2-Substituted thiazole hsd17b13 inhibitors and uses thereof

Abstract

Described herein is a selective HSD17B13 inhibitor and pharmaceutical composition comprising said inhibitor.The compound and composition are useful for treating liver disease, metabolic disease or cardiovascular disease, such as NAFLD or NASH, or drug-induced liver injury (DILI).

Description

[Technical Field]

[0001] cross reference This application claims the benefit of Indian Patent Application No. 202211004338, filed January 26, 2022, U.S. Provisional Patent Application No. 63 / 342,786, filed May 17, 2022, and U.S. Provisional Patent Application No. 63 / 377,421, filed September 28, 2022, which are incorporated herein by reference in their entireties. [Background technology]

[0002] Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is considered a hepatic manifestation 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 concomitant insulin resistance. The incidence of NAFLD / NASH is rapidly increasing worldwide in line with the increasing prevalence of obesity, making it the most common chronic liver disease today.

[0003] NAFLD is classified into simple steatosis, in which only fatty liver is observed, and nonalcoholic steatohepatitis (NASH), in which fatty liver is accompanied by intralobular inflammation and ballooning degeneration of hepatocytes. The proportion of NAFLD patients with NASH is unclear, but it may range from 20 to 40%. NASH is a progressive disease that can lead to cirrhosis and hepatocellular carcinoma. It has been reported that 20% of patients with NASH develop cirrhosis, and 30 to 40% of patients with NASH cirrhosis 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, pharmacological treatment is essential because obese patients with NAFLD often have difficulty maintaining an improved lifestyle.

[0004] 17β-hydroxysteroid dehydrogenase (HSD17B) comprises 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 identified hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), an enzyme with unknown biological function, as a novel liver-specific lipid droplet (LD)-associated protein in mice and humans. HSD17B13 expression is significantly upregulated in patients and mice with nonalcoholic fatty liver disease (NAFLD). Hepatic overexpression of HSD17B13 promotes lipid accumulation in the liver. 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 is the method, compound and composition that is useful for reducing the expression or activity of HSD17B13 in object.In addition, provided herein is also the method, compound and composition that comprises HSD17B13 specific inhibitor, that can be useful for reducing the morbidity of HSD17B13-related disease or condition in object.Such method, compound and composition can be useful for treating, preventing, delaying or improving liver disease, metabolic disease or cardiovascular disease, for example.

[0006] As used herein, the formula (I)

[0007] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is thiazolyl; R 1is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 2 is hydrogen or C1-C6 alkyl, R 3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyls, C1-C 10 Hydroxyalkyl, C1-C 10 Aminoalkyl, C1-C 10 Heteroalkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a is replaced by R 3a 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)Ra , -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 3a come together to form oxo, R 4 is deuterium, halogen, C1-C6 alkyl, C2-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional and may be joined by one or more R 4a is replaced by R 4a 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)ORb , -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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom 4a come together to form oxo, Alternatively, two R on the same carbon 4a together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on different atoms 4a together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; X is N or CR X and R X are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 6 are each independently a halogen, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C( =O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Alternatively, two R on the same atom form an oxo.

[0008] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0009] [ka] It is of the type.

[0010] In some embodiments of the compound of Formula (I), the compound has the formula (Ib):

[0011] [ka] It is of the type.

[0012] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0013] Also disclosed herein are methods for treating a disease in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments of the methods for treating a disease, the disease is a liver disease, a metabolic disease, or a cardiovascular disease. In some embodiments of the methods for treating a disease, the disease is NAFLD. In some embodiments of the methods for treating a disease, the disease is NASH. In some embodiments of the methods for treating a disease, the disease is drug-induced liver injury (DILI). In some embodiments of the methods for treating a disease, the disease is associated with HSD17B13. In some embodiments of the methods for treating a disease, the disease is alcoholic liver disease. In some embodiments of the methods for treating a disease, the disease is cirrhosis. In some embodiments of the methods for treating a disease, the disease is decompensated portal hypertension. In some embodiments of the methods for treating a disease, the disease is cholestatic liver disease.

[0014] Also disclosed herein is a method for selectively inhibiting HSD17B13, comprising administering a pharmaceutically effective amount of a compound disclosed herein, or its pharmaceutically acceptable salt, solvate, or stereoisomer. In some embodiments, the compound selectively inhibits HSD17B13 over HSD17B2, HSD17B14, or any combination thereof.

