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US-12617772-B2 - Hydroxypyridine HSD17B13 inhibitors and uses thereof

US12617772B2US 12617772 B2US12617772 B2US 12617772B2US-12617772-B2

Abstract

Described herein are hydroxypyridine HSD17B13 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of liver disease, metabolic disease, or cardiovascular disease, such as NAFLD or NASH, or drug induced liver injury (DILI).

Inventors

  • Joshua Odingo
  • Sampath Kumar Anandan
  • Heather Kay Webb Hsu
  • Vincent FLORIO
  • Subramanyam Janardhan TANTRY
  • Athisayamani Jeyaraj Duraiswamy
  • Bharathi Mohan KUPPUSAMY

Assignees

  • INIPHARM, INC.

Dates

Publication Date
20260505
Application Date
20220404

Claims (20)

  1. 1 . A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein: each R 1 is hydrogen; m is 1 or 2; L is —C(═O)NR 2 — or —NR 2 C(═O)—; R 2 is hydrogen, —C(═O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R B is hydrogen, deuterium, halogen, —CN, —OH, —OR 10 , —OC(═O)R 10 , —OC(═O)OR 11 , —OC(═O)NR 12 R 13 , —S(═O)R 10 , —S(═O) 2 R 10 , —S(═O) 2 NR 12 R 13 , —NR 12 R 13 , —NR 11 C(═O)NR 12 R 13 , —NR 11 C(═O)R 10 , —NR 11 C(═O)OR 11 , —NR 11 S(═O) 2 R 10 , —C(═O)R 10 , —C(═O)OR 11 , —C(═O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Ba ; each R Ba is independently deuterium, halogen, —CN, —OH, —OR 10 , —OC(═O)R 10 , —OC(═O)OR 11 , —OC(═O)NR 12 R 13 , —S(═O)R 10 , —S(═O) 2 R 10 , —S(═O) 2 NR 12 R 13 , —NR 12 R 13 , —NR 11 C(═O)NR 12 R 13 , —NR 11 C(═O)R 10 , —NR 11 C(═O)OR 11 , —NR 11 S(═O) 2 R 10 , —C(═O)R 10 , —C(═O)OR 11 , —C(═O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R Ba on the same atom form an oxo; each R 7 is independently hydrogen, deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NHS(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 7 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 7 are taken together to form an oxo; p is 1-4; each R 10 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a ; each R 11 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 11a ; each R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 12a ; or R 12 and R 13 are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R 12b ; each R 10a , R 11a , R 12a , or R 12b are independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NHS(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 10a , or two R 11a , or two R 12a , or two R 12b on the same atom are taken together to form an oxo; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three deuterium, oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three deuterium, oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, deuterium, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three oxo, deuterium, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 2 is hydrogen.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring B is aryl or heteroaryl.
  4. 4 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring B is 5-membered heteroaryl.
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring B is 6-membered heteroaryl.
  6. 6 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring B is a bicyclic heteroaryl.
  7. 7 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: wherein X 1 is N or CR X1 ; R X1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; X 2 is N or CR X2 ; R X2 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; X 3 is N or CR X3 ; R X3 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R 7′ is hydrogen or C 1 -C 6 alkyl.
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R B is —C(═O)R 10 , —C(═O)OR 11 , —C(═O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 alkyl)cycloalkyl, (C 1 -C 6 alkyl)heterocycloalkyl, (C 1 -C 6 alkyl)aryl, or (C 1 -C 6 alkyl)heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Ba .
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R B is —C(═O)NR 12 R 13 , C 1 -C 6 alkyl, cycloalkyl, or (C 1 -C 6 alkyl)aryl; wherein the alkyl, cycloalkyl, and aryl is optionally and independently substituted with one or more R Ba .
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R Ba is independently deuterium, halogen, —CN, —OH, —OR 10 , —NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  11. 11 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, (C 1 -C 6 alkyl)cycloalkyl, or (C 1 -C 6 alkyl)aryl; wherein the alkyl, cycloalkyl, and aryl is optionally and independently substituted with one or more R 12a .
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R 12a is independently deuterium, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  13. 13 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R 7 is independently hydrogen, deuterium, halogen, —OH, or C 1 -C 6 alkyl; or two R 7 are taken together to form an oxo.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: p is 1.
  15. 15 . The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  16. 16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  17. 17 . A method of treating a liver disease, a metabolic disease, or a cardiovascular disease in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  18. 18 . The compound of claim 7 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
  19. 19 . The compound of claim 7 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
  20. 20 . The compound of claim 19 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X 1 is CR X1 and R X1 is hydrogen; X 2 is CR X2 and R X2 is hydrogen; and X 3 is CR X3 and R X3 is hydrogen.

