Liver x receptor modulators

Abstract

Provided herein are novel compounds and pharmaceutically acceptable salts thereof that are liver X receptor modulators. Also provided are compositions comprising compounds of the invention and a carrier. Additionally, use of the compounds herein and methods for treating a disease or disorder associated with the liver X receptor are further described.

What is claimed is: 
     
         1 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is N or CR c ; 
 R 1  is alkyl or —NR a R b ; 
 R 2  is H; halogen; —CN; —NRC(O)R; —C(O)OR; —C(O)NR a R b ; monocyclic heteroaromatic optionally substituted with one or more groups selected from alkyl, —CN, —NRC(O)R, —C(O)OR, —C(O)NR a R b  and halogen; monocyclic non-aromatic heterocycle optionally substituted with one or more groups selected from alkyl, halogen, —CN and ═O; or alkyl optionally substituted by one or more groups selected from halogen, hydroxy, alkoxy, —NR a R b , —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R) 2 , —C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —OC(O)N(R) 2  and —C(O)NR a R b ; 
 R 3  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, monocyclic non-aromatic heterocycle, monocyclic heteroaromatic or phenyl, wherein the phenyl, monocyclic non-aromatic heterocycle and monocyclic heteroaromatic group represented by R 3  are optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and —CN; 
 R 4  and R 5  independently are halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2 , —NRSO 2 N(R) 2 , haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl, monocyclic non-aromatic heterocycle, monocyclic heteroaromatic or alkyl, wherein the alkyl, monocyclic non-aromatic heterocycle and monocyclic heteroaromatic group represented by R 4  or R 5  are optionally substituted with one or more groups selected from —CN, —OR, —SR, —N(R) 2 , ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2  and —NRSO 2 N(R) 2 ; 
 R 6  is H, halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2 , —NRSO 2 N(R) 2 , haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl or alkyl, wherein the alkyl group represented by R 6  is optionally substituted with one or more groups selected from —CN, —OR, —SR, —N(R) 2 , ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2  and —NRSO 2 N(R) 2 ; or 
 R 5  and R 6 , taken together with the carbon atoms to which they are bonded, form a monocyclic non-aromatic heterocycle optionally substituted with one or more groups selected from alkyl, halogen, hydroxyalkyl, alkoxyalkyl, haloalkyl and ═O; and 
 each R independently is H or alkyl; 
 R a  and R b  are independently H, alkyl or R a  and R b  can be taken together with the nitrogen to which they are attached to form a monocyclic non-aromatic heterocycle; and 
 R c  is H, alkyl, or halogen. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 R 3  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, or phenyl, wherein the phenyl group represented by R 3  is optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and —CN;   R 4  and R 5  independently are halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2 , —NRSO 2 N(R) 2 , haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl or alkyl, wherein the alkyl represented by R 4  or R 5  is optionally substituted with one or more groups selected from —CN, —OR, —SR, —N(R) 2 , ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2  and —NRSO 2 N(R) 2 ;   R 6  is H, halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —OC(O)O(alkyl), —C(O)O(haloalkyl), —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2 , —NRSO 2 N(R) 2 , haloalkyl, haloalkoxy, cycloalkoxy, cycloalkyl or alkyl, wherein the alkyl group represented by R 6  is optionally substituted with one or more groups selected from —CN, —OR, —SR, —N(R) 2 , ═O, —C(O)R, —C(O)OR, —C(O)O(haloalkyl), —OC(O)R, —OC(O)O(alkyl), —C(O)N(R) 2 , —OC(O)N(R) 2 , —NRC(O)R, —NRC(O)O(alkyl), —S(O)R, —SO 2 R, —SO 2 N(R) 2 , —NRS(O)R, —NRSO 2 R, —NRC(O)N(R) 2  and —NRSO 2 N(R) 2 .   
     
     
         3 . The compound of  claim 2 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 4 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 5 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 4 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 7 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 8 , wherein:
 R 1  is methyl or —NH 2 ;   R 2  is H or methyl, wherein the methyl group represented by R 2  is optionally substituted with one or more groups selected from halogen, hydroxy, alkoxy, —NR a R b , —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R) 2 , —C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —C(O)NR a R b  and —OC(O)N(R) 2 ;   R 3  is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, iso-butyl, —CH 2 CF 3 , —CH(CH 2 F) 2 , —CH(CHF 2 ) 2 , —CH(CF 3 ) 2 , —CF(CH 3 ) 2 , —CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), or   phenyl, wherein the phenyl group represented by R 3  is optionally substituted with one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, nitro and —CN; and   R c , where present, is H.   
     
     
         10 . The compound of  claim 9 , wherein R 2  is H or —CH 2 OH. 
     
     
         11 . The compound of  claim 10 , wherein:
 R 1  is methyl;   R 2  is —CH 2 OH; and   R 3  is isopropyl.   
     
     
         12 . The compound of  claim 11 , wherein R 4  and R 5  independently are halogen, hydroxy, alkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, haloalkyl, —N(R) 2 , —C(O)OH, —C(O)O(alkyl), —C(O)O(haloalkyl), —C(O)(alkyl), —C(O)N(R) 2 , —NRC(O)R, —SO 2 N(R) 2 , —OC(O)N(R) 2 , —CN, hydroxyalkyl or dihydroxyalkyl. 
     