[0015] 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 INVENTION

[0016] definition In the following description, specific details are set forth to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art 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 the context otherwise requires, throughout the following specification and claims, the word "comprise" and variations thereof (e.g., "comprises" or "comprising") are intended to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the subject invention.

[0017] References herein to "some embodiments" or "embodiments" 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 are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Similarly, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0018] As used herein, the following terms have the following meanings unless otherwise specified:

[0019] "Oxo" refers to =O.

[0020] "Carboxyl" refers to --COOH.

[0021] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 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. Wherever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses appearances of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1-C6 alkyl. 10In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless otherwise specified in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[0022] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Wherever appearing herein, a numerical range such as "C-C alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkenyl" where no numerical range is explicitly stated. Unless otherwise specified in the specification, an alkenyl group can 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, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0023] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" where no numerical range is explicitly stated. Unless otherwise specified in the specification, an alkynyl group can 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, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can 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.

[0025] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined above. Unless otherwise specified in the specification, an alkoxy group can 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, -NH, or -NO. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0026] "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 (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. 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 can 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, 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.

[0027] "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, a cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C4). 15Cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (C3-C 10 Cycloalkyl or C3-C 10Examples of cycloalkyl include 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, cycloalkyl is a 3 to 10-membered cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, cycloalkyl is a 3 to 6-membered cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, cycloalkyl is a 5 to 6-membered cycloalkyl or a 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise stated 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, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "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.

[0031] "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.

[0032] "Deuterated alkyl" refers to an alkyl radical, as defined above, substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuterated alkyls include, for example, CD3, CHD, CHD, CHCD, CDCD, CHDCD, CHCHD, or CHCHD. In some embodiments, the deuterated alkyl is CD3.

[0033] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, 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, sulfur, phosphorus, or a combination thereof, and 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 two atoms selected from the group consisting of oxygen, nitrogen, and sulfur, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0034] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 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 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 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 can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (C2-C3). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10Examples of heterocycloalkyl include heterocycloalkyls 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-C6 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). In some embodiments, heterocycloalkyls are 3-8 membered rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. In some embodiments, heterocycloalkyls are 3-6 membered rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. In some embodiments, the heterocycloalkyl is a 5-6 membered ring containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. Examples of such heterocycloalkyl radicals include, but are not limited to, 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-piperazinyl, and 4-piperazinyl. lydonyl, pyrrolidinyl, pyrazolidinyl, 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. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specified herein, heterocycloalkyl can 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, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0035] "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, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogen atoms. In some embodiments, a heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, a heteroaryl contains 1 nitrogen atom. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is joined by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can 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. In some embodiments, the heteroaryl is a 5-6 membered ring containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, 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 nyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyro Examples of heteroaryl include phenyl, 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 specified otherwise in the specification, heteroaryl can 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, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0036] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at levels ranging between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that it is not intended that such group introduce any substitution or substitution pattern that is sterically impractical and / or synthetically impractical (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as potentially including an infinite number of optionally substituted alkyl groups). Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more specifically, up to about 500 daltons.

[0037] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0038] An "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, that is effective to produce a desired therapeutic effect.

[0039] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition after the onset of a pathological event or after contact with a pathogen, and includes stabilization of disease (e.g., disease does not worsen) or alleviation of disease. In some embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected of suffering from liver disease, e.g., NAFLD).

[0040] "Synergism" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

[0041] "HSD17B13" refers to hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13. For example, in some embodiments, HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from the DNA encoding HSD17B13 (including genomic DNA containing introns and exons). HSD17B13 may also refer to any amino acid sequence of HSD17B13 (which may include the secondary or tertiary structure of the protein molecule) encoded by the DNA sequence and / or RNA sequence. Targets can also be referred to in either uppercase or lowercase.

[0042] compound The compound of formula (I) or its pharmaceutically acceptable salt, solvate or stereoisomer is described herein as being useful for treating liver disease.In some embodiments, liver disease is NAFLD.In some embodiments, the compound disclosed herein is selective HSD17B13 inhibitor.

