Dichlorophenol hsd17b13 inhibitors and uses thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 113,555, filed November 13, 2020; U.S. Provisional Application Serial No. 63 / 113,557, filed November 13, 2020; U.S. Provisional Application Serial No. 63 / 170,855, filed April 5, 2021; and U.S. Provisional Application Serial No. 63 / 225,282, filed July 23, 2021, which are hereby incorporated by reference in their entirety. BACKGROUND

[0003] Nonalcoholic fatty liver disease (NAFLD), including NASH (nonalcoholic steatohepatitis), is considered a hepatic manifestation of metabolic syndrome and is characterized by the accumulation of triglycerides in the liver of patients with no history of excessive alcohol consumption. Most patients with NAFLD are obese or morbidly obese and are accompanied by insulin resistance. In line with the increasing prevalence of obesity, the incidence of NAFLD / NASH is rapidly increasing worldwide and it is the most common chronic liver disease at present.

[0004] NAFLD is classified into simple steatosis, in which only hepatic steatosis is observed, and NASH, in which intralobular inflammation and hepatocyte ballooning are observed together with hepatic steatosis. The proportion of NAFLD patients with NASH is still unclear, but can be in the range of 20-40%. NASH is a progressive disease and can lead to cirrhosis and hepatocellular carcinoma. It is reported that 20% of NASH patients manifest cirrhosis, and 30-40% of NASH cirrhosis patients suffer from liver-related death. Recently, NASH has become the third most common indication for liver transplantation in the United States. At present, the main treatment for NAFLD / NASH is lifestyle modification by diet and exercise. However, drug therapy is essential because obese patients with NAFLD often have difficulty maintaining an improved lifestyle.

[0005] 17β-hydroxysteroid dehydrogenases (HSD17B) comprise a large family of 15 members, some of which are involved in sex hormone metabolism. Some HSD17B enzymes also play a key role in cholesterol and fatty acid metabolism. A recent study showed that hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), as an enzyme with unknown biological function, is a novel liver-specific lipid droplet (LD)-associated protein in mice and humans. HSD17B13 expression is significantly upregulated in patients and mice with nonalcoholic fatty liver disease (NAFLD). Liver overexpression of HSD17B13 promotes lipid accumulation in the liver. HSD17B13 can also have the potential to be a biomarker for chronic liver diseases such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) (e.g., steatosis, nonalcoholic steatohepatitis (NASH), NASH-fibrosis or cirrhosis), steatohepatitis, and liver cancer. SUMMARY

[0006] Provided herein are methods, compounds, and compositions useful for reducing the expression or activity of HSD17B13 in a subject in need thereof. Further, provided herein are methods, compounds, and compositions including HSD17B13-specific inhibitors useful for reducing the incidence of a HSD17B13-related disease or condition in a subject in need thereof. Such methods, compounds, and compositions can be used, for example, to treat, prevent, delay, or ameliorate a liver disease, a metabolic disease, or a cardiovascular disease.

[0007] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0008]

[0009] wherein:

[0010] Ring B is

[0011] Y is N or CR 1 ;

[0012] each Z is independently N or CR 1 ;

[0013] each R 1 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0014] L is -O-, -C(=O)NR 3 -, - NR 3C(=O)-, -C(=O)C(R 4 )2- or -C(R 4 )2C(=O)-;

[0015] R 3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6deuteroalkyl;

[0016] each R 4 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6deuteroalkyl;

[0017] Ring A is a 3- to 12-membered ring optionally containing 1-4 heteroatoms selected from O, S, N, P and B;

[0018] each R 5 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl or C1-C6deuteroalkyl;

[0019] or two R 5 on the same atom together form oxo;

[0020] n is 0-6;

[0021] R A is:

[0022] (a) -C(=O)NR 10 R 11 ; or

[0023] (b) C4-C Aa alkyl optionally substituted with one or more R 10 ; or

[0024] (c) -(C(R 12 )2) p cycloalkyl, -(C(R 12 )2) p heterocycloalkyl, -(C(R 12 )2) p aryl or -(C(R 12 )2) p heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ab ;

[0025] R 10 and R 11 are independently hydrogen, C1-C10 alkyl, C1-C 10 haloalkyl, C1-C 10 deuteroalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 heteroalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents;

[0026] each R 10a is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R dC1-C6alkyl, C1-C6haloalkyl, C1-C6hydrogenoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10b substituents;

[0027] or two R 10a on the same atom taken together form oxo;

[0028] each R 10b is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydrogenoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0029] or two R 10b on the same atom taken together form oxo;

[0030] each R Aaindependently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0031] or two R Aa on the same atom are taken together to form oxo;

[0032] each R Ab is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR c R d , -NR c R d , -NR bC(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydrogens, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa substituents;

[0033] or two R Ab on the same atom are taken together to form an oxo;

[0034] each R Aaa is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , -C(=O)C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0035] each R 12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0036] or two R 12 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; wherein cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0037] or two R 12 on adjacent carbons are taken together to form a cycloalkyl optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0038] p is 1-4;

[0039] each R a is independently 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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;

[0040] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently prefixed with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3

[0041] -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl

[0042] The radical, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl may be optionally substituted; and each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl,

[0043] C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently radicalized by one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl are optionally substituted;

[0044] or R c and R dwith the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; provided that the compound is not:

[0045]

[0046]

[0047] Disclosed herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0048]

[0049] Disclosed herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0050]

[0051] Disclosed herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0052]

[0053] Disclosed herein is a compound of Formula (Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0054]

[0055] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0056] Also disclosed herein is a method of treating a disease in a subject in need thereof, comprising administering a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments of the method of treating a disease, the disease is a liver disease, a metabolic disease, or a cardiovascular disease. In some embodiments of the method of treating a disease, the disease is NAFLD. In some embodiments of the method of treating a disease, the disease is NASH. In some embodiments of the method of treating a disease, the disease is drug-induced liver injury (DILI). In some embodiments of the method of treating a disease, the disease is associated with HSD17B13. In some embodiments of the method of treating a disease, the disease is alcoholic liver disease. In some embodiments of the method of treating a disease, the disease is cirrhosis. In some embodiments of the method of treating a disease, the disease is decompensated portal hypertension. In some embodiments of the method of treating a disease, the disease is cholestatic liver disease.

[0057] INCORPORATION BY REFERENCE

[0058] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0059] Definitions

[0060] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the relevant arts will appreciate that the application can be practiced without such details. In other instances, well-known structures have not been described in detail in order to avoid obscuring the descriptions of the embodiments. Unless otherwise noted, the word "comprise" and variations thereof such as "comprises" and "comprising," shall not be construed as being limited to a specific manner of description, that is, as being construed to mean "including but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed application.

[0061] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Additionally, the terms "a" and "an," as used herein, mean "one or more." Also, the term "or" as used herein, generally means "and / or," unless otherwise indicated.

[0062] The following terms as used herein have the following meanings unless indicated otherwise:

[0063] "Oxy" means =0.

[0064] "Carboxyl" means -COOH.

[0065] "Alkyl" means a straight or branched chain saturated hydrocarbon monovalent radical of one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-C6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-6 "Alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-10 "Alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-6 "Alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-5 "Alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-4 "Alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl is C1-C4 alkyl. In some embodiments, alkyl is C1-C3 alkyl. In some embodiments, alkyl is C1-C2 alkyl. In some embodiments, alkyl is C1 alkyl. 1-3Alkyl. Unless specifically stated in the specification, an alkyl group can optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkyl group is optionally substituted with halogen.

[0066] “Alkenyl” refers to a straight or branched chain hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The radical can be in the cis or trans configuration about one or more double bonds and is to be understood as including both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3- butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-C6 alkenyl” is intended to refer to both the lower and the higher number in the range. For example, “C2-C6 alkenyl” means that there are 2, 3, 4, 5, or 6 carbon atoms in the alkenyl group. Whenever it appears in the present specification, a numerical range such as “C2-C6 alkenyl” or “C2-C6 alkenyl” is intended to refer to both the lower and the higher number in the range. For example, “C2-C6 alkenyl” means that there are 2, 3, 4, 5, or 6 carbon atoms in the alkenyl group. 2-6 Alkenyl” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also encompasses occurrences of the term “alkenyl” where no numerical range is specified. Unless specifically stated in the specification, an alkenyl group can optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl group is optionally substituted with halogen.

[0067] “Alkynyl” refers to a straight or branched chain hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-C6 alkynyl” is intended to refer to both the lower and the higher number in the range. For example, “C2-C6 alkynyl” means that there are 2, 3, 4, 5, or 6 carbon atoms in the alkynyl group. Whenever it appears in the present specification, a numerical range such as “C2-C6 alkynyl” or “C2-C6 alkynyl” is intended to refer to both the lower and the higher number in the range. For example, “C2-C6 alkynyl” means that there are 2, 3, 4, 5, or 6 carbon atoms in the alkynyl group. 2-6"Alynyl" means that an alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0068] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene groups may optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene group is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with halogen.

[0069] "Alkoxy" refers to the formula -OR a Group, wherein R a It is an alkyl group as defined. Unless otherwise specifically stated in the specification, the alkoxy group may optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0070] "Aryl" refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl) group. Aryl groups include, but are not limited to, those derived from anthraceneyl, naphthyl, phenanthreneyl, anthracene, azulene, benzene, etc. Aryl groups derived from the hydrocarbon ring systems of fluoranthene, fluorene, as-dicyclopentadienzobenzene, s-dicyclopentadienzobenzene, indene, indene, naphthalene, propylene naphthalene, phenanthrene, heptane, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may optionally be substituted, for example, with halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogens.

[0071] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded through non-aromatic ring atoms) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C3-C5). 15 cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (C3-C) 10 cycloalkyl or C3-C 10cycloalkyl of three to eight carbon atoms (C3-C8cycloalkyl), three to six carbon atoms (C3-C6cycloalkyl), three to five carbon atoms (C3-C5cycloalkyl), or three to four carbon atoms (C3-C4cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, the cycloalkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogen.

[0072] “Halo” or “halogen” means a bromo, chloro, fluoro, or iodo group. In some embodiments, the halogen is a fluoro or chloro group. In some embodiments, the halogen is a fluoro group.

[0073] “Haloalkyl” means an alkyl group as defined above substituted with one or more halogen groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0074] "Heteroalkyl" refers to an alkyl group as defined above in which one or more skeletal atoms are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl, wherein the heteroalkyl consists of from 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl groups are, e.g., -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted by, e.g., oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted by halogen.

