Dichlorophenol HSD17B13 inhibitors and uses thereof

Abstract

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

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 113,555, filed November 13, 2020, U.S. Provisional Application No. 63 / 113,557, filed November 13, 2020, U.S. Provisional Application No. 63 / 170,855, filed April 5, 2021, and U.S. Provisional Application No. 63 / 225,282, filed July 23, 2021, which are incorporated by reference in their entireties herein. [Background technology]

[0002] Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is considered to be the hepatic phenotype of metabolic syndrome and is characterized by the accumulation of triglycerides in the liver in patients without a history of excessive alcohol consumption. The majority of patients with NAFLD are obese or morbidly obese and have associated insulin resistance. The incidence of NAFLD / NASH is rapidly increasing worldwide in line with the increasing prevalence of obesity, and it is now the most common chronic liver disease.

[0003] NAFLD is classified into simple steatosis, where only hepatic steatosis is observed, and NASH, where hepatic steatosis is accompanied by intralobular inflammation and balloon-like degeneration of hepatocytes. The proportion of NAFLD patients with NASH is not yet clear, but is thought to be in the range of 20-40%. NASH is a progressive disease that may lead to cirrhosis and hepatocellular carcinoma. It has been reported that 20% of patients with NASH develop cirrhosis, and 30-40% of patients with NASH cirrhosis will experience liver-related death. In recent years, NASH has become the third most common indication for liver transplantation in the United States. Currently, the primary treatment for NAFLD / NASH is lifestyle modification through diet and exercise. However, obese patients with NAFLD often have difficulty maintaining lifestyle modifications, making pharmacological treatment essential.

[0004] 17β-hydroxysteroid dehydrogenases (HSD17B) constitute a large family of 15 members, some of which are involved in sex hormone metabolism. Some HSD17B enzymes also play important roles in cholesterol and fatty acid metabolism. Recent studies have demonstrated that the enzyme hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), whose biological function is unknown, is a novel liver-specific lipid droplet (LD)-associated protein in mice and humans. HSD17B13 is significantly upregulated in patients and mice with nonalcoholic fatty liver disease (NAFLD). Hepatic overexpression of HSD17B13 promotes hepatic lipid accumulation. HSD17B13 may also have potential as 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 of the Invention

[0005] Provided herein are methods, compounds and compositions that are useful for reducing the expression or activity of HSD17B13 in subjects that need disease treatment.Also provided herein are methods, compounds and compositions that include HSD17B13 specific inhibitors that can be useful for reducing the incidence of HSD17B13-related disease or pathology in subjects that need disease treatment.Such methods, compounds and compositions can be useful for treating, preventing, delaying or alleviating liver disease, metabolic disease or cardiovascular disease, for example.

[0006] Disclosed herein is a compound of formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring B is

[0008] [ka] and Y is N or CR 1 and Each Z is independently N or CR 1 and R 1 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; L is -O-, -C(=O)NR 3 -, -NR 3 C(=O)-, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 4 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is a 3-12 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R 5 are each 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; Alternatively, two R on the same atom 5 come together to form oxo, n is 0 to 6; R A teeth, (a) -C(=O)NR 10 R 11,or (b) one or more R Aa C4-C optionally substituted with 10 Alkyl, or (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 where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab and 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10a and R 10a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SRa , -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10b and Alternatively, two R on the same atom 10a come together to form oxo, R 10b are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 10b come together to form oxo, R Aa are each 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-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Aa come together to form oxo, R Ab are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Ab come together to form oxo, R Aaa are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, where the 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; Alternatively, two R on adjacent carbons 12 together 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; p is 1 to 4; R aare each independently 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and each 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; R bare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; R c and R dare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; Or, R c and R d together 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, with the proviso that the above compounds are

[0009] [ka]

[0010] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, provided that

[0011] Disclosed herein is a compound of formula (Ia)

[0012] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] Disclosed herein is a compound of formula (Ib)

[0014] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0015] Disclosed herein is a compound of formula (Ic):

[0016] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0017] Disclosed herein is a compound of formula (Id):

[0018] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0019] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0020] Also disclosed herein is a method of treating a disease in a subject in need of such treatment, comprising administering a pharma- tically effective amount of a compound disclosed herein, or a pharma- tically 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.

[0021] Incorporation by Reference 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 OF THE PREFERRED EMBODIMENTS

[0022] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout this specification and the claims that follow, the word "comprise" and variations thereof (such as "comprises" and "comprising") are intended to be interpreted in an open and inclusive sense, i.e., "including, but not limited." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0023] References throughout this specification to "some embodiments" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content dictates otherwise. It should also be noted that the term "or" is generally utilized in the sense of including "and / or" unless the content dictates otherwise.

[0024] As used herein, the following terms have the following meanings unless specified otherwise.

[0025] "Oxo" refers to =O.

[0026] "Carboxyl" refers to --COOH.

[0027] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" appears herein, it means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but when no numerical range is specified, this definition also encompasses the occurrence of the term "alkyl." In some embodiments, alkyl is any of the C1- 10In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specified herein, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0028] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration at the double bond and should be understood to include 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 a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" appears herein, it means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but when no numerical range is specified, the definition also encompasses the occurrence of the term "alkenyl". Unless otherwise specified in the specification, an alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0029] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" appears herein, it means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but when no numerical range is specified, this definition also encompasses the occurrence of the term "alkynyl". Unless otherwise specified in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0030] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0031] "Alkoxy" is R a is an alkyl radical as defined above; a Unless otherwise specified in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0032] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0033] "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 attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl or C3-C 15Cycloalkenyl, 3 to 10 carbon atoms (C3-C 10 Cycloalkyl or C3-C 10Cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, cycloalkyls are 3 to 10 membered cycloalkyl or 3 to 10 membered cycloalkenyl. In some embodiments, cycloalkyls are 3 to 6 membered cycloalkyl or 3 to 6 membered cycloalkenyl. In some embodiments, cycloalkyls are 5 to 6 membered cycloalkyl or 5 to 6 membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include 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]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0034] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0035] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0036] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0037] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0038] "Deuterated alkyl" refers to an alkyl radical, as defined above, substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, and CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0039] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, a heteroalkyl is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0040] "Heterocycloalkyl" refers to a partially or fully saturated 3-24 membered ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, and the like. These include, but are not limited to, lysinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. It is understood that the number of carbon atoms in a heterocycloalkyl, when referring to the number of carbon atoms in a heterocycloalkyl, is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specified herein, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0041] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (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 radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and phenyl. These include, but are not limited to, linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-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 otherwise specified in the specification, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0042] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples in which the aforementioned event or circumstance occurs and examples in which they do not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level anywhere between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those of skill in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any sterically impractical and / or synthetically impractical substitutions or substitution patterns (e.g., substituted alkyl is defined to include optionally substituted cycloalkyl groups, which may contain an infinite number of optionally substituted alkyl groups). Thus, any substituents described will generally be understood to have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0043] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose, or as part of a series, which is effective to produce the desired therapeutic effect.

[0044] "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention used to attempt to change the natural course of an individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition after the onset of a pathological event or after contact with a causative microorganism, and includes stabilization of disease (e.g., disease does not worsen) or mitigation of disease. In other embodiments, treatment also includes preventive treatment (e.g., administration of a composition described herein when an individual is suspected of having a liver disease, such as NAFLD).

