobutyl-1-(2-morpholinoethyl)-3-((3-(4-(2-((2,2,2-trifluoroethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;   3-((3-(3-chloro-4-(2-(isobutylsulfonyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(3-(pyrrolidin-1-yl)propyl)imidazolidine-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(pyridin-2-ylmethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-((2-hydroxypropyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydro-2H-pyran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   1-(cyclopropylmethyl)-3-((3-(4-(2-((2-methoxyethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethylimidazolidine-2,4-dione;   5,5-dimethyl-3-((3-(4-(2-(methylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]decane-2,4-dione;   3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-((2-methoxyethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(2-((tetrahydrofuran-3-yl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   5-((dimethylamino)methyl)-3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-((2-(bis(2-methoxyethyl)amino)ethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   3-((3-(4-(2-((2-(bis(2-hydroxyethyl)amino)ethyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione;   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione;   (R or S) 5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione, and   (R or S) 5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(4-(2-(((tetrahydrofuran-2-yl)methyl)sulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione.   
     
     
         21 . The compound of  claim 20 , wherein the compound is 3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione. 
     
     
         22 . The compound of  claim 20 , wherein the compound is 8-cyclobutyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-((3-(4-(3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A pharmaceutical composition comprising a compound according to any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         24 . A method for the treatment of meibomian gland dysfunction comprising administration of a therapeutically effective amount of a compound according to any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, to a patient in need of treatment thereof. 
     
     
         25 . Use of a compound according to any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, in the manufacture of a medicament for the treatment of meibomian gland dysfunction. 
     
     
         26 . Use of a compound according to any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for the treatment of meibomian gland dysfunction. 
     
     
         27 . A compound according to any one of  claims 1 - 22 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for use in the treatment of meibomian gland dysfunction. 
     
     
         28 . A crystalline form of 3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethyl-1-(2-morpholinoethyl)imidazolidine-2,4-dione characterized by an X-ray powder diffraction pattern comprising one or more peaks at 2-Theta angles selected from 7.2 0.2, 7.8±0.2, 8.2 0.2, 10.7 0.2, 11.6 0.2, 12.5 0.2, 13.8+0.2, 14.5+0.2, 15.0±0.2, 15.8+0.2, 17.7+0.2, 18.9 0.2, 20.7 0.2, 21.3±0.2, 21.8 0.2, 22.1±0.2, and 23.1±0.2. 
     
     
         29 . A compound according to Formula (I′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph, or stereoisomer thereof, 
         wherein: 
         R 1 ′ is 
       
       
         
           
           
               
               
           
         
         
           C 1 -C 6 alkyl, 
           phenyl or 
           5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, 
           wherein the phenyl and heteroaryl are optionally substituted with one R 10 ′, and the C 1 -C 6 alkyl is optionally substituted with one or two —CF 3 ; 
         
         R 2 ′ is C 1 -C 6 haloalkyl or halo; 
         R 3a  is
 hydrogen or 
 C 1 -C 6 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH and —N(R 12 ′) 2 ; 
 
         R 3b  is
 hydrogen or 
 C 1 -C 6 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH and —N(R 12 ′) 2 ; 
 
         or R 3a  and R 3b  together with the carbon atom they are attached to may combine to form a C 3 -C 8 cycloalkyl, wherein said cycloalkyl is optionally substituted with one R 5 ; 
         or R 3a  and R 3b  together with the carbon atom they are attached to may combine to form a 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, wherein said heterocycloalkyl is optionally substituted with one R 5 ; 
         R 4 ′ is
 hydrogen, or 
 C 1 -C 6 alkyl optionally substituted with one or two groups independently selected from: 
 R 6 , 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, and 
 C 3 -C 8 cycloalkyl, 
 wherein the heterocycloalkyl is optionally substituted with one or two substituents independently selected from —OH and C 1 -C 3 alkyl; 
 
         each R 5  is independently selected from
 —C(═O)R 8 , 
 C 1 -C 3 alkyl, 
 C 3 -C 8 cycloalkyl, and 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, 
 wherein the C 1 -C 3 alkyl is optionally substituted with one R 9 , and the heterocycloalkyl is optionally substituted with one C 1 -C 3 alkyl or —C(═O)R 8 ′; 
 
         each R 6  is independently selected from —OH and C 1 -C 3 alkyl; 
         R 7  is
 C 1 -C 6 alkyl, 
 —N(R 1 2′) 2 , 
 C 3 -C 8 cycloalkyl, or 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, 
 wherein the C 1 -C 6 alkyl is optionally substituted with one or more R 11 , and the C 3 -C 8 cycloalkyl is optionally substituted with one or more —OH; 
 