Description

CROSS-REFERENCE This application claims the benefit of U.S. Provisional Application Ser. No. 63/170,852 filed Apr. 5, 2021 which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Nonalcoholic fatty liver diseases (NAFLDs) including NASH (nonalcoholic steatohepatitis) are considered to be hepatic manifestations of the metabolic syndrome and are characterized by the accumulation of triglycerides in the liver of patients without a history of excessive alcohol consumption. The majority of patients with NAFLD are obese or morbidly obese and have accompanying insulin resistance. The incidence of NAFLD/NASH has been rapidly increasing worldwide consistent with the increased prevalence of obesity, and it is currently the most common chronic liver disease. NAFLD is classified into simple steatosis, in which only hepatic steatosis is observed, and NASH, in which intralobular inflammation and ballooning degeneration of hepatocytes is observed along with hepatic steatosis. The proportion of patients with NAFLD who have NASH is still not clear but might range from 20-40%. NASH is a progressive disease and may lead to liver cirrhosis and hepatocellular carcinoma. Twenty percent of NASH patients are reported to develop cirrhosis, and 30-40% of patients with NASH cirrhosis experience liver-related death. Recently, NASH has become the third most common indication for liver transplantation in the United States. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. 17β-Hydroxysteroid dehydrogenases (HSD17Bs) comprise a large family of 15 members some of which involved in sex hormone metabolism. Some HSD17Bs enzymes also play key roles in cholesterol and fatty acid metabolism. A recent study showed that hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), an enzyme with unknown biological function, is a novel liver-specific lipid droplet (LD)-associated protein in mouse and humans. HSD17B13 expression is markedly upregulated in patients and mice with non-alcoholic fatty liver disease (NAFLD). Hepatic overexpression of HSD17B13 promotes lipid accumulation in the liver. HSD17B13 could also have potential as a biomarker of chronic liver disease, such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) (for example: steatosis, nonalcoholic steatohepatitis (NASH), NASH-fibrosis, or cirrhosis), steatohepatitis, and liver cancer. SUMMARY OF THE INVENTION Provided herein are methods, compounds, and compositions useful for reducing expression or activity of HSD17B13 in a subject in need thereof. Also, provided herein are methods, compounds, and compositions comprising HSD17B13 specific inhibitors, which can be useful in reducing the morbidity of HSD17B13-related diseases or conditions in a subject in need thereof. Such methods, compounds, and compositions can be useful, for example, to treat, prevent, delay or ameliorate liver disease, metabolic disease, or cardiovascular disease. Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein:each R1 is independently hydrogen, deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;m is 1-3;R2 is hydrogen, —C(═O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R3 is hydrogen, deuterium, halogen, —CN, —OH, —OR10, —OC(═O)R10, —OC(═O)OR11, —OC(═O)NR12R13, —S(═O)R10, —S(═O)2R10, —S(═O)2NR12R13, —NR12R13, —NR11C(═O)NR12R13, —NR11C(═O)R10, —NR11C(═O)OR11, —NR11S(═O)2R10, —C(═O)R10, —C(═O)OR11, —C(═O)NR12R13, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6alkyl)cycloalkyl, (C1-C6alkyl)heterocycloalkyl, (C1-C6alkyl)aryl, or (C1-C6alkyl)heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R3a;each R3a is independently deuterium, halogen, —CN, —OH, —OR10, —OC(═O)R10, —OC(═O)OR11, —OC(═O)NR12R13, —S(═O)R10, —S(═O)2R10, —S(═O)2NR12R13, —NR12R13, —NR11C(═O)NR12R13, —NR11C(═O)R10, —NR11C(═O)OR11, —NR11S(═O)2R10, —C(═O)R10, —C(═O)OR11, —C(═O)NR12R13, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocy