Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease

Abstract

This invention provides compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB); pharmaceutically acceptable salts and solvates thereof, and compositions thereof. This invention further provides methods for treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.

What is claimed is: 
     
         1 . A compound of Formula (IF): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 each p is independently 1, 2, 3, 4, 5, 6, or 7; 
 each Z 1  and Z 2  is independently —C(R 1 )(R 2 )—(CH 2 ) c —X or —W—(CH 2 ) c —C(R 3 )(R 4 )—Y; 
 each c is independently 0, 1, 2, or 3; 
 each R 1  and R 2  is independently —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, phenyl or benzyl, or each carbon atom together with the R 1  and R 2  attached to the carbon atom independently form a —C 3 -C 7  cycloalkyl group; 
 each R 3  and R 4  is independently H, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —O(C 1 -C 6  alkyl), phenyl, benzyl, Cl, Br, CN, NO 2 , or CF 3 , or each carbon atom together with the R 3  and R 4  attached to the carbon atom independently form a —C 3 -C 7  cycloalkyl group; 
 Q 1  and Q 2  are independently H, OH, —C 1 -C 6  alkyl, —O(C 1 -C 6  alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR 1A , —NR 1A R 2A , F, Cl, Br, I, —CF 3 , —COR 1A , heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q 1  and Q 2  attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group; 
 V is (CH 2 ) t  or arylene; 
 t is 0, 1, 2, 3, or 4; 
 each X and Y is independently —OH, —COOH, —COOR 5 , —SO 3 H, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each R 6  is independently H, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, or —C 2 -C 6  alkynyl, wherein the —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, or —C 2 -C 6  alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C 1 -C 6  alkyl), or phenyl groups; 
         each R 7  is independently H, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, or —C 2 -C 6  alkynyl; 
         each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O) 2 —, or —Se—; and 
         each R 5  is independently —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C 1 -C 6  alkyl), or phenyl groups. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt or solvate of  claim 1 , wherein Z 1  and Z 2  are each independently —C(R 1 )(R 2 )—(CH 2 ) c —X. 
     
     
         3 . The compound or pharmaceutically acceptable salt or solvate of  claim 1 , wherein X is —COOH or —COOR 5 . 
     
     
         4 . The compound or pharmaceutically acceptable salt or solvate of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         5 . A composition comprising an effective amount of a compound, pharmaceutically acceptable salt or solvate of the compound of  claim 1  and a pharmaceutically acceptable carrier or vehicle. 
     
     
         6 . The composition of  claim 5 , further comprising another pharmaceutically active agent that is sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. 
     
     
         7 . A composition comprising an effective amount of a compound, pharmaceutically acceptable salt or solvate of the compound of  claim 4  and a pharmaceutically acceptable carrier or vehicle 
     
     
         8 . The composition of  claim 7 , further comprising another pharmaceutically active agent that is sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYPOO1a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. 
     
     
         9 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         10 . A composition comprising:
 (i) an effective amount of the compound of  claim 9 , or a pharmaceutically acceptable salt or solvate thereof; and   (ii) a pharmaceutically acceptable carrier or vehicle.   
     
     
         11 . The composition of  claim 10 , further comprising sorafenib or lenvatinib. 
     
     
         12 . A method for treating or preventing hepatocellular carcinoma, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt or solvate of the compound of  claim 1 . 
     
     
         13 . The method of  claim 12 , further comprising administering to the subject sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYPOO1a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. 
     
     
         14 . The method of  claim 12 , further comprising administering to the subject sorafenib or lenvatinib. 
     
     
         15 . A method for treating or preventing hepatocellular carcinoma, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt or solvate of the compound of  claim 9 . 
     
     
         16 . The method of  claim 15 , further comprising administering to the subject sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. 
     
     
         17 . The method of  claim 15 , further comprising administering to the subject sorafenib or lenvatinib. 
     
     
         18 . A method for treating or preventing hepatocellular carcinoma, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt or solvate of the compound of  claim 4 . 
     
     
         19 . The method of  claim 18 , further comprising administering to the subject sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. 
     
     
         20 . The method of  claim 18 , further comprising administering to the subject sorafenib or lenvatinib.