[0075] "Deuterated alkyl" refers to an alkyl group as defined above in which one or more hydrogens are replaced by deuterium. In some embodiments, an alkyl group is replaced by one deuterium. In some embodiments, an alkyl group is replaced by one, two, or three deuterium. In some embodiments, an alkyl group is replaced by one, two, three, four, five, or six deuterium. Deuterated alkyl groups include, e.g., CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, a deuterated alkyl is CD3.

[0076] "Heteroalkyl" refers to an alkyl group as defined above in which one or more skeletal atoms are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl, wherein the heteroalkyl consists of from 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl groups are, e.g., -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted by, e.g., oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted by halogen.

[0077] "Heterocyclic alkyl" refers to a 3- to 24-membered or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl contains one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl contains one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl contains one nitrogen atom. In some embodiments, the heterocyclic alkyl contains one nitrogen atom and one oxygen atom. Unless otherwise specifically stated in the specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded by non-aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having two to fifteen carbon atoms (C2-C4). 15 Heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (C2-C) 10 Heterocyclic alkyl or C2-C 10heterocycloalkyl of two to eight carbon atoms (C2-C8heterocycloalkyl or C2-C8heterocycloalkenyl), two to seven carbon atoms (C2-C7heterocycloalkyl or C2-C7heterocycloalkenyl), two to six carbon atoms (C2-C6heterocycloalkyl or C2-C7heterocycloalkenyl), two to five carbon atoms (C2-C5heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (C2-C4heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzenefuran-1-yl, 3-oxo-1,3-dihydroisobenzenefuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, a heterocycloalkyl group has from 2 to 10 carbons in the ring. It should be appreciated that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl group is a 3- to 8-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3- to 7-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3- to 8-membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 3- to 7-membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 3- to 6-membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 4- to 6-membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 5- to 6-membered heterocycloalkenyl group. Unless specifically set forth otherwise in the specification, a heterocycloalkyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0078] “Heteroaryl” refers to a 5- to 14-membered ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group contains one to three nitrogens. In some embodiments, the heteroaryl group contains one or two nitrogens. In some embodiments, the heteroaryl group contains one nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzo dioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzo furanyl, dibenzo thiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indoxazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxo pyridinyl, 1-oxo pyrimidinyl, 1-oxo pyrazinyl, 1-oxo pyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, the heteroaryl group can be optionally substituted, e.g., with halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0079] The term "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes situations where the event or circumstance occurs and where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level of substitution between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, the skilled person will appreciate that such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which in turn is defined to include optionally substituted alkyl, which can be endless). Thus, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 Daltons, and more typically of at most about 500 Daltons.

[0080] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective to produce a desired therapeutic effect.

[0081] "Treatment" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to modify the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition after the onset of a pathological event or contact with a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or ameliorating the condition. In some embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected of suffering from a liver disease, e.g., NAFLD).

[0082] "Synergy" or "synergistic" refers to the combined effect of greater than additive of each component individually at the same dose.

[0083] “HSD17B13” means hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13. For example, in some embodiments, HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13, including genomic DNA comprising introns and exons. HSD17B13 can also refer to any amino acid sequence of HSD17B13 encoded by the DNA sequence and / or RNA sequence, which can include secondary or tertiary structure of the protein molecule. The target can be referred to in upper case or lower case.

[0084] Compound

[0085] Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, useful for treating a liver disease. In some embodiments, the liver disease is NAFLD.

[0086] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0087]

[0088] wherein:

[0089] Ring B is

[0090] Y is N or CR 1 ;

[0091] each Z is independently N or CR 1 ;

[0092] each R 1 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0093] L is -O-, -C(=O)NR 3 , -NR 3 C(=O)-, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-;

[0094] R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0095] each R 4It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl;

[0096] Ring A is a 3- to 12-membered ring that optionally contains 1 to 4 heteroatoms selected from O, S, N, P, and B;

[0097] Each R 5 Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0098] Or two R atoms on the same atom 5 Together they form oxygen;

[0099] n is 0-6;

[0100] R A yes:

[0101] (a)-C(=O)NR 10 R 11 ;or

[0102] (b) by one or more R Aa Optional substitution of C4-C 10 Alkyl; or

[0103] (c)–(C(R 12 )2) p cycloalkyl, -(C(R) 12 )2) p Heterocyclic alkyl, -(C(R) 12 )2) p Aryl or -(C(R) 12 )2) p Heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently influenced by one or more R groups. Ab replace;

[0104] R 10 and R 11 Independently, it is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Heteroalkyl, C2-C 10 alkenyl, C2-C 10alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents;

[0105] each R 10a is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydrogens, C1-C6 hydrogens, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10b substituents;

[0106] or two R 10a on the same atom taken together form oxo;

[0107] each R 10b is independently deuterium, halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydro dealkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0108] or two R 10b on the same atom, together form an oxo;

[0109] each R Aa is independently deuterium, halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0110] or two R Aa on the same atom are taken together to form an oxo;

[0111] each R Ab is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R dC1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa substituents;

[0112] or two R Ab on the same atom taken together form oxo;

[0113] each R Aaa is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0114] each R 12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0115] or two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl; wherein cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterioalkyl;

[0116] or two R on the same carbon 12 together form a cycloalkyl, which cycloalkyl is optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterioalkyl;

[0117] p is 1-4;

[0118] each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0119] each R bindependently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0120] R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl,

[0121] C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0122] or R c and R dtogether with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; provided that the compound is not:

[0123]

[0124]

[0125] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0126]

[0127] wherein:

[0128] Ring B is

[0129] Y is N or CR 1 ;

[0130] each Z is independently N or CR 1 ;

[0131] each R 1 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0132] L is -O-, -C(=O)NR 3 , -NR 3 C(=O)-, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-;

[0133] R 3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0134] each R 4 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0135] Ring A is a 3- to 12-membered ring optionally containing 1-4 heteroatoms selected from O, S, N, P, and B;

[0136] each R 5 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0137] or two R 5 on the same atom are taken together to form oxo;

[0138] n is 0-6;

[0139] R A is:

[0140] (a) -C(=O)NR 10 R 11 ; or

[0141] (b) C4-C Aa alkyl optionally substituted with one or more R 10 ; or

[0142] (c) -(C(R 12 )2) p cycloalkyl, -(C(R 12 )2) p heterocycloalkyl, -(C(R 12 )2) p aryl, or -(C(R 12 )2) p heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R Ab ;

[0143] R 10 and R 11 are independently hydrogen, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 deuterated alkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 heteroalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, C3-C6 deuterated cycloalkyl, C4-C8 cycloalkenyl, C6 aryl, C1-C6 heteroalkyl, or 3- to 8-membered heterocycloalkyl;alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents;

[0144] each R 10a is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium-substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10b substituents;

[0145] or two R 10a on the same atom are taken together to form an oxo;

[0146] each R 10b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a-C(=O)R a -C(=O)OR b -C(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydrodealkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0147] or two R 10b on the same atom are taken together to form an oxo;

[0148] each R Aa is independently deuterium, halogen, -CN, -NO2, -OH, -OR a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0149] or two R Aa on the same atom are taken together to form an oxo;

[0150] each R Ab is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R dC1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa substituents;

[0151] two R Ab on the same atom taken together form oxo;

[0152] each R Aaa is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0153] each R 12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0154] two R12 Together they form cycloalkyl or heterocycloalkyl groups; wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl;

[0155] p is 1-4;

[0156] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently radicalized by one or more oxo, deuterated, halogenated, or alkyl groups. The following can be substituted: -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0157] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently influenced by one or more oxo, deuterated, halogenated, or alkyl groups. The following can be optionally substituted: -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; and

[0158] each R c and R d independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium- substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium-substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0159] or R c and R d are taken together with the atom to which they are attached to form heterocycloalkyl, which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium-substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; provided that the compound is not:

[0160]

[0161]

[0162]

[0163] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0164]

[0165] wherein:

[0166] Ring B is

[0167] Y is N or CR 1 ;

[0168] Each Z is independently either N or CR. 1 ;

[0169] Each R 1 Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0170] L is -O-, -C(=O)NR 3 -、-C(=O)C(R 4 )2- or -C(R 4 )2C(=O)-;

[0171] R 3 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0172] Each R 4 It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl;

[0173] Ring A is a 3- to 12-membered ring that optionally contains 1 to 4 heteroatoms selected from O, S, N, P and B;

[0174] Each R 5 Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0175] Or two R atoms on the same atom 5 Together they form oxygen;

[0176] n is 0-6;

[0177] R A yes:

[0178] (a)-C(=O)NR 10 R 11 ;or

[0179] (b) by one or more R Aa Optional substitution of C4-C 10 Alkyl; or

[0180] (c) -C(R 12 )2) p cycloalkyl, -(C(R 12 )2) p heterocycloalkyl, -(C(R 12 )2) p aryl, or -(C(R 12 )2) p heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R Ab ;

[0181] R 10 and R 11 are independently hydrogen, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 deuteroalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 heteroalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a ;

[0182] each R 10a is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a-C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently represented by one or more R 10b replace;

[0183] Or two R atoms on the same atom 10a Together they form oxygen;

[0184] Each R 10b Independently, it is deuterium, halogen, -CN, -NO2, -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)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R dC1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0185] or two R 10b on the same atom are taken together to form an oxo;

[0186] each R Aa is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0187] or two R Aa on the same atom are taken together to form an oxo;

[0188] each R Ab is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)ORb -OC(=O)R c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR 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)2R a -C(=O)R a -C(=O)C(=O)R a -C(=O)OR b -C(=O)NR c R d -C(=O)C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydro dealkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0189] or two R Ab on the same atom taken together form oxo;

[0190] each R Aaa is independently deuterium, halogen, -CN, -NO2, -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)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NRc R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0191] each R 12 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0192] or two R 12 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; wherein cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0193] or two R 12 on adjacent carbons are taken together to form a cycloalkyl optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl;

[0194] p is 1-4;

[0195] each R aindependently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0196] each R b independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; and

[0197] each R c and R dindependently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0198] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; provided that the compound is not:

[0199]

[0200] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0201]

[0202] wherein:

[0203] Ring B is

[0204] Y is N or CR 1 ;

[0205] each Z is independently N or CR 1 ;

[0206] Each R 1 Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0207] L is -O-, -C(=O)NR 3 -、-C(=O)C(R 4 )2- or -C(R 4 )2C(=O)-;

[0208] R 3 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl;

[0209] Each R 4 It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl;

[0210] Ring A is an optional 3- to 12-membered ring containing 1 to 4 heteroatoms selected from O, S, N, P, and B; each R 5 Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl

[0211] C1-C6 haloalkyl or C1-C6 deuteralkyl;