         R 8 ′ is
 C 1 -C 6 alkyl, 
 C 1 -C 6 alkyl-COOH, 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, or 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, 
 wherein the heterocycloalkyl is optionally substituted with one C 1 -C 6 alkyl, and the C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —C(═O)OH, N(R 12 ′) 2 , and C 3 -C 8 cycloalkyl; 
 
         R 9  is
 phenyl, 
 C 3 -C 8 cycloalkyl, 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S, or 
 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from the heteroatoms N, O and S as ring members, 
 wherein the heteroaryl is optionally substituted with —OH, the heterocycloalkyl is optionally substituted with C 1 -C 6 alkyl, and the phenyl is optionally substituted with one or two —OH; 
 
         R 10 ′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or S—CF 3 ; 
         each R 11  is independently selected from
 halogen, 
 C 1 -C 6 haloalkyl, 
 C 1 -C 6 alkoxy, 
 —N(R 13 ) 2 , 
 —OH, and 
 4-6 membered heterocycloalkyl having 1 to 2 ring members independently selected from N, NH, NR 12 ′, O and S; 
 
         each R 12 ′ is independently selected from
 hydrogen, 
 C 1 -C 6 alkyl, and 
 —C(═O)R 8′ ; and 
 
         each R 13  is independently selected from
 hydrogen, and 
 C 1 -C 6 alkyl, 
 
         wherein the alkyl is optionally substituted with —OH or C 1 -C 6 alkoxy. 
       
     
     
         30 . The compound according to  claim 29 , wherein R 1 ′ is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . The compound according to  claim 29 , wherein R 1 ′ is C 1 -C 6 alkyl substituted with one or two —CF 3 . 
     
     
         32 . The compound according to any one of  claims 29 - 30 , wherein R 3a  and R 3b  are each independently selected from the group consisting of: H, CH 3 , —(CH 2 ) 2 CH 3 , —CH 2 OH, and 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound according to any one of  claims 29 - 30 , wherein R 3a  and R 3b  together combine to form a group selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 . The compound according to  claim 29 , wherein the compound is a compound of Formula (Ia′) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, wherein:
 X is NR 5 , CH 2 , or O; 
 n is 0 or 1, and 
 m is 0 or 1. 
 
       
     
     
         35 . The compound according to  claim 34 , wherein X is NR 5 , CH 2 , or O. 
     
     
         36 . The compound according to any one of  claims 34 - 35 , wherein X is CH 2 . 
     
     
         37 . The compound according to any one of  claims 34 - 35 , wherein X is O. 
     
     
         38 . The compound according to any one of  claims 34 - 35 , wherein X is NR 5 . 
     
     
         39 . The compound according to  claim 38 , wherein R 5  is selected from the group consisting of: CH 3 ,—CH 2 CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound according to any one of  claims 34 - 39 , wherein n is 0 or 1. 
     
     
         41 . The compound according to any one of  claims 34 - 40 , wherein n is 0. 
     
     
         42 . The compound according to any one of  claims 34 - 40 , wherein n is 1. 
     
     
         43 . The compound according to any one of  claims 34 - 42 , wherein m is 0 or 1. 
     
     
         44 . The compound according to any one of  claims 34 - 43 , wherein m is 1. 
     
     
         45 . The compound according to  claim 29 , wherein the compound is a compound of Formula (Ie′) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof. 
     
     
         46 . The compound according to  claim 34  or  45 , wherein R 7  is selected from the group consisting of: —CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound according to any one of  claims 29 - 46 , wherein R 2  is CF 3 . 
     