     
         13 . The compound of  claim 12 , wherein R 4  and R 5  independently are methyl, ethyl, hydroxy, CF 3 , isopropyl, cyclopropyl, —CH 2 OH, —CH(OH)(CH 2 )(OH), —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), —CH(OH)(CH 2 )(CH 3 ), —CH(OH)(CH 2 ) 2 (CH 3 ), —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)OH, —C(O)NH(CH 3 ), —C(O)CH 3 , —C(O)CH 2 CH 3 , —C(O)O(CH 2 )(CH 3 ), —C(O)O(tert-butyl), —C(O)O(C)(CH 3 ) 2 (CF 3 ), —NHC(O)CH 3 , —OCHF 2 , —OCF 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2  or —OCH 3 . 
     
     
         14 . The compound of  claim 13 , wherein R 4  is alkyl, haloalkyl, cycloalkyl, alkoxy, or haloalkoxy. 
     
     
         15 . The compound of  claim 14 , wherein R 4  is methyl, halogenated methyl, cyclopropyl, —OCHF 2  or —OCH 3 . 
     
     
         16 . The compound of  claim 15 , wherein R 4  is CF 3 . 
     
     
         17 . The compound of  claim 16 , where R 5 —C(OH)(CH 3 ) 2 . 
     
     
         18 . The compound of  claim 1 , wherein the compound is represented by a structural formula selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A pharmaceutical composition comprising a pharmaceutical carrier or diluent and the compound of  claim 1 . 
     
     
         20 . A method of treating a subject with a disease or disorder that is treatable by upregulating LXR activity comprising administering an effective amount of the compound of  claim 1  to the subject. 
     
     
         21 . The method of  claim 20 , wherein the disease or disorder is a lipid disorder; cancer; acneiform skin condition; skin inflammatory disease; immunological disorder; condition characterized by a perturbed epidermal barrier function; condition of disturbed differentiation or excess proliferation of the epidermis or mucous membrane; cardiovascular disease; optic nerve and retinal pathology; degenerative neuropathy occurring in a disease; autoimmune disease; traumatic damage to the central or peripheral nervous system; neurodegenerative disease; a degenerative process due to aging, or diseases or disorders of the kidney. 
     
     
         22 . The method of  claim 21 , wherein the disease or disorder is hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hepatic steatosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), hyperglycemia, insulin resistance, diabetes mellitus, dyslipidemia, cardiovascular disease, atherosclerosis, gallstone disease, acne vulgaris, dermatitis, psoriasis, contact dermatitis, atopic dermatitis, eczema, skin wounds, skin aging, photoaging, wrinkling, diabetes, Niemann-Pick disease type C, Parkinson's disease, Alzheimer's disease, inflammation, xanthoma, obesity, metabolic syndrome, syndrome X, stroke, peripheral occlusive disease, memory loss, diabetic neuropathies, proteinuria, glomerulopathies, diabetic nephropathy, hypertensive nephropathy, IGA nephropathy, focal segmental glomerulosclerosis, hyperphosphatemia, cardiovascular complications of hyperphosphatemia, cancer or multiple sclerosis. 
     
     
         23 . The method of  claim 22 , wherein the disease or disorder is atherosclerosis, Alzheimer's disease, cardiovascular disease, cardiovascular complications of hyperphosphatemia or dermatitis. 
     
     
         24 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         X is N or CR c ; 
         R 10  is alkyl or —NR a R b ; 
         R 20  is H; halogen; —CN; —NRC(O)R; —C(O)OR; —C(O)NR a R b ; monocyclic heteroaromatic optionally substituted with one or more groups selected from alkyl, —CN, —NRC(O)R, —C(O)OR, —C(O)NR a R b  and halogen; monocyclic non-aromatic heterocycle optionally substituted with one or more groups selected from alkyl, halogen, —CN and ═O; or alkyl optionally substituted by one or more groups selected from halogen, hydroxy, alkoxy, —NR a R b , —NRC(O)R, —NRC(O)O(alkyl), —NRC(O)N(R) 2 , —C(O)OR, thiol, alkylthiol, nitro, —CN, ═O, —OC(O)H, —OC(O)(alkyl), —OC(O)O(alkyl), —OC(O)N(R) 2 , —C(O)NR a R b , and —O(protecting group); 
         R 30  is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or phenyl, wherein the phenyl group represented by R 30  is optionally substituted with one or more groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro and —CN; 
         each R independently is H or alkyl; 
         R a  and R b  are independently H, alkyl or R a  and R b  can be taken together with the nitrogen to which they are attached to form a monocyclic non-aromatic heterocycle; and 
         R c  is H, alkyl, or halogen. 
       
     
     
         25 . The compound of  claim 24 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         26 . The compound of  claim 25 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         27 . The compound of  claim 25 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         28 . The compound of  claim 27 , wherein R 10  is —CH 3 . 
     
     
         29 . The compound of  claim 28 , wherein R 20  is —CH 2 OH, —CH 2 O(protecting group), —COOH, or —C(O)O(alkyl). 
     
     
         30 . The compound of  claim 29 , wherein R 30  is isopropyl. 
     
     
         31 . The compound of  claim 30 , wherein R 20  is —CH 2 O(TBDPS) or —C(O)OCH 3 . 
     
     
         32 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.