[0212] Or two R atoms on the same atom 5 Together they form oxygen;

[0213] n is 0-6;

[0214] R A yes:

[0215] (a)-C(=O)NR 10 R 11 ;or

[0216] (b) by one or more R Aa Optional substitution of C4-C 10 Alkyl; or

[0217] (c)-(C(R 12 )2) p cycloalkyl, -(C(R) 12 )2) p Heterocyclic alkyl, -(C(R) 12 )2) p Aryl or -(C(R) 12)2) p heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Ab substituents;

[0218] R 10 and R 11 are independently hydrogen, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 deuteroalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 heteroalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents;

[0219] each R 10a is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c Rd , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10b ;

[0220] or two R 10a on the same atom, together form oxo;

[0221] each R 10b is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0222] or two R 10b on the same atom, together form oxo;

[0223] each R Aaindependently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0224] or two R Aa on the same atom are taken together to form oxo;

[0225] each R Ab is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR c R d , -NR c R d , -NR bC(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydrogens, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R Aaa ;

[0226] or two R Ab on the same atom are taken together to form oxo;

[0227] each R Aaa is independently deuterium, halogen, -CN, -NO2, -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)2R a , -S(=O)2NR 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)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium- substituted alkyl,

[0228] C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0229] each R 12 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterium- substituted alkyl;

[0230] or two R 12 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; wherein cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterium- substituted alkyl;

[0231] p is 1-4;

[0232] each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium- substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium- substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0233] each R bindependently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; and

[0234] each R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 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, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0235] or R c and R dwith the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; provided that the compound is not:

[0236]

[0237] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is not In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is not In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is not

[0238] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is not

[0239] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ia):

[0240] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is N.

[0241] In some embodiments of the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is CR 1 .

[0242] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ib):

[0243] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ic):

[0244] In some embodiments of the compound of Formula (I) or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one Z is CR 1 and one Z is N.

[0245] In some embodiments of the compound of Formula (I) or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Z is CR 1 .

[0246] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Id):

[0247] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, or C1-C6alkyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen.

[0248] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -O-, -C(=O)NR 3 -, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -C(=O)C(R 4 )2- or -C(R 4 )2C(=O)-. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -O-. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -NR 3 C(=O)- or -C(=O)NR 3- In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -C(=0)NR 3 -.

[0249] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or Ci-C6alkyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen.

[0250] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-10 membered ring, optionally containing 1-4 heteroatoms selected from O, S, N, P, and B. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-10 membered ring, optionally containing 1-4 heteroatoms selected from O, S, or N. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-6 membered ring, optionally containing 1-4 heteroatoms selected from O, S, or N. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is an 8-12 membered bicyclic ring, optionally containing 1-4 heteroatoms selected from O, S, or N. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is an 8-10 membered bicyclic ring, optionally containing 1-4 heteroatoms selected from O, S, or N. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl or 5 or 6 membered heteroaryl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is 5 membered heteroaryl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is 6 membered heteroaryl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thienyl, oxazolyl, isoxazolyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is oxazolyl, isoxazolyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not thienyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not thiazolyl or isothiazolyl.In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not thiazole. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not isothiazole. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thienyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thiazole or isothiazole. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is oxazole or isoxazole. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is pyridine. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is dihydroquinazoline, isoindoline, or 2,3-dihydrobenzoxazepine.

[0251] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n’ is 0-4 and n” is 0-2.

[0252] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n’ is 0-4 and n” is 0-2. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

[0253] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5a , R 5b , R 5c , and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a ​​​​, -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0254] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is wherein R 5a , R 5b and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0255] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5a is deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0256] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5a is deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and R 5b , R 5c and R 5d are independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0257] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5bdeuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a , R 5c , and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -SR a , -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0258] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5b is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a , R 5c , and R 5d are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0259] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5c is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a , R 5b , and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0260] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5c is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a , R 5b , and R 5dIt is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

[0261] In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, wherein R 5d It is deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; and R 5a R 5b and R 5c Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

[0262] In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, wherein R 5d It is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a R 5b and R 5c It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

[0263] In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, wherein R 5c It is deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; R 5d It is deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; and R 5a and R 5b Independently, it is hydrogen, deuterium, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

[0264] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5c is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5d is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and R 5a and R 5b are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0265] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is

[0266] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 5 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 5 on the same atom are taken together to form oxo. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 5 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl; or two R 5 on the same atom are taken together to form oxo. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 5 is independently hydrogen, halogen, or C1-C6 alkyl; or two R 5 on the same atom are taken together to form oxo. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 5 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R5 together form oxo. In some embodiments of the compound of Formula (I), (la)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 5 together form oxo.

[0267] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0-5. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0-4. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0-3. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0-2. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 or 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 0. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 3. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 4. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 5. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 6. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0-3. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0-2. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0 or 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n' is 2.In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n’ is 3. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n’ is 4.

[0268] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n” is 0 or 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n” is 0. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n” is 1. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n” is 2.

[0269] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R A is -C(=O)NR 10 R 11 .

[0270] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 11 is hydrogen or C1-C6alkyl. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 11 is hydrogen.

[0271] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 deuteroalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 heteroalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10asubstituted. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C 10 alkyl, optionally substituted with one or more R 10a substituents. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C6alkyl(aryl) or C1-C6alkyl(heteroaryl); wherein each alkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10a substituents. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C6alkyl(aryl), wherein aryl is optionally substituted with one or more R 10a substituents.

[0272] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 10a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 10b substituents. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 10a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl group is optionally and independently radically influenced by one or more R 10b Substitution. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 10a Independently, it is deuterium, halogen, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; wherein each alkyl group is optionally and independently influenced by one or more R 10b Substitution. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 10a Independently, it is deuterium, halogen, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates, or stereoisomers, each R 10a Independently, it is deuterium, halogen, -OR a C1-C6 alkyl or C1-C6 haloalkyl.

[0273] In some embodiments of compounds of formula (I), (Ia)-(Id), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, R A It is by one or more R Aa Optional substitution of C4-C 10 alkyl.

[0274] In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R Aa Independently, it is deuterium, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently represented by one or more R Aaa Substitution; or two R atoms on the same atom Aa Together they form an oxo group. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each RAa independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , cycloalkyl, or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more R Aaa In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R Aa is independently deuterium, halogen, -CN, -OH, -OR a , or -NR c R d .

[0275] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p cycloalkyl, -(C(R 12 )2) p heterocycloalkyl, -(C(R 12 )2) p aryl, or -(C(R 12 )2) p heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R Ab In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p aryl, or -(C(R 12 )2) p heteroaryl; wherein aryl and heteroaryl are optionally and independently substituted with one or more R Ab In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p aryl; wherein aryl is optionally and independently substituted with one or more R Ab .

[0276] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 12 is independently hydrogen, deuterium, halogen, or C1-C6alkyl; or two R 12Together they form cycloalkyl or heterocycloalkyl groups. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 12 It is hydrogen or two Rs on the same carbon atom. 12 Together they form a cycloalkyl group. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 12 It is hydrogen. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, the two Rs on the same carbon are hydrogen. 12 Together they form a cycloalkyl group. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, the two Rs on adjacent carbons... 12 Together they form cycloalkyl groups.

[0277] In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R Ab Independently, it is deuterium, halogen, -CN, -OH, -OR a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently represented by one or more R Aaa Substitution; or two R atoms on the same atom Ab Together they form an oxo group. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R Ab Independently, it is deuterium, halogen, -CN, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently represented by one or more R Aaa Substitution. In some embodiments of compounds of formula (I), (Ia)-(Id) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R Ab Independently, it is deuterium, halogen, -CN, -OH, -OR a, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R Aaa substituted.

[0278] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R Aaa is independently deuterium, halogen, -CN, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R Aaa is independently deuterium, halogen, -CN, -OH, -OR a , C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0279] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 3.

[0280] In some embodiments of the compounds disclosed herein, each R aindependently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a independently C1-C6 alkyl.

[0281] In some embodiments of the compounds disclosed herein, each R bindependently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl. In some embodiments of the compounds disclosed herein, each R b independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl. In some embodiments of the compounds disclosed herein, each R b independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of the compounds disclosed herein, each R b independently hydrogen or C1-C6alkyl.

[0282] In some embodiments of the compounds disclosed herein, each R c and R dindependently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium- substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium-substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium-substituted alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d independently hydrogen or C1-C6 alkyl.

[0283] In some embodiments of the compounds disclosed herein, R c and R dtogether with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0284] In some embodiments of the compounds disclosed herein, each R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and the heterocycloalkyl group formed when R c and R d are taken together, is independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and the heterocycloalkyl group formed when R c and R d are taken together, is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and the heterocycloalkyl group formed when R c and R d are taken together, is independently substituted with 1 or 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R Aa , R Ab , R 10 , R 10a , R11 a b c d c d heterocycloalkyl formed when R

[0285] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, the groups and substituents thereof are selected by one of skill in the art to provide stable moieties and compounds. Described herein is a compound of Formula (I) selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0286] Table 1. Exemplary Compounds

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] ​​​​​​

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] Other forms of the compounds disclosed herein

[0319] Isomers / stereoisomers

[0320] In some embodiments, the compounds described herein exist in geometric isomeric forms. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, trans (E), and cis (Z) isomers as well as their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers and each center can occur in the R- or S-configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from partial resolution or racemization are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereoisomers have different physical properties [e.g., melting points, boiling points, solubilities, reactivities, etc.] and are separated by exploiting these dissimilarities. In some embodiments, the diastereoisomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered by any practical means which does not cause racemization along with the resolving agent.

[0321] Labeled compounds

[0322] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Accordingly, in some embodiments, the compounds disclosed herein include isotopically labeled compounds which are identical to those recited herein, except for the inclusion of one or more atoms which are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P,32 P, 35 S, 18 F and 36 Cl. Other isotopes of compounds described herein and their pharmaceutically acceptable salts, solvates, or stereoisomers containing the above-mentioned isotopes and / or other isotopes of atoms are within the scope of the application. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H), and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0323] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of a chromophore or fluorescent moiety, bioluminescent label, or chemiluminescent label.

[0324] In some embodiments, the labeled compounds described herein are used to measure the in vitro and in vivo binding of unlabeled HSD17B13 inhibitors.

[0325] Pharmaceutically acceptable salts

[0326] In some embodiments, the compounds described herein exist in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0327] In some embodiments, the compounds described herein have an acidic or basic group and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or solvates or stereoisomers thereof, or by separately reacting the purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. In some embodiments, the compounds described herein form acid addition salts with suitable acids. In some embodiments, the compounds described herein form base salts with suitable bases.