[0045] "Synergism" or "synergizing" refers to the effect of a combination that is greater than the additive effect of each of the components at the same dose.

[0046] "HSD17B13" means hydroxysteroid 17-beta dehydrogenase 13 and refers to the nucleic acid of HSD17B13. For example, in some embodiments, HSD17B13 includes the DNA sequence encoding HSD17B13, the RNA sequence transcribed from the DNA encoding HSD17B13 (including genomic DNA including introns and exons). HSD17B13 may also refer to the amino acid sequence of HSD17B13 encoded by the DNA sequence and / or RNA sequence (which may include the secondary or tertiary structure of the protein molecule). This target may be referred to in either the upper or lower case.

[0047] compound Described herein is a compound of formula (I) or its pharma- ceutically acceptable salt, solvate or stereoisomer, which is useful for treating liver disease. In some embodiments, the liver disease is NAFLD.

[0048] Disclosed herein is a compound of formula (I):

[0049] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring B is

[0050] [ka] and Y is N or CR 1 and Each Z is independently N or CR 1 and R 1 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; L is -O-, -C(=O)NR 3 -, -NR 3 C(=O)-, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 4 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is a 3-12 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R 5 are each 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; Alternatively, two R on the same atom 5 come together to form oxo, n is 0 to 6; R A teeth, (a) -C(=O)NR 10 R 11 ,or (b) one or more R Aa C4-C optionally substituted with 10 Alkyl, or (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 where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab and 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); R 10a are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10b and Alternatively, two R on the same atom 10a come together to form oxo, R 10b are each 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 , -NRb 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; Alternatively, two R on the same atom 10b come together to form oxo, R Aa are each 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 , C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Aa come together to form oxo, R Ab are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Ab come together to form oxo, R Aaa are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, where the 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; Alternatively, two R on adjacent carbons 12 together 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; p is 1 to 4; R aare each independently 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and each 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; R bare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; R c and R dare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, and heteroaryl are each independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=Oi)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; Or, R c and R d together 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, with the proviso that the above compounds are

[0051] [ka]

[0052] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, provided that

[0053] Disclosed herein is a compound of formula (I):

[0054] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring B is

[0055] [ka] and Y is N or CR 1 and Each Z is independently N or CR 1 and R 1 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; L is -O-, -C(=O)NR 3 -, -NR 3 C(=O)-, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 4 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is a 3-12 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Alternatively, two R on the same atom 5 come together to form oxo, n is 0 to 6; R A teeth, (a) -C(=O)NR 10 R 11 ,or (b) one or more R Aa C4-C optionally substituted with 10 Alkyl, or (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 where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab and 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 10alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); R 10a are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10b and Alternatively, two R on the same atom 10a come together to form oxo, R 10b are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 10b come together to form oxo, R Aa are each 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-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Aa come together to form oxo, R Ab are each 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)2Ra , -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, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Ab come together to form oxo, R Aaa are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Alternatively, two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, where the 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; p is 1 to 4; R aare each independently 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and each 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; R bare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; R c and R dare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; Or, R c and R d together 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, with the proviso that the above compounds are

[0056] [ka]

[0057] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, provided that

[0058] Disclosed herein is a compound of formula (I):

[0059] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring B is

[0060] [ka] and Y is N or CR 1 and Each Z is independently N or CR 1 and R 1 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; L is -O-, -C(=O)NR 3 -, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 4 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is a 3-12 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R 5 are each 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; Alternatively, two R on the same atom 5 come together to form oxo, n is 0 to 6; R A teeth, (a) -C(=O)NR 10 R 11 ,or (b) one or more R Aa C4-C optionally substituted with 10 Alkyl, or (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 where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab and 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 10alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); R 10a are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10b and Alternatively, two R on the same atom 10a come together to form oxo, R 10b are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 10b come together to form oxo, R Aa are each 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-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Aa come together to form oxo, R Ab are each 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)2Ra , -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, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Ab come together to form oxo, R Aaa are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, where the 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; Alternatively, two R on adjacent carbons 12 together 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; p is 1 to 4; R aare each independently 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and each 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; R bare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; R c and R dare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; Or, R c and R d together 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, with the proviso that the above compounds are

[0061] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, provided that

[0062] Disclosed herein is a compound of formula (I):

[0063] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring B is

[0064] [ka] and Y is N or CR 1 and Each Z is independently N or CR 1 and R 1 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; L is -O-, -C(=O)NR 3 -, -C(=O)C(R 4 )2-, or -C(R 4 )2C(=O)-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 4 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is a 3-12 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B; R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -ORa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Alternatively, two R on the same atom 5 come together to form oxo, n is 0 to 6; R A teeth, (a) -C(=O)NR 10 R 11 ,or (b) one or more R Aa C4-C optionally substituted with 10 Alkyl, or (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 where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab and 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); R 10aare each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10b and Alternatively, two R on the same atom 10a come together to form oxo, R 10b are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c Rd , -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 10b come together to form oxo, R Aa are each 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)Ra , -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-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Aa come together to form oxo, R Ab are each 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-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, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa and Alternatively, two R on the same atom Ab come together to form oxo, R Aaa are each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Alternatively, two R on the same carbon 12 together form a cycloalkyl or heterocycloalkyl, where the 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; p is 1 to 4; R a are each independently 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and each 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; R b are each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; R c and R dare each 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), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each of the aryl, 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; Or, R c and R d together 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, with the proviso that the above compounds are

[0065] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, provided that

[0066] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is

[0067] [ka] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is

[0068] [ka] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is

[0069] [ka] isn't it.

[0070] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is

[0071] [ka] isn't it.

[0072] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound has the formula (Ia):

[0073] [ka] It is a compound of the formula:

[0074] In some embodiments of the compounds of Formula (I) or (Ia), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is N.

[0075] In some embodiments of the compounds of Formula (I) or (Ia), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is CR 1 It is.

[0076] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound has formula (Ib):

[0077] [ka] It is a compound of the formula:

[0078] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound has formula (Ic):

[0079] [ka] It is a compound of the formula:

[0080] In some embodiments of the compounds of Formula (I) or (Ic), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, one Z is CR 1 and the other Z is N.

[0081] In some embodiments of the compounds of Formula (I) or (Ic), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each Z is CR 1 It is.

[0082] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound has the formula (Id):

[0083] [ka] It is a compound of the formula:

[0084] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen, deuterium, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is hydrogen.

[0085] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is -O-, -C(=O)NR 3 -, -C(=O)C(R 4 )2-, or -C(R 4 In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharma- ceutically 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 compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is -O-. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is -NR 3C(=O)- or -C(=O)NR 3 In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, L is -C(=O)NR 3 -It is.

[0086] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen.

[0087] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-10 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, N, P, and B. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-10 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, or N. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 3-6 membered ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, or N. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is an 8-12 membered bicyclic ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, or N. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is an 8-10 membered bicyclic ring optionally containing 1-4 heteroatoms selected from the group consisting of O, S, or N. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl, or a 5-6 membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 5-membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a thiophene, thiazole, isothiazole, oxazole, isoxazole, phenyl, pyridine, or pyrimidine.In some embodiments of the compounds of formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is thiazole, isothiazole, oxazole, isoxazole, phenyl, pyridine, or pyrimidine. In some embodiments of the compounds of formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is thiophene, oxazole, isoxazole, phenyl, pyridine, or pyrimidine. In some embodiments of the compounds of formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is oxazole, isoxazole, phenyl, pyridine, or pyrimidine. In some embodiments of the compounds of formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is not thiophene. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not thiazole or isothiazole. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not thiazole. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not isothiazole. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thiophene. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is thiazole or isothiazole. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is oxazole or isoxazole. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl.In some embodiments of the compounds of Formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is pyridine.In some embodiments of the compounds of Formula (I), (Ia)-(Id), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, ring A is a dihydroquinazoline, isoindoline, or 2,3-dihydrobenzoxazepine.