     
         48 . The compound according to any one of  claims 29 - 47 , wherein R 4 ′ is selected from the group consisting of: hydrogen, 
       
         
           
           
               
               
           
         
       
     
     
         49 . A compound is selected from the group consisting of:
 3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-5,5-dimethylimidazolidine-2,4-dione,   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione,   5,5-dimethyl-1-(2-morpholinoethyl)-3-((3-(3-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione,   6-(3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-6-oxohexanoic acid, 4-(3-((3-(4-(2-(isobutylsulfonyl)phenoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1-(2-morpholinoethyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)-4-oxobutanoic acid, 6-(1-(2-morpholinoethyl)-2,4-dioxo-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,3,8-triazaspiro[4.5]decan-8-yl)-6-oxohexanoic acid, 5,5-dimethyl-3-((3-(3-(trifluoromethyl)-4-(2-((trifluoromethyl)thio)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione, 5,5-dimethyl-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione, and   1,5,5-trimethyl-3-((3-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)imidazolidine-2,4-dione,   or a pharmaceutically acceptable salt thereof.   
     
     
         50 . A pharmaceutical composition comprising a compound according to any one of  claims 29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph, or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         51 . A method for the treatment of meibomian gland dysfunction comprising administration of a therapeutically effective amount of a compound according to any one of  claims 29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, to a patient in need of treatment thereof. 
     
     
         52 . Use of a compound according to any one of  claims 29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, in the manufacture of a medicament for the treatment of meibomian gland dysfunction. 
     
     
         53 . Use of a compound according to any one of  claims 29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for the treatment of meibomian gland dysfunction. 
     
     
         54 . A compound according to any one of  claims 29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for use in the treatment of meibomian gland dysfunction. 
     
     
         55 . A method for the treatment of evaporative dry eye disease comprising administration of a therapeutically effective amount of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, to a patient in need of treatment thereof. 
     
     
         56 . Use of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, in the manufacture of a medicament for the treatment of evaporative dry eye disease. 
     
     
         57 . Use of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for the treatment of evaporative dry eye disease. 
     
     
         58 . A compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for use in the treatment of evaporative dry eye disease. 
     
     
         59 . A method for the treatment of an ocular disease or disorder comprising administration of a therapeutically effective amount of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, to a patient in need of treatment thereof. 
     
     
         60 . The method according to  claim 59 , wherein the ocular disease or disorder is selected from the group consisting of meibomian gland dysfunction, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy,  acanthamoeba , fibromyalgia, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), blepharitis (anterior, posterior,  Demodex  mites), blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or patients recovering from neurotrophic keratitis, lipid deficient dry eye, tear film lipid deficiency, ocular rosacea, chalazion, and hordeola. 
     
     
         61 . Use of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, in the manufacture of a medicament for the treatment of an ocular disease or disorder. 
     
     
         62 . Use of a compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for the treatment of an ocular disease or disorder. 
     
     
         63 . The use according to any one of  claims 61 - 62 , wherein the ocular disease or disorder is selected from the group consisting of meibomian gland dysfunction, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy,  acanthamoeba , fibromyalgia, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), blepharitis (anterior, posterior,  Demodex  mites), blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or patients recovering from neurotrophic keratitis, lipid deficient dry eye, tear film lipid deficiency, ocular rosacea, chalazion, and hordeola. 
     
     
         64 . A compound according to any one of  claims 1 - 22  or  29 - 49 , or a pharmaceutically acceptable salt, solvate, co-crystal, polymorph or stereoisomer thereof, for use in the treatment of an ocular disease or disorder. 
     
     
         65 . The compound according to  claim 64 , wherein the ocular disease or disorder is selected from the group consisting of meibomian gland dysfunction, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy,  acanthamoeba , fibromyalgia, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), blepharitis (anterior, posterior,  Demodex  mites), blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or patients recovering from neurotrophic keratitis, lipid deficient dry eye, tear film lipid deficiency, ocular rosacea, chalazion, and hordeola.