[0328] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, besylate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0329] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts by reaction of the free base form of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and tetrafluoroboric acids, and organic acids such as acetic, propionic, hexanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, p-toluenesulfonic, tartaric, trifluoroacetic, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic, arylsulfonic, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 2-naphthalenesulfonic, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylenebis-(3-hydroxy-2- ene-1-carboxylic), 3-phenylpropionic, trimethylacetic, tertiary butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, and muconic acids. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0330] In some embodiments, those compounds described herein that contain a free acid group are reacted with a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation; with ammonia; or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4alkyl)4, and the like.

[0331] Representative organic amines which can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include quaternized

[0332] Solvates

[0333] In some embodiments, the compounds described herein exist as solvates. The present application provides methods of treating a disease by administering such solvates. The present application also provides methods of treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0334] Solvates contain either the stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent, such as water, ethanol, or the like. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0335] Tautomers

[0336] In some cases, compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the structural formulae described herein. Tautomers are compounds that can be interconverted by a migration of a hydrogen atom, accompanied by a switch in a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0337] Therapeutic methods

[0338] Provided herein are methods of inhibiting expression or activity of HSD17B13 that can be used to treat, prevent, or ameliorate a disease associated with HSD17B13, such as NAFLD or NASH, in a subject in need thereof by administering a compound targeting HSD17B13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0339] Provided herein are methods of inhibiting the expression or activity of HSD17B13 in a cell, the method comprising contacting the cell with a disclosed HSD17B13 inhibitor or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, thereby inhibiting the expression or activity of HSD17B13 in the cell. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is in the liver. In some embodiments, the cell is in the liver of a subject having or at risk of having a disease, disorder, condition, symptom, or physiological marker associated with a liver disease, metabolic disease, or cardiovascular disease or disorder. In some embodiments, the cell is a fat cell or monocyte from a subject having or at risk of having a disease. In some embodiments, the cell is a lymphocyte from a subject having or at risk of having a disease. In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, fatty liver disease, chronic liver disease, cirrhosis, liver steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, nonalcoholic steatohepatitis (NASH), fulminant Wilson’s disease, rapid fibrosing hepatitis C virus injury, and decompensated portal hypertension. In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is NASH. In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is cholestatic liver disease.

[0340] In some embodiments, the liver disease is primary biliary cirrhosis or primary sclerosing cholangitis.

[0341] Provided herein are methods of treating, preventing, delaying the onset of, slowing the progression of, or ameliorating one or more diseases, disorders, conditions, symptoms, or physiological indicia associated with HSD17B13, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the subject in need is identified as having, or at risk of having, the disease, disorder, condition, symptom, or physiological indicia. In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, liver disease, fatty liver disease, chronic liver disease, cirrhosis, hepatic steatosis, steatohepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is NASH.

[0342] Provided herein are methods of reducing, ameliorating, or modulating liver steatosis, liver fibrosis, triglyceride synthesis, lipid levels, hepatic lipids, ALT levels, NAFLD Activity Score (NAS), cholesterol levels, or triglyceride levels, or a combination thereof, in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating liver steatosis in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating liver fibrosis in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating triglyceride synthesis in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating lipid levels in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating hepatic lipids in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating ALT levels in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating NAFLD Activity Score in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating cholesterol levels in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, ameliorating, or modulating triglyceride levels in an individual. In some embodiments, the subject is identified as having, or at risk of having, a disease, disorder, condition, symptom, or physiological indicia associated with a liver disease, a metabolic disease, or a cardiovascular disease or disorder, or is provided for use in reducing, ameliorating, or modulating a disease, disorder, condition, symptom, or physiological indicia associated with a liver disease, a metabolic disease, or a cardiovascular disease or disorder. In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, liver disease, fatty liver disease, chronic liver disease, cirrhosis, liver steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease, metabolic disease, or cardiovascular disease or disorder is NASH.

[0343] Provided herein are methods for treating, preventing, or delaying the onset of drug-induced liver injury (DILI) in a subject in need thereof. In some embodiments, the liver injury is steatohepatitis. Also provided herein are methods for treating, preventing, or delaying the onset of drug-induced steatohepatitis (DISH) in a subject in need thereof. In some embodiments, the subject in need is undergoing chemotherapy for the treatment of cancer. In some embodiments, the subject in need is undergoing treatment for a cardiovascular disease. In some embodiments, the subject in need is undergoing treatment for a psychiatric disease / condition. In some embodiments, the subject in need is undergoing treatment for pain. In some embodiments, the subject in need is undergoing treatment for arthritis. In some embodiments, the chemotherapy is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the subject in need is undergoing amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the subject in need is undergoing amitriptyline, clozapine, or any combination thereof. In some embodiments, the subject in need is undergoing methotrexate, pirprofen, or any combination thereof.

[0344] Dosing

[0345] In certain embodiments, compositions containing one or more compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition; previous therapy; the patient's health status, weight, and response to the drugs; and the judgment of the treating physician. A therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0346] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be "a prophylactically effective amount or dose." Depending on the patient's health status, weight, etc., the precise amount in this use is also dependent on the severity and course of the disease, disorder, or condition; previous therapy; the patient's health status and response to the drugs; and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated, and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to prevent the recurrence of symptoms of the disease or condition. In one aspect, prophylactic treatment comprises administering to a mammal having a patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to prevent liver injury. The protein variant of the patatin-like phospholipase domain-containing 3 (PNPLA3) protein that has an isoleucine to methionine at position 148 (I148M) has recently been identified as a major determinant of liver fat content, which is expressed in the liver and is involved in lipid metabolism. Several studies confirm that the I148M variant predisposes to the full spectrum of liver injuries related to fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Moreover, the I148M variant represents a major determinant of progression of alcohol-related steatohepatitis to cirrhosis and of fibrosis and related clinical outcomes in chronic hepatitis C virus hepatitis and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis, and primary sclerosing cholangitis. In some embodiments, the PNPLA3 polymorphism is used to predict liver disease progression.

[0347] In certain embodiments where the patient's condition does not improve, administration of the compound is continued for extended periods, at the discretion of the physician, that is, for the duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0348] In certain embodiments where the patient's condition improves, the dosage of the administered drug is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In particular embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the drug holiday is, by way of example only, 10%-100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0349] Once the patient's condition has improved, a maintenance dose is administered as necessary. Subsequently, in particular embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires periodic or daily treatment to maintain remission from the symptoms.

[0350] The amount of a given agent that will correspond to such an amount will vary depending upon such factors as the particular compound, the disease condition and its severity, the identity (e.g., weight, gender) of the subject or host to be treated, and the like, but can be determined as with any drug formula in accordance with the particular circumstances surrounding the case: e.g., the specific agent to be administered, the route of administration, the condition being treated, and the subject or host being treated.

[0351] Generally, however, doses for adult humans typically range from 0.01 mg to 5000 mg per day. In one aspect, the dose for adult humans is about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0352] In one embodiment, a daily dose of a compound described herein, or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg per kg body weight. In some embodiments, the daily dose or the amount of active in a dosage form is lower or higher than the ranges indicated herein, based on a number of variables with respect to an individual treatment regimen. In various embodiments, the daily dose and unit dose are varied depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0353] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD 10and ED 90 The dose ratio between toxic and therapeutic effect is the therapy index and it is expressed as the ratio between LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or a therapeutically effective unit dose to be used in human beings with minimal toxicity. In some embodiments, the daily dose of a compound described herein is within a range that includes a circulating concentration of ED 50 that has minimal toxicity. In certain embodiments, the daily dose range and / or unit dose is varied within this range depending on the dosage form employed and the route of administration utilized.

[0354] In any of the above-mentioned aspects are further embodiments wherein the effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to the mammal; and / or (b) administered orally to the mammal; and / or (c) administered intravenously to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[0355] In any of the above-mentioned aspects are further embodiments comprising a single administration of an effective amount of a compound, including further embodiments wherein (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of a day.

[0356] In any of the above-mentioned aspects are further embodiments comprising multiple administrations of an effective amount of a compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: such as in single doses; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In other or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily stopped, or the dose of the compound administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0357] Routes of administration

[0358] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal, and topical administration. Further, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injections as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0359] In certain embodiments, compounds as described herein are administered in a local rather than systemic manner, for example, via injection directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposome targets the organ and is selectively taken up by the organ. In other embodiments, compounds as described herein are provided in a rapid release formulation, in a prolonged release formulation, or in an intermediate release formulation. In other embodiments, the compounds described herein are administered topically.

[0360] Pharmaceutical Compositions / Formulations

[0361] The compounds described herein are administered in a pharmaceutical composition singly or in combination with pharmaceutically acceptable carriers, excipients or diluents, in accordance with standard pharmaceutical practice. In one embodiment, the compounds of the present application can be administered to an animal. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration. In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients, to provide a formulation suitable for administration to humans or animals. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0362] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0363] The pharmaceutical compositions described herein are administered to a subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. The pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0364] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture, if necessary, to obtain a

[0365] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0366] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders comprising the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium which includes, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and combinations of any of them. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

[0367] Combinations

[0368] Disclosed herein are methods of treating liver disease, metabolic disease, or cardiovascular disease using a combination of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an additional therapeutic agent.

[0369] In some embodiments, the additional therapeutic agent is used to treat diabetes or a diabetes-related disorder or condition.

[0370] In some cases, the additional therapeutic agent comprises a statin, an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a GIP agonist, a THR beta agonist, a PDE inhibitor, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, or dutoglpitin), a catecholamine (such as epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist (e.g., a thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar, farglitazar, muraglitazar, or tesaglitazar), a peroxisome proliferator-activated receptor (PPAR)-alpha agonist, a peroxisome proliferator-activated receptor (PPAR)-delta agonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), or a combination thereof. In some cases, the statin is an HMG-CoA reductase inhibitor. In other cases, the additional therapeutic agent comprises a fish oil, a fibrate, a vitamin such as niacin, retinoic acid (e.g., 9 cis-retinoic acid), nicotinamide riboside, or an analog thereof, or a combination thereof. In other cases, the additional therapeutic agent comprises an ACC inhibitor, an FGF19 and FGF21 mimetic, a CCR2 / CCR5 antagonist, or a combination thereof.

[0371] In some embodiments, the additional therapeutic agent is vivitrol.

[0372] In some embodiments, the additional therapeutic agent is a statin such as an HMG-CoA reductase inhibitor, a fish oil, a fibrate, niacin, or a combination thereof. In other cases, the additional therapeutic agent is a lipids disorder drug that blocks lipid absorption such as orlistat.