[0088] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0089] [ka] teeth,

[0090] [ka] where n' is an integer from 0 to 4, and n" is an integer from 0 to 2.

[0091] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0092] [ka] teeth,

[0093] [ka] wherein n' is 0 to 4 and n" is 0 to 2. In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0094] [ka] teeth,

[0095] [ka] It is.

[0096] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0097] [ka] teeth,

[0098] [ka] where 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-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0099] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0100] [ka] teeth,

[0101] [ka] where R 5a , R 5b , and R 5d are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0102] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5a Deuterium, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5b , R 5c , 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.

[0103] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5a is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5b , R 5c , and R 5d are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0104] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5b Deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R5a , 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.

[0105] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5b is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5a , R 5c , and R 5d are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0106] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5c Deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; 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.

[0107] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5cis deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5a , R 5b , and R 5d are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0108] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5d Deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5a , R 5b , and R 5c are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0109] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5d is deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5a , R 5b , and R 5c are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0110] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5c Deuterium, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5d Deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5a and R 5b 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.

[0111] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, 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; R 5a and R 5b are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0112] In some embodiments of a compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0113] [ka] teeth,

[0114] [ka] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0115] [ka] teeth,

[0116] [ka] In some embodiments of the compound of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0117] [ka] teeth,

[0118] [ka] It is.

[0119] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 5 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently hydrogen, deuterium, halogen, or C1-C6 alkyl; or two R 5 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5are each independently hydrogen, halogen, or C1-C6 alkyl; or two R 5 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 5 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 5 come together to form oxo.

[0120] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 to 5. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 to 4. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 to 3. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 to 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0 or 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 3. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 4. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 5. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 6.

[0121] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0 to 3. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0 to 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0 or 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 0. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 3. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n' is 4.

[0122] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n" is 0 or 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n" is 0. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n" is 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n" is 2.

[0123] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A is -C(=O)NR 10 R 11 It is.

[0124] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 11 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 11 is hydrogen.

[0125] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is 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, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is one or more R 10a C1-C optionally substituted with 10 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10is C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl), where alkyl, aryl, and heteroaryl each are selected from one or more R 10a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10 is C1-C6 alkyl(aryl), where aryl is one or more R 10a is optionally replaced by

[0126] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10a are each 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R 10bIn some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, each alkyl being selected from one or more R 10b In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10a are each independently deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl, where each alkyl is selected from one or more R 10b In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10a are each independently deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 10a are each independently deuterium, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0127] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A is one or more R Aa C4-C optionally substituted with 10 It is an alkyl.

[0128] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each 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 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa or two R Aa In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , cycloalkyl, or heterocycloalkyl, where cycloalkyl and heterocycloalkyl each are selected from one or more R Aaa In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aa are each independently deuterium, halogen, -CN, -OH, -OR a , or -NR c R d It is.

[0129] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p Cycloalkyl, -(C(R12 )2) p Heterocycloalkyl, -(C(R 12 )2) p Aryl, or -(C(R 12 )2) p and heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ab In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p Aryl or -(C(R 12 )2) p heteroaryl, where the aryl and heteroaryl are each independently selected from one or more R Ab In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R A is -(C(R 12 )2) p aryl, where aryl is one or more R Ab and optionally independently substituted by:

[0130] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 12 are each independently hydrogen, deuterium, halogen, or C1-C6 alkyl; or two R 12 and R are taken together to form a cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 12 are each hydrogen, or two R 12In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 12 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, two R 12 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, two R on adjacent carbons are 12 taken together form a cycloalkyl.

[0131] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Ab are each independently 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each selected from one or more R Aaa or two R Ab In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Ab are each independently 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, where alkyl, cycloalkyl, and heterocycloalkyl are each selected from one or more R Aaa In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Ab are each independently deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl, where each alkyl is selected from one or more R Aaa and optionally independently substituted by:

[0132] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aaa are each independently 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R Aaa are each independently deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0133] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 to 3. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 3.

[0134] In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently represent one or more of oxo, deuterium, halogen, -CN, -OH, In some embodiments of the compounds disclosed herein, R is optionally substituted with -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, C1-C6 heteroalkyl. aare each independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each 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, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0135] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more of oxo, deuterium, halogen, -CN, -O In some embodiments of the compounds disclosed herein, R is optionally substituted with H, -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, C1-C6 heteroalkyl. b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each 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, and C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Rb are each independently hydrogen or C1-C6 alkyl.

[0136] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more of oxo, deuterium, halogen, -CN, -O In some embodiments of the compounds disclosed herein, R is optionally substituted with H, -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, C1-C6 heteroalkyl. c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each 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, and C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl.

[0137] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0138] In some embodiments of the compounds disclosed herein, R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, each independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, R A , R Aa , R Ab , R 10 , R 10a , R 11 , Ra , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, each independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, each independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, R A , R Aa , R Ab , R 10 , R 10a , R 11 , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, each of which is independently substituted with one substituent as defined herein.

[0139] Any combination of the above groups in various variations is contemplated herein.Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0140] Described herein are compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, selected from the compounds in Table 1.

[0141] [Table 1-1]

[0142]

Table 1-2

[0143]

Table 1-3

[0144]

Table 1-4

[0145]

Table 1-5

[0146]

Table 1-6

[0147]

Table 1-7

[0148]

Table 1-8

[0149]

Table 1-9

[0150]

Table 1-10

[0151]

Table 1-11

[0152]

Table 1-12

[0153]

Table 1-13

[0154]

Table 1-14

[0155]

Table 1-15

[0156]

Table 1-16

[0157]

Table 1-17

[0158]

Table 1-18

[0159]

Table 1-19

[0160]

Table 1-20

[0161]

Table 1-21

[0162] [Table 1-22]

[0163] [Table 1-23]

[0164] [Table 1-24]

[0165] [Table 1-25]

[0166] [Table 1-26]

[0167] [Table 1-27]

[0168] [Table 1-28]

[0169] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as all of their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, with each center being in the R or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms, as well as all of their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers of the compound 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, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based upon solubility differences. In some embodiments, the optically pure enantiomers are recovered along with the resolving agent by any practical means that does not result in racemization.

[0170] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally 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 chloride, respectively. 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, etc. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, as well as pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of the present invention. Certain isotopically labeled compounds, e.g. 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because they are easy to prepare and detect. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes such as H may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements.

[0171] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0172] In some embodiments, the labeled compounds described herein are used to measure the in vitro and in vivo binding of unlabeled HSD17B13 inhibitors.

[0173] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0174] In some embodiments, the compounds described herein contain acidic or basic groups and can be reacted with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0175] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, bromide, etc. Hydrogen salts include hydroiodide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, 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.

[0176] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, phenylalanine ... Examples of suitable acids include, but are not limited to, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucopeptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, are not themselves pharma- ceutically acceptable, but are utilized in the preparation of salts useful as intermediates in obtaining the compounds of the present disclosure, their solvates, or stereoisomers, and pharma-ceutically acceptable acid addition salts.

[0177] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, or the like, of a pharma- ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4.

[0178] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups contained therein. In some embodiments water- or oil-soluble or dispersible products are obtained by such quaternization.

[0179] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method of treating a disease by administering such a solvate. The present invention further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0180] Solvates include stoichiometric or non-stoichiometric amounts of a solvent, and in some embodiments are formed during the crystallization process using a pharma- ceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. 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 an aqueous / organic solvent mixture, using organic solvents, including but not limited to dioxane, tetrahydrofuran, and methanol. In addition, the compounds provided herein can exist in solvated as well as unsolvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0181] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and adjacent double bonds. In bond configurations where tautomerization can occur, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0182] Treatment Provided herein are methods for inhibiting expression or activity of HSD17B13, which may be useful for treating, preventing or alleviating a disease associated with HSD17B13, such as NAFLD or NASH, in a subject in need thereof, by administration of a compound that targets HSD17B13, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0183] Provided herein is a method of inhibiting expression or activity of HSD17B13 in a cell, comprising contacting the cell with an HSD17B13 inhibitor of the present disclosure, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, thereby inhibiting 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 for a disease, disorder, condition, 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 of a subject having or at risk for a disease. In some embodiments, the cell is a lymphocyte of a subject having or at risk for 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, fatty liver, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, nonalcoholic steatohepatitis (NASH), fulminant Wilson's disease, hepatitis C virus injury that rapidly forms fibrotic tissue, 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.

[0184] In some embodiments, the liver disease is primary biliary cirrhosis or primary sclerosing cholangitis.

[0185] Provided herein is a method of treating, preventing, delaying the onset, slowing the progression, or alleviating one or more diseases, disorders, illnesses, symptoms, or physiological markers associated with HSD17B13, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. In some embodiments, the subject in need thereof is identified as having or at risk of having the disease, disorder, illness, symptom, or physiological marker. 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, fatty liver, 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.

[0186] Provided herein is a method for reducing, improving, or modulating fatty liver, liver fibrosis, triglyceride synthesis, lipid levels, liver lipids, ALT levels, NAFLD activity score (NAS), cholesterol levels, or triglyceride levels, or a combination thereof, comprising administering to a 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, improving, or modulating fatty liver 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, improving, 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, improving, or modulating triglyceride synthesis in an individual. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are provided for use in lowering, improving, or modulating lipid levels in an individual. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are provided for use in lowering, improving, or modulating liver lipids in an individual. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are provided for use in lowering, improving, or modulating ALT levels in an individual. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are provided for use in lowering, improving, or modulating NAFLD activity scores in an individual. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are provided for use in lowering, improving, or modulating cholesterol levels in an individual.In some embodiments, the compounds disclosed herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers, are provided for use in lowering, improving, or regulating triglyceride levels in an individual. In some embodiments, the subject is identified as having or at risk for a disease, disorder, illness, condition, or physiological marker associated with liver disease, metabolic disease, or 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, fatty liver, 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.

[0187] Provided herein is a method of treating, preventing, or delaying the onset of drug-induced liver injury (DILI) in a subject. In some embodiments, the liver injury is steatohepatitis. Also provided herein is a method of treating, preventing, or delaying the onset of drug-induced steatohepatitis (DISH) in a subject. In some embodiments, the subject is receiving chemotherapy to treat cancer. In some embodiments, the subject is receiving treatment for cardiovascular disease. In some embodiments, the subject is receiving treatment for a psychiatric disease / disorder. In some embodiments, the subject is receiving treatment for pain. In some embodiments, the subject is receiving 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 is receiving amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the subject is receiving amitriptyline, clozapine, or any combination thereof. In some embodiments, the subject is receiving methotrexate, pirprofen, or any combination thereof.

[0188] dosage In certain embodiments, compositions containing a compound(s) described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of 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 treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation studies and / or dose ranging clinical trials.

[0189] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this application, the exact amount also depends on the patient's health, weight, and the like. When used in a patient, the amount effective for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein, or a pharma- ceutically acceptable salt thereof, to a mammal that has experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent recurrence of the disease or condition. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein, or a pharma- ceutically acceptable salt thereof, to a mammal that has a patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism, to prevent liver damage. The 148 Isoleucine to Methionine protein variant (I148M) of Patatin-Like Phospholipase Domain-Containing 3 (PNPLA3), a protein expressed in the liver and involved in lipid metabolism, has been identified in recent years as a major determinant of liver fat content. Some studies have found that the I148M variant predisposes to the full spectrum of liver injury associated with fatty liver, from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of the progression of alcoholic steatohepatitis to cirrhosis, and influences fibrosis development and associated clinical outcomes in chronic hepatitis C virus hepatitis, possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis, and primary sclerosing cholangitis. In some embodiments, PNPLA3 polymorphisms are used to predict liver disease progression.

[0190] In certain embodiments in which the patient's disease is not ameliorated, administration of the compound is, at the physician's discretion, administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate or otherwise inhibit or limit the patient's disease or symptoms of the disease.

[0191] In certain embodiments where the patient's condition improves, the dose of the drug being administered is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In certain 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, or 28 days or more. The dose 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%.

[0192] Once the patient's condition has improved, a maintenance dose is administered as needed. In certain embodiments, the dosage or frequency of administration, or both, is then reduced, depending on the symptoms, to a degree that improvement in the disease, disorder, or condition is maintained. In some embodiments, however, patients require intermittent or daily treatment for an extended period of time following the recurrence of symptoms.

[0193] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the state and severity of the disease, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0194] Generally, however, the dosage used for adult treatment typically ranges from 0.01 mg to 5000 mg per day. In one aspect, the dosage utilized for adult treatment is from about 1 mg / day to about 1000 mg / day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0195] In one embodiment, a suitable daily dosage for the compounds described herein or pharma- ceutically acceptable salts thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or amount of active ingredient in the dosage form will be lower or higher than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the individual requirements of the subject, the severity of the disease or condition being treated, and the physician's judgment.

[0196] The toxicity and efficacy of these treatment regimens are 10 and ED 90 The therapeutic index is the dose ratio between toxic and therapeutic effects and is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD 50 and ED 50 In some embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is administered at an ED that is minimally toxic. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0197] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal.

[0198] In any of the foregoing aspects, there are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal over the course of a day.

[0199] In any of the above aspects, further embodiments are provided that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered as a single dose continuously or intermittently, (ii) the multiple doses are spaced apart by 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, and (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and 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.

[0200] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, transdermal, vaginal, auricular, nasal, and topical.In addition, parenteral delivery includes, but is not limited to, intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0201] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, via direct injection of the compound into an organ, often in a depot or sustained release formulation. In some embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In yet other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes are targeted to and selectively absorbed by the organ. In yet other embodiments, the compounds described herein are provided in the form of a rapid release formulation, a sustained release formulation, or an intermediate release formulation. In yet other embodiments, the compounds described herein are administered locally.