[0373] In some embodiments, the additional therapeutic agent is a vitamin such as retinoic acid or tocopheryl acetate for treating diabetes and diabetes-related disorders or conditions, such as reducing increased body weight and / or reducing elevated blood glucose from food intake.

[0374] In some embodiments, the additional therapeutic agent is a glucose lowering agent. In some embodiments, the additional therapeutic agent is an anti-obesity agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of a peroxisome proliferator-activated receptor (PPAR) agonist (gamma, dual, or pan), a dipeptidyl peptidase iv) inhibitor, a glucagon-like peptide- 1 (GLP-I) analog, insulin or an insulin analog, an insulin secretagogue, a sodium glucose co-transporter 2 (SGLT2) inhibitor, glucophage, a human amylin analog, a biguanide, an alpha-glucosidase inhibitor, a meglitinide, a thiazolidinedione, and a sulfonylurea. In some embodiments, the additional therapeutic agent is metformin, sitagliptin, saxaglitpin, repaglinide, nateglinide, exenatide, liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, and glucagon-like peptide 1, or any combination thereof. In some embodiments, the additional therapeutic agent is a lipid lowering agent. In some embodiments, the additional therapeutic agent is an antioxidant, a corticosteroid such as budesonide, an anti-tumor necrosis factor (TNF) agent, or a combination thereof.

[0375] In some embodiments, the additional therapeutic agent is administered concurrently with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0376] Examples

[0377] Example 1 : Synthesis of N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5- dichloro-4-hydroxybenzamide

[0378]

[0379] Step 1 : Synthesis of 3-benzyl-5-bromoquinazolin-4(3H)-one

[0380] To a suspension of 5-bromo-2,4-dihydro-1H-3,1-benzoxazin-2,4-dione (5.00 g, 20.7 mmol) in orthoformic acid trimethyl ester (12.0 mL) was added benzylamine (2.66 g, 24.8 mmol) at ambient temperature and then heated to 100 °C for 12 h. After completion of the reaction, the reaction mixture was poured into ice cold water (70 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organics were washed with brine solution (70 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get a crude residue which was purified by flash column chromatography using 20% ethyl acetate in hexane as eluent to afford 3-benzyl-5-bromoquinazolin-4(3H)-one (4.50 g, 69%) as off-white solid. LCMS (ES) m / z: Calculated for C15H11BrN2O: 314.01 ; Found: 315.0 (M+H).

[0381] Step 2: Synthesis of tert-butyl (3-benzyl-4-oxo-3,4-dihydroquinazolin-5- yl)carbamate

[0382] To a stirred solution of 3-benzyl-5-bromo-3,4-dihydroquinazolin-4-one (4.70 g, 14.9 mmol) in 1,4-dioxane (30.0 mL) was added tert-butyl carbamate (2.62 g, 22.4 mmol) and cesium carbonate (9.72 g, 29.8 mmol), the mixture was degassed under nitrogen gas for 10 min. To this was added Xantphos (1.73 g, 2.98 mmol), Pd(dba)2(858 mg, 1.49 mmol) and then heated to 100 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was washed with brine solution (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get a crude residue which was purified by flash column chromatography to afford tert-butyl (3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)carbamate (5.00 g, 95.41%) as yellow solid. LCMS (ES) m / z: Calculated for C20H21N3O3: 351.16; Found: 352.2 (M+H).

[0383] Step 3: Synthesis of 5-amino-3-benzylquinazolin-4(3H)-one

[0384] To a stirred solution of tert-butyl N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5- yl)carbamate (5.24 g, 14.9 mmol) in 1,4-dioxane was added 4M HC1 in dioxane (5.18 mL, 149 mmol) at 0 °C. The resulting reaction mixture was heated to 80 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure vacuum to get crude solid which was triturated with diethyl ether (100 mL) to afford 5-amino-3-benzylquinazolin-4(3H)-one (3.50 g, 93% crude), as a yellow solid. LCMS (ES) m / z: Calcd. for C15H13N3O: 251.11; Found: 252.1 (M+H).

[0385] Step 4: Synthesis of N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5-dichloro-4- hydroxybenzamide

[0386] To a stirred solution of 5-amino-3-benzyl-3,4-dihydroquinazolin-4-one (0.2 g, 0.796 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (198 mg, 0.955 mmol) in chlorobenzene (4.00 mL) was added phosphorous trichloride (0.7 mL, 0.796 mmol) at 0 °C. The resulting reaction mixture was heated to 130 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) under stirring for 5 min. The obtained solid was collected by filtration. The solid was washed with acetonitrile (15 mL), diethyl ether (15 mL) and dried under vacuum to get crude. The crude material was purified by preparative HPLC to afford N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5-dichloro-4- hydroxybenzamide (0.025 g, 7%) as off white solid. LCMS (ES) m / z: Calcd. for C22H15Cl2N3O3: 439.05; Found: 440.1 (M+H); 1 HNMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 11.17 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H), 7.85 (m, 3H), 7.35 (m, 5H), 5.26 (s, 2H).

[0387] Example 2: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(2-(trifluoromethoxy)benzyl)- 3,4-dihydroquinazolin-5-yl)benzamide

[0388]

[0389] Step 1 : Synthesis of 5-nitro-3-(2-(trifluoromethoxy)benzyl)quinazolin-4(3H)-one

[0390] To a stirred solution of 1-[2-(trifluoromethoxy)phenyl]methanamine (3.00 g, 15.7 mmol) in ethanol (25.0 mL) was added 2-amino-6-nitrobenzoic acid (2.86 g, 15.7 mmol), trimethoxymethane (3.74 mL, 31.4 mmol) and iodine (0.2 g, 1.57 mmol) at ambient temperature. The resulting reaction mixture was heated to 80 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get a crude residue which was purified by flash chromatography to afford 5-nitro-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-4-one as a yellow solid (2.1 g, 37% yield). LCMS (ES) m / z: [M+H] calcd for C16H10F3N3O4: 365.06; found: 366.1.

[0391] Step 2: Synthesis of 5-amino-3-(2-(trifluoromethoxy)benzyl)quinazolin-4(3H)-one:

[0392] To a stirred solution of 5-nitro-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4- dihydroquinazolin-4-one (2.10 g, 5.75 mmol) in methanol:water: tetrahydrofuran (1 : 1 :4) (40.0 mL) was added ammonium acetate (4.43 g, 57.5 mmol) and zinc powder (3.76 g, 57.5 mmol) at ambient temperature and then stirred for 1 h. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure to get a crude residue which was purified by flash chromatography to afford 5-amino-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-4-one (1.29 g, 3.85 mmol) as off-white solid (1.29 g, 67% yield). LCMS (ES) m / z: [M+H] calcd for C16H12F3N3O2: 335.09; found: 336.1.

[0393] Step 3: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(2-(trifluoromethoxy)benzyl)- 3,4-dihydroquinazolin-5-yl)benzamide

[0394] To a stirred solution of 5-amino-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4- dihydroquinazolin-4-one (0.2 g, 597 pmol) in chlorobenzene (2.00 mL) was added 3,5- dichloro-4-hydroxybenzoic acid (0.12 g, 0.597 mmol) and phosphorous trichloride (0.7 mL, 0.796 mmol) at 0 °C. The resulting reaction mixture was heated to 130 °C for 6 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) under stirring for 5 min. The obtained solid was collected by filtration. The solid was washed with methanol (15 mL), pentane (15 mL) and dried under vacuum to provide 3,5-dichloro-4-hydroxy-N-(4-oxo-3-{[2- (trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-5-yl)benzamide as a brown solid (0.14 g, 45%). LCMS (ES) m / z: Calculated for C23Hi4Cl2F3N3O4: 523.03; found: 524.1 (M+H). 1 H NMR (400 MHz, DMSO d6) δ 12.85 (s, 1H), 11.14 (s, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.57 (s, 1H), 7.8 (t, J = 8.4 Hz, 3H), 7.49 - 7.37 (m, 5H), 5.35 (s, 2H).

[0395] Example 3: Synthesis of 3,5-dichloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4- dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0396]

[0397] Step 1: Synthesis of 3-(cyclopropylmethyl)-5-nitroquinazolin-4(3H)-one

[0398] In a sealed tube, to a stirred solution of 2-amino-6-nitrobenzoic acid (3.00 g, 16.5 mmol) and cyclopropylmethylamine (1.52 g, 21.4 mmol) in ethanol (15.0 mL) was added iodine (0.209 g, 1.65 mmol) and trimethyl orthoformate (3.64 mL, 32.9 mmol) and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mass was cooled to ambient temperature and the reaction mass was concentrated under vacuum. The crude was purified by flash chromatography column as eluent to provide 3-(cyclopropylmethyl)-5-nitroquinazolin-4(3H)-one (2.50 g, 62%) as a yellow gummy solid. LCMS (ES) m / z: Calculated for C12Hi1N3O3: 245.24; found: 246.1 (M+H).

[0399] Step 2: Synthesis of 5-amino-3-(cyclopropylmethyl)quinazolin-4(3H)-one.

[0400] To a stirred solution of 3-(cyclopropylmethyl)-5-nitroquinazolin-4(3H)-one (2.50 g, 10.2 mmol) in tetrahydrofuran: methanol: water (4: 1: 1) (25.0 mL) was added zinc dust (6.66 g, 102 mmol) and ammonium acetate (7.86 g, 102 mmol) at 0 °C and stirred slowly at room temperature for 1 h. After completion of the reaction, the reaction mass was filtered through a bed of celite and washed with 50% methanol in dichloromethane (100 mL), the resulting filtrate was concentrated under vacuum to get a crude residue. The residue was dissolved in 10% methanol in dichloromethane and washed with ice cold water (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to afford 5-amino-3-(cyclopropylmethyl)quinazolin-4(3H)-one (2.00 g, 91%) as off-white solid. LCMS (ES) m / z: Calculated for C12H13N3O: 215.26; found: 216.2 (M+H).

[0401] Step 3: Synthesis of 3,5-dichloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-5- yl)-4-hydroxybenzamide

[0402] To a stirred solution of 5-amino-3-(cyclopropylmethyl)quinazolin-4(3H)-one (0.150 g, 0.697 mmol) in chlorobenzene (5.0 mL) was added 3,5-dichloro-4-hydroxybenzoic acid (0.144 g, 0.697 mmol) and phosphorous trichloride (0.03 mL, 0.348 mmol) at 0 °C. The resulting reaction mixture was heated to 130 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) under stirring for 5 min. The obtained solid was collected by filtration. The crude solid was purified by preparative HPLC to afford 3,5-dichloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-4- hydroxybenzamide) (0.025 g, 8.87%) as a white solid. LCMS (ES) m / z: Calculated for C19H15Cl2N3O3: 403.25; found: 404.0 (M+1H). 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 11.16 (br, 1H), 8.73-8.71 (m, 1H), 8.50 (s, 1H), 7.94 (s, 2H), 7.85 (t, J = 8.4 Hz, 1H), 7.43-7.41 (m, 1H), 3.92 (d, J = 7.2 Hz, 2H), 1.37-1.31 (m, 1H), 0.57-0.45 (m, 4H).