[0202] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition according to standard pharmaceutical practice.In one embodiment, the compounds of the present invention may be administered to animals.The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0203] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharma- ceutically acceptable excipient. Pharmaceutical compositions are conventionally formulated with one or more pharma- ceutically acceptable inactive ingredients that facilitate processing of the active compound into a pharma- ceutical usable preparation. The appropriate formulation depends on the route of administration selected. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and PR. Actice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, MaR. c el Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0204] In some embodiments, the pharma- ceutically acceptable excipient is selected from a carrier, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrant, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a wetting agent, a plasticizer, a stabilizer, a permeation enhancer, a humectant, an anti-foaming agent, an antioxidant, a preservative, and any combination thereof.

[0205] The pharmaceutical compositions described herein may be administered to a subject by a number of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0206] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0207] Oral pharmaceutical compositions can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granulated mixture after adding suitable auxiliaries as necessary to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate are added. In some embodiments, dyes or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0208] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules contain the active ingredients mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

[0209] Pharmaceutical compositions for parenteral use are formulated as infusion or injection. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the compounds described herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers. In some embodiments, pharmaceutical compositions include liquid carriers. In some embodiments, liquid carriers are solvents or liquid dispersion media, including, for example, water, saline, ethanol, polyols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, pharmaceutical compositions further include a preservative to prevent the growth of microorganisms.

[0210] combination Disclosed herein are methods of treating hepatic, metabolic, or cardiovascular diseases using the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0211] In some embodiments, the additional therapeutic agent is used to treat diabetes or a diabetes-related disease or condition.

[0212] In some examples, the additional therapeutic agent is a statin, an insulin sensitizer, 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, anagliptin, teneligliptin, alogliptin, gemigliptin, or dutogliptin), a catecholamine (such as epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor agonist (such as vasodilator, vasodilator, or vasodilator), or a vasodilator. The additional therapeutic agent may be a 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 examples, the additional therapeutic agent may be a fish oil, a fibrate, a vitamin such as niacin, a retinoic acid (e.g., 9-cis-retinoic acid), a nicotinamide ribonucleoside, or an analog thereof, or a combination thereof. In other examples, the additional therapeutic agents include ACC inhibitors, FGF19 and FGF21 mimetics, CCR2 / CCR5 antagonists, or combinations thereof.

[0213] In some embodiments, the additional therapeutic agent is vivitrol.

[0214] In some embodiments, the additional therapeutic agent is an HMG-CoA reductase inhibitor, fish oil, a fibrate, a statin such as niacin, or a combination thereof. In other examples, the additional therapeutic agent is a lipid-lowering agent that prevents lipid absorption, such as orlistat.

[0215] In some embodiments, the additional therapeutic agent is a vitamin, such as retinoic acid or tocopherol acetate, for the treatment of diabetes and diabetes-related disorders or diseases, such as reducing weight gain and / or blood glucose elevation due to food intake.

[0216] 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 among peroxisome proliferator-activated receptor (PPAR) agonists (gamma, dual, or pan), dipeptidyl peptidase (IV) inhibitors, glucagon-like peptide-1 (GLP-I) analogs, insulin or insulin analogs, insulin secretagogues, sodium glucose cotransporter 2 (SGLT2) inhibitors, glucophage, human amylin analogs, biguanides, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, and sulfonylureas. In some embodiments, the additional therapeutic agent is metformin, sitagliptin, saxagliptin, 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.

[0217] In some embodiments, the additional therapeutic agent is an antioxidant, a corticosteroid such as budesonide, an anti-tumor necrosis factor (TNF), or a combination thereof.

[0218] In some embodiments, the additional therapeutic agent is administered simultaneously 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. EXAMPLES

[0219] Example 1: Synthesis of N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5-dichloro-4-hydroxybenzamide

[0220] [ka] Step 1: Synthesis of 3-benzyl-5-bromoquinazolin-4(3H)-one To a suspension of 5-bromo-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (5.00 g, 20.7 mmol) in trimethyl orthoformate (12.0 mL) was added benzylamine (2.66 g, 24.8 mmol) at ambient temperature and then heated to 60° C. for 12 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water (70 mL) and extracted with ethyl acetate (2×250 mL). The combined organics were washed with brine solution (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude residue. The crude residue was purified by flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give 3-benzyl-5-bromoquinazolin-4(3H)-one (4.50 g, 69%) as an off-white solid. LCMS(ES)m / z calcd.For C15H11BrN2O, 314.01; found, 315.0 (M+H).

[0221] Step 2: Synthesis of tert-butyl (3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)carbamate 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) and the mixture was degassed under nitrogen atmosphere for 10 minutes. 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 hours. 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 give the crude residue. The crude residue was purified by flash column chromatography to give tert-butyl (3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)carbamate (5.00 g, 95.41%) as a yellow solid. LCMS (ES) m / z calcd. For C20H21N3O3, 351.16; found, 352.2 (M+H).

[0222] Step 3: Synthesis of 5-amino-3-benzylquinazolin-4(3H)-one To a suspension 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 HCl 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 to give a crude residue. The crude residue was triturated with diethyl ether (100 ml) to give 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).

[0223] Step 4: Synthesis of N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5-dichloro-4-hydroxybenzamide 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 phosphorus 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 by stirring with ice-cold water (30 mL) for 5 min. The resulting solid was collected by filtration. The solid was washed with acetonitrile (15 mL), diethyl ether (15 mL) and dried under vacuum to obtain the crude product. The crude material was purified by preparative HPLC to give N-(3-benzyl-4-oxo-3,4-dihydroquinazolin-5-yl)-3,5-dichloro-4-hydroxybenzamide (0.025 g, 7%) as an off-white solid. LCMS (ES) m / z calcd. For C22H15Cl2N3O3, 439.05; found, 440.1 (M+H); 1 H NMR (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).

[0224] Example 2: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(2-(trifluoromethoxy)benzyl)-3,4-dihydroquinazolin-5-yl)benzamide

[0225] [ka] Step 1: Synthesis of 5-nitro-3-(2-(trifluoromethoxy)benzyl)quinazolin-4(3H)-one 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 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude residue. The crude residue was purified by flash chromatography to give 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 calcd.C16H10F3N3O4, 365.06; found, 366.1(M+H).

[0226] Step 2: Synthesis of 5-amino-3-(2-(trifluoromethoxy)benzyl)quinazolin-4(3H)-one 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 hour. 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 give a crude residue. The crude residue was purified by flash chromatography to give 5-amino-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-4-one (1.29 g, 3.85 mmol) as an off-white solid (1.29 g, 67% yield). LCMS (ES) m / z calcd. C16H12F3N3O2, 335.09; found, 336.1 (M+H).

[0227] Step 3: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(2-(trifluoromethoxy)benzyl)-3,4-dihydroquinazolin-5-yl)benzamide To a stirred solution of 5-amino-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-4-one (0.2 g, 597 μmol) in chlorobenzene (2.00 mL) was added 3,5-dichloro-4-hydroxybenzoic acid (0.12 g, 0.597 mmol) and phosphorus trichloride (0.7 mL, 0.796 mmol) at 0° C. The resulting reaction mixture was heated to 130° C. for 6 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) by stirring for 5 minutes. The resulting solid was collected by filtration. The solid was washed with methanol (15 mL), pentane (15 mL) and dried under vacuum to give 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 calcd. C23H14Cl2F3N3O4, 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).