[0403] Example 4: Synthesis of 3,5-dichloro-4-hydroxy-N-(3-((2-hydroxypyridin-4- yl)methyl)-4-oxo-3,4-dihydroquinazolin-5-yl)benzamide

[0404]

[0405] Step 1: Synthesis of 3-[(2-methoxypyridin-4-yl)methyl]-5-nitro-3,4-dihydroquinazolin- 4-one

[0406] To a stirred solution of 2-amino-6-nitrobenzoic acid (1.00 g, 5.49 mmol), 1-(2- methoxypyridin-4-yl)methanamine (0.766 mL, 5.49 mmol) and trimethoxymethane (12.0 mL, 110 mmol) in ethanol (10.0 mL) was added iodine (69.7 mg, 0.549 mmol) and heated to 80 °C for 4 h. After completion of the reaction, the reaction mass was cooled to ambient temperature and concentrated under vacuum to get crude product, which was diluted with ethyl acetate (100 mL) and stirred for 5 min, the solid was collected by filtration and dried under vacuum to provide 3-[(2-methoxypyridin-4-yl)methyl]-5-nitro-3,4- dihydroquinazolin-4-one (680 mg, 40%) as off-white solid. LCMS (ES) m / z: Calcd. for C15H12N4O4: 312.0; Found: 313.0 (M+1H).

[0407] Step 2: Synthesis of 5-amino-3-((2-methoxypyridin-4-yl)methyl)quinazolin-4(3H)-one

[0408] To a stirred solution of 3-[(2-methoxypyridin-4-yl)methyl]-5-nitro-3,4- dihydroquinazolin-4-one (680 mg, 2.18 mmol) in THF: water: MeOH (8:1:1) was added ammonium acetate (1.68 g, 21.8 mmol), zinc (1.42 g, 21.8 mmol) and then stirred at room temperature for 1 h. After completion of the reaction, the reaction mass was filtered through a pad of celite and washed with MeOH (10 mL), the filtrate was concentrated under vacuum to get a crude residue which was purified by flash column chromatography to afford 5-amino-3-[(2-methoxypyridin-4-yl)methyl]-3,4- dihydroquinazolin-4-one (600 mg, 98%) as off-white solid. LCMS (ES) m / z: Calcd. for C15H14N4O2: 282.1; Found: 283 (M+1H).

[0409] Step 3: Synthesis of 3,5-dichloro-4-hydroxy-N-(3-((2-hydroxypyridin-4- yl)methyl)-4-oxo-3,4-dihydroquinazolin-5-yl)benzamide

[0410] To a stirred solution of 5-amino-3-[(2-methoxypyridin-4-yl)methyl]-3,4- dihydroquinazolin-4-one (300 mg, 1.06 mmol) in acetonitrile (4.00 mL) was added 3,5-dichloro-4-hydroxybenzoic acid (220 mg, 1.06 mmol), phosphorous trichloride (0.726 mL, 0.744 mmol) and heated at 120 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature and quenched with ice cold water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated under vacuum to afford crude. The crude compound was purified by preparative HPLC to afford 3,5-dichloro-4-hydroxy-N-{3-[(2-hydroxypyridin-4-yl)methyl]-4-oxo-3,4- dihydroquinazolin-5-yl}benzamide (29.0 mg, 5.97%) as off-white solid. LCMS (ES) m / z: Calcd. for C21H14Cl2N4O4: 456.0; Found: 455.0 (M-1H). 1 H NMR (400 MHz, DMSO d6): δ 12.66 (s, 1H), 11.55 (br, 1H), 8.75 (d, J = 8 Hz, 1H), 8.50 (s, 1H), 7.79-7.86 (m, 3H), 7.34-7.40 (m, 2H), 7.09 (br, 1H), 6.10-6.16 (m, 2H), 5.11 (s, 2H).

[0411] The following compounds were synthesized as described in Example 2.

[0412]

[0413]

[0414]

[0415] Example 20: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(1- phenylcyclopropyl)-3,4-dihydroquinazolin-5-yl)benzamide

[0416]

[0417] Step 1 : Synthesis of 2-amino-6-nitro-N-(1-phenylcyclopropyl)benzamide

[0418] To a stirred solution of 2-amino-6-nitrobenzoic acid (0.5 g, 2.74 mmol) and 1- phenylcyclopropan-1-amine (658 mg, 3.02 mmol) in DMF (5 mL) was added HATU (2.09 g, 4.11 mmol) and DIPEA (0.956 mL, 8.22 mmol) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice cold water, the precipitated solid was filtered and washed with n-hexane and dried under vacuum to afford 2-amino-6-nitro-N-(1- phenylcyclopropyl)benzamide as beige solid (0.620 g, 69%) LCMS (ES) m / z: [M+H]+calcd for C16H15N3O3: 297.1 ; found: 298.1.

[0419] Step 2: Synthesis of 5-nitro-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one

[0420] In a sealed tube, a stirred solution of 2-amino-6-nitro-N-(1- phenylcyclopropyl)benzamide (0.62 g, 2.08 mmol) in chlorobenzene (13 mL) was added copper acetate (0.05 mg, 0.2 mmol), trimethyl orthoformate (2.28 mL, 20.8 mmol) and imidazole (0.42 g, 3.12 mmol). The resulting reaction mixture was stirred at 150 °C for 48 h. After completion of the reaction, the reaction mixture was evaporated in vacuum to obtain crude. The crude product was purified by flash chromatography by using 40% ethyl acetate in hexane as eluent to afford 5-nitro-3-(1- phenylcyclopropyl)quinazolin-4(3H)-one as beige solid (0.37 g, 58%). LCMS (ES) m / z: Calcd. for C17H13N3O3: 307.1; Found: 308.1 [M+H]+.

[0421] Step 3: Synthesis of 5-amino-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one

[0422] To a stirred solution of 5-nitro-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one (0.37 g, 1.2 mmol) in THF (5 mL), water (0.5 mL) and methanol (0.5 mL) was added Zn dust (172 mg, 3.6 mmol) and NH4Cl (270 mg, 6.01 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (15 mL) and extracted with ethyl acetate (25 x 2 mL). The organic phase was washed with brine solution (10 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to afford 5-amino-3-(1- phenylcyclopropyl)quinazolin-4(3H)-one as light yellow solid (0.301 g, crude). LC-MS m / z: Calcd. for C17H15N3O: 277.1; Found: 278.2 [M+H]+.

[0423] Step 4: 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(1-phenylcyclopropyl)-3,4- dihydroquinazolin-5-yl)benzamide

[0424] To a stirred solution of 5-amino-3-(l-phenylcyclopropyl)quinazolin-4(3H)-one (0.14 g, 0.505 mmol) in chlorobenzene was added 3,5-dichloro-4-hydroxybenzoic acid (0.092 g, 0.505 mmol) and phosphorous trichloride (0.06 mL, 0.75 mmol) at 0 °C. The resulting reaction mixture was heated to 130 °C for 3 h. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The organic phase was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to get the crude product. It was further purified by preparative HPLC, pure fractions were collected and lyophilized to afford 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(l-phenylcyclopropyl)-3,4-dihydroquinazolin-5-yl)benzamide as beige solid (10 mg, 4 %). LCMS (ES) m / z: Calcd. for C24H17Cl2N3O3, 465.06; found, 466.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 11.15 (s, 1H), 8.69-8.62 (m, 2H), 7.86-7.82 (m, 3H), 7.43-7.41 (d, J = 8 Hz, 1H), 7.32-6.92 (m, J = 8.4 Hz, 5H), 1.68-1.61 (m, 4H).

[0425] Example 21 : Synthesis of 3,5-dichloro-N-(3-(l-(2-fluorophenyl)cyclopropyl)-4-oxo-3,4- dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0426]

[0427] The title compound was synthesized as described in example 20. LCMS (ES) m / z: Calcd. for C24H16Cl2FN3O3, 483.06; found, 484.0 (M+H); 1 H NMR (400 MHz, DMSO-d6): δ 12.91 (s, 1H), 11.19 (br, 1H), 8.65-8.60 (m, 2H), 7.89 (s, 2H), 7.89-7.71 (m, 2H), 7.38-7.32 (m, 2H), 7.21-7.14 (m, 2H), 1.69-1.67 (m, 2H), 1.56-1.54 (m, 2H).

[0428] Example 22: 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}- 5-hydroxypyridine-2-carboxamide The title compound was synthesized as described in example 20. LCMS (ES) m / z: Calcd. for C24H16Cl2FN3O3, 483.06; found, 484.0 (M+H);

[0429]

[0430] Step 1: 2-Bromo-6-carboxy-3-methoxypyridine 1-oxide

[0431] To a stirred solution of 6-bromo-5-methoxypyridine-2-carboxylic acid (1.20 g, 5.17 mmol) in TFA (20 mL) was added hydrogen peroxide (20 mL, 50%) and stirred at 90 °C under nitrogen atmosphere for 36 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford 2-bromo-6-carboxy-3-methoxypyridine 1-oxide as off-white solid (1.2 g). LCMS (ES) m / z: Calculated for C7H6BrNO4: 246.95; Found: 248.0 (M+H).

[0432] Step 2: Methyl 4,6-dichloro-5-methoxypyridine-2-carboxylate

[0433] A mixture of 2-bromo-6-carboxy-3-methoxypyridine 1-oxide (0.8 g, 3.23 mmol) and sulphuric acid chloride (5 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. After completion of the reaction, excess sulphuric acid chloride was removed under vacuum to get a residue which was quenched with methanol under stirring for 1 h. Methanol was removed under reduced pressure to get a crude residue which was dissolved in 20% IPA in DCM (10 mL). The organic layer was washed with sodium bicarbonate solution (5 mL), brine solution, dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography using 15% ethyl acetate in hexane as eluent to afford methyl 4,6-dichloro-5-methoxypyridine-2-carboxylate as off-white solid (0.35 g). LCMS (ES) m / z: Calculated for C8H7Cl2NO3: 234.98; Found: 236.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 3.97 (s, 3H), 3.89 (s, 3H).