[0228] Example 3: Synthesis of 3,5-dichloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0229] [ka] Step 1: Synthesis of 3-(cyclopropylmethyl)-5-nitroquinazolin-4(3H)-one To a stirred solution of 2-amino-6-nitrobenzoic acid (3.00 g, 16.5 mmol) and cyclopropylmethanamine (1.52 g, 21.4 mmol) in ethanol (15.0 mL) in a sealed tube, iodine (0.209 g, 1.65 mmol) and trimethyl orthoformate (3.64 mL, 32.9 mmol) were added 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 column chromatography as the eluent to give 3-(cyclopropylmethyl)-5-nitroquinazolin-4(3H)-one (2.50 g, 62%) as a yellow gummy solid. LCMS (ES) m / z calculated. for C12H11N3O3, 245.24; found 246.1 (M+H).

[0230] Step 2: Synthesis of 5-amino-3-(cyclopropylmethyl)quinazolin-4(3H)-one. 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) in a sealed tube, zinc dust (6.66 g, 102 mmol) and ammonium acetate (7.86 g, 102 mmol) were added at 0° C. and stirred slowly at room temperature for 1 h. After completion of the reaction, the reaction mass was filtered through a celite bed, washed with 50% methanol in dichloromethane (100 mL) and the filtrate obtained was concentrated under vacuum to obtain a crude residue. This residue was dissolved in 10% methanol in dichloromethane, washed with ice-cold water (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to obtain 5-amino-3-(cyclopropylmethyl)quinazolin-4(3H)-one (2.00 g, 91%) as an off-white solid. LCMS (ES) m / z calculated for C12H13N3O, 215.26; found 216.2 (M+H).

[0231] Step 3: Synthesis of 3,5-dichloro-N-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide 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 phosphorus 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) by stirring for 5 min. The resulting solid was collected by filtration. The crude solid was purified by preparative HPLC to give 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 calcd. for C19H15Cl2N3O3, 403.25; found 404.0 (M+1H). 1 H-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).

[0232] Example 4: Synthesis of 3,5-dichloro-4-hydroxy-N-(3-((2-hydroxypyridin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-5-yl)benzamide

[0233] [ka] Step 1: Synthesis of 3-[(2-methoxypyridin-4-yl)methyl]-5-nitro-3,4-dihydroquinazolin-4-one 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 hours. After completion of the reaction, the reaction mass was cooled to ambient temperature and concentrated under vacuum to obtain the crude product, which was diluted with ethyl acetate (100 mL), stirred for 5 minutes, the solid was collected by filtration and dried under vacuum to obtain 3-[(2-methoxypyridin-4-yl)methyl]-5-nitro-3,4-dihydroquinazolin-4-one (680 mg, 40%) as an off-white solid. LCMS (ES) m / z calcd. for C15H12N4O4, 312.0; found 313.0 (M+1H).

[0234] Step 2: Synthesis of 5-amino-3-((2-methoxypyridin-4-yl)methyl)quinazolin-4(3H)-one 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 celite bed, washed with MeOH (10 mL) and the filtrate was concentrated under vacuum to give the crude residue. The crude residue was purified by flash column chromatography to give 5-amino-3-[(2-methoxypyridin-4-yl)methyl]-3,4-dihydroquinazolin-4-one (600 mg, 98%) as an off-white solid. LCMS (ES) m / z calcd. for C15H14N4O2, 282.1; found 283 (M+1H).

[0235] Step 3: Synthesis of 3,5-dichloro-4-hydroxy-N-(3-((2-hydroxypyridin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-5-yl)benzamide 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), phosphorus 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, quenched with ice-cold water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by preparative HPLC to give 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 an off-white solid. LCMS (ES) m / z calcd. 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, 1 H), 8.50 (s, 1H), 7.79-7.86 (m, 3H), 7.34-7.40 (m, 2 H), 7.09 (br, 1H), 6.10-6.16 (m, 2H), 5.11 (s, 2H).

[0236] The following compounds were synthesized as described in Example 2:

[0237] [Table 2-1]

[0238] [Table 2-2]

[0239] Example 20: Synthesis of 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(1-phenylcyclopropyl)-3,4-dihydroquinazolin-5-yl)benzamide

[0240] [ka] Step 1: Synthesis of 2-amino-6-nitro-N-(1-phenylcyclopropyl)benzamide 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 water (10 mL) and the precipitated solid was filtered, washed with n-hexane and dried under vacuum to give 2-amino-6-nitro-N-(1-phenylcyclopropyl)benzamide as a beige solid (0.620 g, 69%). LCMS (ES) m / z calcd for C16H15N3O3, 297.1; found 298.1 [M+H]+.

[0241] Step 2: Synthesis of 5-nitro-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one To a stirred solution of 2-amino-6-nitro-N-(1-phenylcyclopropyl)benzamide (0.62 g, 2.08 mmol) in chlorobenzene (13 ml) in a sealed tube, copper acetate (0.05 mg, 0.2 mmol), trimethyl orthoformate (2.28 ml, 20.8 mmol), and imidazole (0.42 g, 3.12 mmol) were added. The resulting reaction mixture was stirred at 150° C. for 48 hours. After completion of the reaction, the reaction mixture was evaporated under vacuum to obtain the crude material. The crude product was purified by flash chromatography using 40% ethyl acetate in hexane as eluent to give 5-nitro-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one as a beige solid (0.37 g, 58%). LCMS (ES) m / z calcd for C17H13N3O3, 307.1; found 308.1 [M+H] +.

[0242] Step 3: Synthesis of 5-amino-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one 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 zinc dust (172 mg, 3.6 mmol) and NH4Cl (270 mg, 6.01 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with ethyl acetate (25×2 mL). The organic phase was washed with brine solution (10 ml), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to give 5-amino-3-(1-phenylcyclopropyl)quinazolin-4(3H)-one as a pale yellow solid (0.301 g, crude). LC-MS m / z calcd for C17H15N3O, 277.1; found 278.2 [M+H] +.

[0243] Step 4: 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(1-phenylcyclopropyl)-3,4-dihydroquinazolin-5-yl)benzamide To a stirred solution of 5-amino-3-(1-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 phosphorus 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 (2×25 mL). The organic phase was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to give the crude material. This was further purified by preparative HPLC and the pure fractions were collected and lyophilized to give 3,5-dichloro-4-hydroxy-N-(4-oxo-3-(1-phenylcyclopropyl)-3,4-dihydroquinazolin-5-yl)benzamide as a 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).

[0244] Example 21: Synthesis of 3,5-dichloro-N-(3-(1-(2-fluorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0245] [ka] The title compound was synthesized as described in Example 20. LCMS (ES) m / z calcd. for C24H16Cl2FN3O3 483.06; found, 484.0 (M+H); 1H 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).

[0246] Example 22: 4,6-Dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-hydroxypyridine-2-carboxamide

[0247] [ka] Step 1: 2-Bromo-6-carboxy-3-methoxypyridine 1-oxide To a stirred solution of 6-bromo-5-methoxypyridine-2-carboxylic acid (1.20 g, 5.17 mmol) in TFA (20 ml), hydrogen peroxide (20 ml, 50%) was added and stirred at 90° C. for 36 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2-bromo-6-carboxy-3-methoxypyridine 1-oxide as an off-white solid (1.2 g). LCMS (ES) m / z calcd. for C7H6BrNO4, 246.95; found, 248.0 (M+H).

[0248] Step 2: Methyl 4,6-dichloro-5-methoxypyridine-2-carboxylate A mixture of 2-bromo-6-carboxy-3-methoxypyridine 1-oxide (0.8 g, 3.23 mmol) and thionyl chloride (5 ml) was stirred at 80° C. for 2 hours under nitrogen atmosphere. After completion of the reaction, excess thionyl chloride was removed under vacuum to give a residue. The residue was quenched with methanol by stirring for 1 hour. Methanol was removed under reduced pressure to give a crude residue. The crude residue 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 sulfate, filtered and concentrated. The crude was purified by flash column chromatography using 15% ethyl acetate in hexane as eluent to give methyl 4,6-dichloro-5-methoxypyridine-2-carboxylate as an off-white solid (0.35 g). LCMS (ES) m / z calcd. 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).

[0249] Step 3: 4,6-Dichloro-5-methoxypyridine-2-carboxylic acid To a stirred solution of methyl 4,6-dichloro-5-methoxypyridine-2-carboxylate (0.3 g, 1.27 mmol) in TFA: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 give a residue. The residue was diluted with water (10 mL) and acidified with 1N HCl (pH~6). The resulting solid was filtered, washed with water and dried to give 4,6-dichloro-5-methoxypyridine-2-carboxylic acid as an off-white solid (0.25 g). LCMS (ES) m / z calcd. for C7H5Cl2NO3, 220.96; found, 222.0 (M+H).

[0250] Step 4: 4,6-Dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-methoxypyridine-2-carboxamide 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 phosphorus trichloride (0.031 mg, 0.225 mmol) at ambient temperature and then heated to 130° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water (10 mL) and extracted with 20% IPA in DCM (2×10 mL). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give crude 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-methoxypyridine-2-carboxamide as an off-white solid (0.07 g). LCMS (ES) m / z calcd. for C22H15Cl2FN4O3, 472.05; found, 473.0 (M+H).

[0251] Step 5: 4,6-Dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-hydroxypyridine-2-carboxamide 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 paratoluenesulfonic 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 hours. 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 give 4,6-dichloro-N-{3-[(3-fluorophenyl)methyl]-4-oxo-3,4-dihydroquinazolin-5-yl}-5-hydroxypyridine-2-carboxamide (13.2 mg) as an off-white solid. LCMS (ES) m / z calcd. 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=8Hz, 1H), 7.26 (d, J=8Hz, 1H), 7.17 (m, 1H), 5.26 (s, 2H).

[0252] Example 23: 4,6-Dichloro-5-hydroxy-N-(4-oxo-3-{[2-(trifluoromethoxy)phenyl]methyl}-3,4-dihydroquinazolin-5-yl)pyridine-2-carboxamide

[0253] [ka] The title compound was synthesized as described in Example 22. LCMS (ES) - m / z calcd. for C 22 H 13Cl2F3N4O4, 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).

[0254] Example 24: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)thiazole-5-carboxamide

[0255] [ka] Step 1: Synthesis of methyl 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5-carboxylate 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 phosphorus trichloride (332 μL, 3.79 mmol) dropwise under nitrogen atmosphere. The reaction mass was heated to 100° C. for 3 hours. After completion of reaction, the reaction mass was cooled to room temperature, added to ice-cold water (20 ml), filtered and dried under vacuum to obtain methyl 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5-carboxylate (800 mg, 60%) as a yellow solid. LCMS (ES) m / z calcd, For C12H8Cl2N2O4S, 345.96; found, 347 (M+H).

[0256] Step 2: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)thiazole-5-carboxylic acid 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 obtain the crude product. The crude was diluted with water (10 mL), acidified with 1M HCl (10 mL) to pH 2-3, extracted with EtOAc (2×10 mL), washed with water (2×15 mL) and brine solution. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain 4-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-5-carboxylic acid (300 mg, 0.901 mmol) as an off-white solid. LCMS (ES) m / z calcd, For C11H6Cl2N2O4S, 333.94; found, 334.9(M+H).

[0257] Step 3: Synthesis of 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)thiazole-5-carboxamide A stirred solution of 4-(3,5-dichloro-4-hydroxybenzamido)-1,3-thiazole-5-carboxylic acid (140 mg, 0.420 mmol) in thionyl chloride (3.00 mL, 41.4 mmol) was heated to 95° C. for 2 h. Excess thionyl chloride was distilled off under a rota evaporator. The resulting residue was dissolved in DMF (1 mL) and added to 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) and heated at 85° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, quenched with water (10 mL), extracted with ethyl acetate (2 x 10 mL), washed with brine (10 mL), and the organic layer was collected, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. This crude product was purified by reverse phase preparative HPLC. The pure fractions were collected and concentrated to give pure 4-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)thiazole-5-carboxamide (30.0 mg, 16%) as an off-white solid. LCMS (ES) m / z calcd.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, 2 H), 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).

[0258] The following compounds were synthesized as described in Example 24:

[0259] [Table 3]

[0260] Example 31: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide

[0261] [ka] Step 1: Synthesis of 5-amino-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide A stirred solution of methyl 5-amino-3-methyl-1,2-thiazole-4-carboxylate (100 mg, 581 μmol) and 1-(2-fluorophenyl)methanamine (80.0 μL, 697 μmol) in toluene (1.00 mL) was cooled to 0° C., to which trimethylalmane (871 μL, 1.74 mmol) was added 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 with EtOAc (2×5 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 5-amino-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide as a yellow solid (130 mg, 84%). The crude compound was carried forward to the next step without any further purification. LCMS(ES)m / z calcd.For C12H12FN3OS, 265.31; found, 266 (M+H) + .

[0262] Step 2: Synthesis of 5-(3,5-dichloro-4-methoxybenzamido)-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide To a stirred solution of 3,5-dichloro-4-methoxybenzoic acid (200 mg, 905 μmol) in pyridine (2.50 mL) was added phosphoryl chloride (127 μL, 1.36 mmol) at 0° C. and stirred for 10 minutes. To this was added 5-amino-N-[(2-fluorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (240 mg, 905 μmol) and then stirred at ambient temperature for 1 hour. After completion of reaction, the reaction mass was quenched with cold water (10 mL). The precipitated solid was filtered, washed with hexane (10 mL) and dried to give 5-(3,5-dichloro-4-methoxybenzamido)-N-[(2-fluorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (200 mg, 48%) as a brown solid. This solid was carried onto the next step without further purification. LCMS(ES)m / z calcd.For C20H16Cl2FN3O3S, 468.32; found, 468 (M+H) + .

[0263] Step 3: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2-fluorobenzyl)-3-methylisothiazole-4-carboxamide 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 μmol) in DCM (0.1 mL) cooled to 0° C., tribromoborane (405 μL, 4.27 mmol) was added dropwise and stirred at ambient temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography. The column purified compound was purified by reverse phase preparative HPLC to give 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 C19H14Cl2FN3O3S 454.30; found, 454 (M+H) + .1H NMR (400 MHz, DMSO d6) δ 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).

[0264] Example 32: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0265] [ka] Step 1: Synthesis of methyl 5-(3,5-dichloro-4-methoxybenzamido)thiazole-4-carboxylate To a stirred solution of methyl 5-amino-1,3-thiazole-4-carboxylate (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 minutes. To this, 3,5-dichloro-4-methoxybenzoyl chloride (298 mg, 1.24 mmol) in dichloromethane (4.00 mL) was slowly added at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for an additional hour. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with DCM (2×100 mL). The combined organics were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, filtered and dried under vacuum to obtain the crude material. The crude material was purified by flash column chromatography to give methyl 5-(3,5-dichloro-4-methoxybenzamido)thiazole-4-carboxylate (150 mg, 33.37%) as an off-white solid. LCMS (ES) m / z calcd. For C13H10Cl2N2O4S, 359.9; found, 361.0 (M+H).