[0434] Step 3: 4,6-Dichloro-5-methoxypyridine-2-carboxylic acid

[0435] To a stirred solution of 4,6-dichloro-5-methoxypyridine-2-carboxylic acid methyl ester (0.3 g, 1.27 mmol) in THF: water (1 : 1) (6 mL) was added lithium hydroxide (0.152 g, 6.35 mmol) and then stirred at ambient temperature for 2 h. After completion of the reaction, the reaction mixture was evaporated under vacuum to get a residue which was diluted with water (10 mL) and acidified with IN HC1 (pH ~ 6). The obtained solid was filtered and washed with water, dried to provide 4,6-dichloro-5-methoxypyridine-2-carboxylic acid as off-white solid (0.25 g). LCMS (ES) m / z: Calculated for C7H5Cl2NO3: 220.96; Found: 222.0 (M+H).

[0436] Step 4: 4,6-Dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}- 5-methoxypyridine-2-carboxamide

[0437] To a stirred solution of 4,6-dichloro-5-methoxypyridine-2-carboxylic acid (0.05 g, 0.225 mmol), 5-amino-3-[(3-fluorophenyl)methyl]-3,4-dihydroquinazolin-4-one (0.06 g, 0.225 mmol) in chlorobenzene (1 mL) was added phosphorous trichloride (0.031 mg, 0.225 mmol) at ambient temperature and then heated to 130 °C for 3 h. After completion of the reaction, the reaction mixture was poured into ice cold water (10 mL) and extracted with 20% IPA in DCM (2 x 10 mL). The combined organic phase was washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated to get crude 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-methoxypyridine-2-carboxamide as off-white solid (0.07 g). LCMS (ES) m / z: Calculated for C22H15Cl2FN4O3: 472.05; Found: 473.0 (M+H).

[0438] Step 5: 4,6-Dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5- hydroxypyridine-2-carboxamide

[0439] To a stirred solution of 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4- dihydroquinazolin-5-yl}-5-methoxypyridine-2-carboxamide (0.06 g, 0.127 mmol) in 1- methylpyrrolidin-2-one (1.00 mL) was added p-toluenesulfonic acid (0.109 g, 0.634 mmol) and lithium chloride (26.9 mg, 0.634 mmol). The resulting reaction mixture was heated to 200 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with 20% IPA / DCM (10 mL). The organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to provide 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4- dihydroquinazolin-5-yl}-5-hydroxypyridine-2-carboxamide (13.2 mg) as off-white solid. LCMS (ES) m / z: Calculated for C21H13Cl2FN4O3: 458.03; Found: 459.1 (M+H),1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 8.60 (s, 1H), 8.11 (s, 1H), 7.87 (m, 1H), 7.45 (m, 2H), 7.31 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 7.17 (m, 1H), 5.26 (s, 2H).

[0440] Example 23: Synthesis of 4,6-dichloro-5-hydroxy-N-(4-oxo-3-{[2- (trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-5-yl)pyridine-2-carboxamide

[0441]

[0442] The title compound was synthesized as described in Example 22. LCMS (ES)- m / z: Calculated for C 22 H 13 Cl2F3N4O4: 524.03; Found: 525.0 (M+H), 99.84% at 254 nm.1H NMR (400 MHz, DMSO-d6) δ 13.5 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 7.88-7.84 (m, 1H), 7.49 (m, 3H), 7.37 (m, 2H), 5.33 (s, 2H).

[0443] Example 24: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2- fluorobenzyl)thiazole-5-carboxamide

[0444]

[0445] Step 1: Synthesis of methyl 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5- carboxylate

[0446] To a suspension of methyl 4-amino-1,3-thiazole-5-carboxylate (600 mg, 3.79 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (785 mg, 3.79 mmol) in acetonitrile (12.0 mL) was added phosphorous trichloride (332 μL, 3.79 mmol) drop wise under nitrogen atmosphere. The reaction mass was heated to 100 °C for 3 h. After completion of the reaction, the reaction mass was cooled to room temperature and ice cold water (20 mL) was added, filtered and dried under vacuum to afford methyl 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5-carboxylate (800 mg, 60%) as a yellow solid, LCMS (ES) m / z: Calculated for C12H8Cl2N2O4S: 345.96; found: 347 (M+H).

[0447] Step 2: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5-carboxylic acid

[0448] To a stirred solution of methyl 4-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-5- carboxylate (400 mg, 1.15 mmol) in THF:MeOH:H2O (6:2:2) was added lithium hydroxide (96.7 mg, 2.30 mmol). The reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the reaction mass was concentrated to get crude product. The crude was diluted with water (10 mL) and acidified to pH 2-3 with 1 M HCI (10 mL) and extracted with EtOAc (2 X 10 mL) and washed with water (2 X 15 mL) and brine solution, the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 4-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-5-carboxylic acid (300 mg, 0.901 mmol) as off white solid, LCMS (ES) m / z: Calculated for C11H6Cl2N2O4S: 333.94; found: 334.9 (M+H).

[0449] Step 3: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)thiazole-5- carboxamide

[0450] A stirred solution of 4-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-5- carboxylic acid (140 mg, 0.420 mmol) in sulfurous chloride (3.00 mL, 41.4 mmol) was heated to 95 °C for 2 h. The excess sulfurous chloride was distilled off under a Rota evaporator. The resulting residue was dissolved in DMF (1 mL) and a stirred solution of (2-fluorophenyl)methanamine (47.8 μL, 0.420 mmol), DMAP (103 mg, 0.840 mmol), DiPEA (0.734 mL, 4.20 mmol) in DMF (2 mL) was added and heated at 85 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature and quenched with water (10 mL) and extracted with ethyl acetate (10 mL X 2) and washed with brine (10 mL) and the organic layer was collected, dried over sodium sulfate and filtered and concentrated under vacuum to yield the crude product which was purified by reverse phase preparative HPLC. The pure fractions were collected and concentrated to afford pure 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2- fluorobenzyl)thiazole-5-carboxamide (30.0 mg, 16%) as off-white solid. LCMS (ES) m / z: Calcd. for C18H12Cl2FN3O3S: 439.0; Found: 440.0 (M+1). 1 H NMR (400 MHz, DMSO d6) δ: 11.02 (br, 1H), 10.94 (s, 1H), 9.12 (s, 1H), 8.71 (br, 1H), 7.93 (s, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.26-7.24 (m, 1H), 7.12-7.03 (m, 2H), 4.41 (d, J = 4.8 Hz, 2H).

[0451] The title compound was synthesized as described in Example 24.

[0452]

[0453]

[0454] Example 31: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2- fluorobenzyl)-3-methylisothiazole-4-carboxamide

[0455]

[0456] Step 1: Synthesis of 5-amino-N-(2-fluorobenzyl)-3-methylisothiazole-4- carboxamide

[0457] To a stirred solution of 5-amino-3-methyl-l,2-thiazole-4-carboxylic acid methyl ester (100 mg, 581 μmol) and l-(2-fluorophenyl)methanamine (80.0 μL, 697 μmol) in toluene (1.00 mL) cooled to 0 °C was added trimethylaluminium hydride (871 μL, 1.74 mmol) dropwise. The resulting reaction mixture was heated to 100 °C for 1 h. After completion of the reaction, the reaction mixture was quenched with cold water (5 mL) and extracted into EtOAc (5 mL x 2). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate and evaporated under reduced pressure to yield 5-amino-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide as a yellow solid (130 mg, 84%). The crude compound was taken to the next step without further purification. LCMS (ES) m / z: Calcd. for C12H12FN3OS: 265.31 ; Found: 266 (M+H) + .

[0458] Step 2: Synthesis of 5-(3,5-dichloro-4-methoxybenzamido)-N-(2- fluorobenzyl)-3-methylisothiazole-4-carboxamide

[0459] To a stirred solution of 3,5-dichloro-4-methoxybenzoic acid (200 mg, 905 μmol) in pyridine (2.50 mL) at 0 °C was added phosphoryl chloride (127 μL, 1.36 mmol) and stirred for 10 min. To this was added 5-amino-N-[(2-fluorophenyl)methyl]-3-methyl-l,2-thiazole-4- carboxamide (240 mg, 905 μmol) and then stirred at ambient temperature for 1 h. After completion of the reaction, the reaction mass was quenched with cold water (10 mL). The precipitated solid was filtered, washed with hexane (10 mL) and dried to afford 5-(3,5-dichloro-4-methoxybenzamido)-N-[(2-fluorophenyl)methyl]-3-methyl-l,2-thiazole-4-carboxamide (200 mg, 48%) as a brown solid which was taken to the next step without further purification. LCMS (ES) m / z: Calcd. for C20H16Cl2FN3O3S: 468.32; Found: 468 (M+H) + .

[0460] Step 3: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2- fluorobenzyl)-3-methylisothiazole-4-carboxamide

[0461] To a stirred solution of 5-(3,5-dichloro-4-methoxybenzamido)-N-[(2- fluorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (200 mg, 427 pmol) in DCM cooled to 0 °C, was added tri bromoborane (405 pL, 4.27 mmol) and stirred at ambient temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted into EtOAc (10 mL X 2). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate and evaporated under reduced pressure to yield crude compound which was purified by flash chromatography. The column purified compound was purified by reverse phase preparative HPLC to afford pure 5-(3,5-dichloro-4-hydroxybenzamido)-N-[(2- fluorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (40.0 mg, 20.62 %). LCMS (ES) m / z: Calcd. for C19H14CI2FN3O3S: 454.30; Found: 454 (M+H) + .1H NMR (400 MHz, DMSO d6) d 11.95 (br, 1H), 11.5 (br, 1H), 8.63 (br, 1H), 7.93 (s, 2H), 7.45 (t, J = 14.8 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.30 - 7.28 (m, 2H), 4.57 (d, J = 5.6 Hz, 2H), 2.48 (br, 3H).

[0462] Example 32: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2- (trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0463]

[0464] Step 1: Synthesis of 5-(3,5-dichloro-4-methoxybenzamido)methyl thiazole-4- carboxylate

[0465] To a stirred solution of 5-amino-l,3-thiazole-4-carboxylic acid methyl ester (0.15 g, 0.99 mmol) in dichloromethane (4.00 mL) was added N,N-dimethylpyridin-4-amine (152 mg, 1.24 mmol) and triethylamine (1.73 mL, 12.4 mmol) at ambient temperature and then stirred for 10 min. To this was added 3,5-dichloro-4-methoxybenzoyl chloride (298 mg, 1.24 mmol) in dichloromethane (4.00 mL) slowly at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for an additional 1 h. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with DCM (2 x 100 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate, filtered and dried under vacuum to provide the crude. The crude material was purified by flash column chromatography to provide 5-(3,5-dichloro-4-methoxybenzamido)thiazole-4-carboxylic acid methyl ester (150 mg, 33.37%) as off-white solid. LCMS (ES) m / z: Calcd. for C13H10Cl2N2O4S: 359.9; Found: 361.0 (M+H).

[0466] Step 2: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)thiazole-4-carboxylic acid

[0467] To a stirred suspension of 5-(3,5-dichloro-4-methoxybenzamido)-l,3-thiazole-4- carboxylic acid methyl ester (126 mg, 0.349 mmol) in dichloromethane (0.5 mL) was added tri bromoborane (0.596 mL, 3.49 mmol) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 12 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organics were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude 5-(3,5-dichloro-4-hydroxybenzamido)thiazole-4-carboxylic acid (93.0 mg, 80%, crude) as off-white solid. LCMS (ES) m / z: Calcd. for C11H6Cl2N2O4S: 333.91; Found: 335.0 (M+H).

[0468] Step 3: Synthesis of 5-(3,5-dichloro-4-hydroxyphenyl)-7H-thiazolo[5,4- d] [l,3]oxazin-7-one

[0469] To a stirred solution of 5-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-4- carboxylic acid (93.0 mg, 0.279 mmol) in 1,2 dichloroethane (5 mL) was added sulphurous chloride (0.202 mL, 2.79 mmol) and then heated to 70 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under vacuum to afford crude 5-(3,5-dichloro-4-hydroxyphenyl)-7H-thiazolo[5,4- d][1,3]oxazin-7-one (78.0 mg, 88.67% crude) as a brown solid. LCMS (ES) m / z: Calcd. for C11H4Cl2N2O3S: 313.93; Found: 312.9 (M-H).

[0470] Step 4: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2- (trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0471] To a stirred solution of 5-(3,5-dichloro-4-hydroxyphenyl)-7H-[1,3]thiazolo[5,4- d][1,3]oxazin-7-one (93.0 mg, 0.295 mmol) in N,N-dimethylformamide (4.00 mL) was added DiPEA (0.154 mL, 0.885 mmol) and 1-[2- (trifluoromethoxy)phenyl]methanamine (67.7 mg, 0.354 mmol) at ambient temperature. The resulting reaction mixture was heated to 90 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine solution (30 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude material was purified by flash column chromatography to afford 5-(3,5-dichloro-4- hydroxybenzamido)-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide (23.0 mg, 15.39%) as off white solid. LCMS (ES) m / z: Calcd. for C19H12Cl2F3N3O4S: 504.99; Found: 503.9 (M-H). HNMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.31 (s, 1H), 7.94 (s, 2H), 7.68 (br, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.37-7.25 (m, 3H), 6.30 (s, 1H), 4.77 (d, J = 6 Hz, 2H).

[0472] The following compounds were synthesized using the procedures described in Examples 1-4, 20-24 and 31-32.

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498] Example A: Estrone detection assay for assessing HSD17β13 activity and identifying inhibitors

[0499] Liquid chromatography / mass spectrometry (LC / MS) estrone detection assay to monitor conversion of estradiol to estrone by HSD17B13. This assay was performed in a 96-well plate format (Eppendorf deep well plate 96 / 500) in a 80 μΐ reaction volume containing: 4 μΜ estradiol (E2; Cayman; #10006315), 6 mM NAD + (Sigma; #N0623) and 30 nM HSD17B13 enzyme (in-house; E. coli expressed His-tagged purified soluble protein) in a reaction containing 1 M potassium phosphate buffer (pH 7.4) and 0.5% vehicle (DMSO). Reactions were incubated at 26.5 °C for 2 hours and conversion of estradiol (E2) to estrone (El) was quantified using LC-MS / MS based analyte detection for both E2 and El using LCMS grade reagents.

[0500] Reactions were terminated by the addition of two volumes of acetonitrile (MeCN; LCMS grade; CAS #75 / 05 / 8) containing deuterated (D4)-El (Clear Synth; #CS-T-54273; 500 ng / mL final concentration) used as an internal standard. Samples were applied to pre-prepared Bond Elut-C18 extraction cartridges (3 mL; Agilent; #12102028), washed and eluted in MeCN. Eluates were dried under nitrogen and re-suspended in 60% methanol (LCMS grade methanol; CAS #67 / 56 / 1) prior to submission for analysis. An aqueous solution linearity for E2 and El was included for quantification.

[0501] Analysis of samples was performed on an XBridge BEH C18 column (Waters; #186003033) using 0.1% diethylamine in MeCN (mobile phase A; DEA CAS #109-89-7) and 0.1% diethylamine in milli-Q water (mobile phase B) with a 3 min gradient allowing 25% B. MRM analysis was used with analytes detected in negative mode with E2 having an RT of 1.85 min and El having an RT of 2 min. Enzyme activity in the absence of NAD + < was used to assess the specificity of conversion. Enzyme activity in the presence of test samples was expressed as a percentage of uninhibited enzyme activity and plotted against inhibitor concentration. Non-linear regression was performed using a four parameter logistic model and GraphPad Prism software (GraphPad Software, La Jolla, CA). All evaluations were assessed in duplicate and pooled during the extraction process and then injected in duplicate for LC-MS / MS analysis.

[0502] The data is shown in Table 2 below:

[0503] Table 2:

[0504]

[0505]

[0506]

[0507]

[0508]

[0509] IC in the case of estradiol 50

[0510] A is less than or equal to 0.1 μM;

[0511] B is greater than 0.1 μM and less than or equal to 0.5 μM;

[0512] C is greater than 0.5 μM and less than or equal to 1.0 μM;

[0513] D is greater than 1.0 μM and less than or equal to 10 μM;

[0514] E is greater than 10 μM;

[0515] NT: Not tested.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: in: Ring B is Y is N or CR 1 ; Each Z is independently either N or CR. 1 ; Each R 1 It is hydrogen; L is -C(=O)NR 3 -; R 3 It is hydrogen; yes R 5a R 5b R 5c and R 5d It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl; R A yes: C4-C 10 Alkyl; or -(C(R 12 )2) p cycloalkyl, -(C(R) 12 )2) p Heterocyclic alkyl, -(C(R) 12 )2) p Phenyl or -(C(R) 12 )2) p Heteroaryl; wherein the cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl groups are optionally and independently influenced by one or more R Ab replace; Each R Ab Independently, it is deuterium, halogen, -CN, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl group is optionally and independently influenced by one or more R Aaa replace; Or two R atoms on the same atom Ab Together they form oxygen; Each R Aaa It is independently deuterium, halogen, or C1-C6 alkyl; Each R 12 It is independently hydrogen, deuterium, C1-C6 alkyl, or phenyl; Or two R on the same carbon 12 Together they form cycloalkyl groups; Or two R on adjacent carbons 12 Together they form cycloalkyl groups; p is 1 or 2; Each R a It is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, or C1-C6 hydroxyalkyl; and Each R c and R d It is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl; The cycloalkyl group refers to a fully saturated monocyclic carbon ring having three to eight carbon atoms; the heterocyclic alkyl group refers to a fully saturated 3 to 8-membered monocyclic cyclic group containing 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the nitrogen, carbon or sulfur atom in the heterocyclic alkyl group may optionally be oxidized; and the heteroaryl group refers to a 5 to 14-membered monocyclic or bicyclic cyclic system group containing one to thirteen carbon atoms, one to three heteroatoms selected from nitrogen, oxygen and sulfur and at least one aromatic ring.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is of formula (Ia):

3. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is N.

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is CR 1 .

5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is of formula (Ib):

6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is of formula (Ic):

7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: One Z is CR 1 And one Z is N.

8. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each Z is a CR 1 .

9. The compound of claim 6 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each Z is a CR 1 .

10. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is of formula (Id):

11. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 5a It is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; and And R 5b R 5c and R 5d It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Where R 5b It is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; And R 5a R 5c and R 5d It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Where R 5c It is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; And R 5a R 5b and R 5d It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

14. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Where R 5d It is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; And R 5a R 5b and R 5c It is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuteralkyl.

15. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R A It is -(C(R) 12 )2) p cycloalkyl, -(C(R) 12 )2) p Heterocyclic alkyl, -(C(R) 12 )2) p Phenyl or -(C(R) 12 )2) p Heteroaryl; wherein the cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl groups are optionally and independently influenced by one or more R Ab replace.

16. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R A It is -(C(R) 12 )2) p Phenyl or -(C(R) 12 )2) p Heteroaryl; wherein the phenyl and heteroaryl groups are optionally and independently influenced by one or more R Ab replace.

17. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R A It is -(C(R) 12 )2) p Phenyl; wherein the phenyl is optionally and independently reacted with one or more R Ab replace.

18. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each R 12 It is independently hydrogen, deuterium, or a C1-C6 alkyl group; or two Rs on the same carbon atom. 12 Together they form cycloalkyl groups.

19. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each R 12 It is hydrogen, or two Rs on the same carbon atom. 12 Together they form cycloalkyl groups.

20. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each R 12 It is hydrogen, or two R on adjacent carbon atoms. 12 Together they form cycloalkyl groups.

21. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each R 12 It is hydrogen.

22. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Two Rs on the same carbon 12 Together they form cycloalkyl groups.

23. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Two Rs on adjacent carbons 12 Together they form cycloalkyl groups.

24. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: p is 1.

25. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: p is 2.

26. Selected from the following compounds as described in claim 1, or pharmaceutically acceptable salts thereof: Or its pharmaceutically acceptable salts or stereoisomers.

27. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

28. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

29. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

30. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

31. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

32. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

33. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

34. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

35. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

36. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

37. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

38. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

39. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

40. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

41. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

42. The compound of claim 26, wherein it is Or its pharmaceutically acceptable salts or stereoisomers.

43. A pharmaceutical composition comprising the compound of any one of claims 1-42 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

44. Use of any compound of claims 1-42 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating liver disease, metabolic disease or cardiovascular disease in a subject of need, wherein the liver disease, metabolic disease or cardiovascular disease is related to HSD17B13.

45. The use as described in claim 44, wherein the disease is NAFLD.

46. ​​The use as described in claim 44, wherein the disease is NASH.

47. The use as described in claim 44, wherein the disease is drug-induced liver injury.

48. The use as described in claim 44, wherein the disease is alcoholic liver disease.

49. The use as described in claim 44, wherein the disease is cirrhosis.

50. The use as described in claim 44, wherein the disease is decompensated portal hypertension.

51. The use as claimed in claim 44, wherein the disease is cholestatic liver disease.

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