[0266] Step 2: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)thiazole-4-carboxylic acid To a stirred suspension of methyl 5-(3,5-dichloro-4-methoxybenzamido)-1,3-thiazole-4-carboxylate (126 mg, 0.349 mmol) in dichloromethane (0.5 mL) was added borane tribromide (0.596 mL, 3.49 mmol) at 0° C. The resulting reaction mixture was stirred at ambient temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organics were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give crude 5-(3,5-dichloro-4-hydroxybenzamido)thiazole-4-carboxylic acid (93.0 mg, 80%, crude) as an off-white solid. LCMS (ES) m / z calcd. for C11H6Cl2N2O4S, 333.91; found, 335.0 (M+H).

[0267] Step 3: Synthesis of 5-(3,5-dichloro-4-hydroxyphenyl)-7H-thiazolo[5,4-d][1,3]oxazin-7-one 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 thionyl chloride (0.202 mL, 2.79 mmol) and then heated to 70° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum to give 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 (MH).

[0268] Step 4: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide 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 (2×50 mL). The combined organics were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by flash column chromatography to give 5-(3,5-dichloro-4-hydroxybenzamido)-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide (23.0 mg, 15.39%) as an off-white solid. LCMS (ES) m / z calcd.For C19H12Cl2F3N3O4S, 504.99; found, 503.9 (MH).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).

[0269] The following compounds were synthesized using procedures as described in Examples 1-4, 20-24 and 31-32.

[0270] [Table 4-1]

[0271] [Table 4-2]

[0272]

Table 4-3

[0273]

Table 4-4

[0274]

Table 4-5

[0275]

Table 4-6

[0276]

Table 4-7

[0277]

Table 4-8

[0278]

Table 4-9

[0279]

Table 4-10

[0280]

Table 4-11

[0281]

Table 4-12

[0282]

Table 4-13

[0283] Example A: Estrone detection assay for assessing HSD17B13 activity and identifying inhibitors A liquid chromatography / mass spectrometry (LC / MS) estrone detection assay monitors the conversion of estradiol to estrone by HSD17B13. The assay is run in a 96wp format (Eppendorf deep well plate 96 / 500) containing 4 μM estradiol (E2; Cayman; #10006315), 6 mM NAD + (Sigma; #N0623), and 30 nM HSD17B13 enzyme (in-house; E. coli expressed purified soluble His-tagged protein) in an 80 μl reaction volume with 1 M potassium phosphate buffer at 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 (E1) was quantified by LC-MS / MS-based analyte detection for both E2 and E1 using LCMS grade reagents.

[0284] The reaction was terminated by adding 2 volumes of acetonitrile (MeCN; LCMS grade; CAS#75 / 05 / 8) containing deuterated (D4)-E1 (Clear Synth; #CS-T-54273; final concentration 500ng / mL) used as an internal standard. Samples were applied to pre-prepared Bond Elut-C18 extraction cartridges (3mL; Agilent; #12102028), washed, and eluted in MeCN. The eluate was dried under nitrogen and resuspended in 60% methanol (LCMS grade methanol; CAS#67 / 56 / 1) before being submitted for analysis. Quantification included aqueous linearity of E2 and E1.

[0285] Samples were analyzed on an XBridge BEH C18 column (Waters; #186003033) with 0.1% diethylamine in MeCN (mobile phase A; DEA CAS#109-89-7) and 0.1% diethylamine in milli-Q water (mobile phase B) in a 3 min gradient at 25% B. MRM analysis was used to detect the analytes in negative mode, with RTs of 1.85 min for E2 and 2 min for E1. Enzyme activity was used to assess the specificity of conversion in the absence of NAD+. Enzyme activity in the presence of test sample was expressed as a percentage of uninhibited enzyme activity and plotted against inhibitor concentration. Nonlinear regression was performed using a four parameter logistic model and GraphPad Prism software (GraphPad Software, La Jolla, CA). All runs were performed in replicates and pooled during the extraction process before being injected as replicates in the LC-MS / MS analysis.

[0286] The data is shown in Table 2 below.

[0287] [Table 5-1]

[0288] [Table 5-2]

[0289] [Table 5-3]

Claims

1. Formula (Ia) 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Y is N or CR １ and R １ are each independently hydrogen, deuterium, a halogen, -CN, -OH, or -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ is a deuterated alkyl; L is -C(=O)NR ３ - and R ３ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ is a deuterated alkyl; 【Chemistry 2】 teeth 【Chemistry 3】 and 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 , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ is a deuterated alkyl; R Ａ is -(C(R １２ ) ２ ) ｐ Aryl or -(C(R １２ ) ２ ) ｐ heteroaryl, where the aryl and heteroaryl are each independently one or more R Ａｂ and R Ａｂ are each independently deuterium, halogen, -CN, or -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NHS(=O) ２ R ａ , -C(=O)R ａ , -C(=O)C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -C(=O)C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each are selected from one or more R Ａａａ and R Ａａａ are each independently deuterium, halogen, -CN, or -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NHS(=O) ２ R ａ , -C(=O)R ａ , -C(=O)C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -C(=O)C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １２ are each independently hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same carbon １２ taken together form a cycloalkyl or heterocycloalkyl, where the cycloalkyl and heterocycloalkyl are selected from the group consisting of deuterium, halogen, —OH, —OCH ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ Optionally substituted with deuterated alkyl; p is 1; R ａ are each independently １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl each independently represent one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ optionally substituted with heteroalkyl; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently represent one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ optionally substituted with heteroalkyl; R ｃ and R ｄ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently represent one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ optionally substituted with heteroalkyl; Or, R ｃ and R ｄ may be, together with the atom to which they are attached, one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ A compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which forms a heterocycloalkyl optionally substituted by heteroalkyl.

2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N.

3. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is CR1.

4. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is hydrogen.

5. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3 is hydrogen.

6. R 5d is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl; The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5a, R5b, and R5c are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

7. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R A is -(C(R 12 ) 2 ) p aryl, where aryl is optionally independently substituted with one or more R Ab .

8. The compound of claim 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R Ab is independently deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl, wherein each alkyl is optionally and independently substituted with one or more R Aaa .

9. The compound of claim 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R12 is hydrogen.

10. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】

11.

13. 11. The compound of claim 10, wherein:

12.

14. 11. The compound of claim 10, wherein:

13.

15. 11. The compound of claim 10, wherein:

14.

16. 11. The compound of claim 10, wherein:

15.

17. 11. The compound of claim 10, wherein:

16.

18. 11. The compound of claim 10, wherein:

17.

19. 11. The compound of claim 10, wherein:

18.

20. 11. The compound of claim 10, wherein:

19.

21. 11. The compound of claim 10, wherein:

20.

22. 11. The compound of claim 10, wherein:

21.

23. 11. The compound of claim 10, wherein:

22.

24. 11. The compound of claim 10, wherein:

23.

25. 11. The compound of claim 10, wherein:

24.

26. 11. The compound of claim 10, wherein:

25.

27. 11. The compound of claim 10, wherein:

26.

28. 11. The compound of claim 10, wherein:

27. A pharmaceutical composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

28. A pharmaceutical composition comprising the compound of claim 10, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

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