[0043] As used herein, the formula (I)

[0044] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is thiazolyl; R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 2 is hydrogen or C1-C6 alkyl, R 3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyls, C1-C 10 Hydroxyalkyl, C1-C 10 Aminoalkyl, C1-C10 Heteroalkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a is replaced by R 3a 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 atom3a come together to form oxo, R 4 is deuterium, halogen, C1-C6 alkyl, C2-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional and may be joined by one or more R 4a is replaced by R 4a 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom 4a come together to form oxo, Alternatively, two R on the same carbon 4a together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on different atoms 4a together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; X is N or CR X and R X are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 6 are each independently a halogen, R aare each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C( =O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Alternatively, two R on the same atom form an oxo.

[0045] As used herein, the formula (I)

[0046] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is thiazolyl; R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 2 is hydrogen or C1-C6 alkyl, R 3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyls, C1-C 10 Hydroxyalkyl, C1-C 10 Aminoalkyl, C1-C 10 Heteroalkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a is replaced by R 3a 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 , -NRb 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 3a come together to form oxo, R 4 is deuterium, halogen, C1-C6 alkyl, C2-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional and may be joined by one or more R 4a is replaced by R 4a 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)NRc R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NHS(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom 4a come together to form oxo, Alternatively, two R on the same carbon 4a together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on different atoms 4a together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; X is N or CR X and R X are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 5 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 6 are each independently a halogen, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C( =O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Alternatively, two R on the same atom form an oxo.

[0047] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0048] [ka] It is of the type.

[0049] In some embodiments of the compound of Formula (I), the compound has the formula (Ib):

[0050] [ka] It is of the type.

[0051] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 1 is hydrogen.

[0052] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2 is C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 2 is hydrogen.

[0053] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyls, C1-C 10 Hydroxyalkyl, C1-C 10 Aminoalkyl, C1-C 10 heteroalkyl, C-C alkylene (cycloalkyl), C-C alkylene (heterocycloalkyl), C-C alkylene (aryl), or C-C alkylene (heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3aIn some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C4-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyls, C1-C 10 Hydroxyalkyl, C1-C 10 Aminoalkyl, C1-C 10 heteroalkyl, C-C alkylene (cycloalkyl), C-C alkylene (heterocycloalkyl), C-C alkylene (aryl), or C-C alkylene (heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C1-C 10 alkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C4-C 10 alkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C1-C 10 alkyl, or C1-C6 alkylene (aryl), where the alkyl, alkylene, and aryl are optionally independently selected from one or more R 3aIn some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C4-C 10 alkyl, or C-C alkylene (aryl), where the alkyl, alkylene, and aryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 optionally independently one or more R 3a C1-C substituted with 10 In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 optionally independently one or more R 3a C4-C substituted with 10 In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is C4-C 10 In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is a C1-C6 alkylene (aryl), and the alkylene and aryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is a C2-C6 alkylene (aryl), and the alkylene and aryl are optionally independently selected from one or more R 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3 is a C2-C6 alkylene (aryl), and the aryl optionally and independently contains one or more R 3a is replaced by

[0054] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)ORb , -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, or two R on the same atom 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3a are each independently deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R on the same atom 3a In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3a are each independently a halogen, -OR a or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 3a are each independently C1-C6 haloalkyl.

[0055] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), X is N. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), X is CR X is.

[0056] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R X is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R X is hydrogen.

[0057] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R5 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 5 is hydrogen.

[0058] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 6 and R are each chloro. In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 6 and R are each fluoro. In some embodiments of compounds of Formula (I), (Ia), or (Ib), one R 6 is fluoro and the other R 6 is chloro.

[0059] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0060] [ka] teeth

[0061] [ka] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0062] [ka] teeth

[0063] [ka] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0064] [ka] teeth

[0065] [ka] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0066] [ka] teeth

[0067] [ka] is.

[0068] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R 4a is replaced by

[0069] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R 4a is replaced by

[0070] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is one or more R 4a is cycloalkyl optionally substituted with

[0071] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is one or more R 4a is heterocycloalkyl optionally substituted with

[0072] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is aryl or heteroaryl, and aryl and heteroaryl are optionally joined by one or more R 4a is replaced by

[0073] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is one or more R 4a is aryl optionally substituted with

[0074] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4 is one or more R 4a is heteroaryl optionally substituted with

[0075] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -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, wherein alkyl is optionally independently substituted with one or more R, or two R on the same atom. 4acome together to form oxo.

[0076] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)R a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, wherein alkyl is optionally independently substituted with one or more R, or two R on the same atom. 4a come together to form oxo.

[0077] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently deuterium, halogen, -CN, or -S(=O)R a or C1-C6 alkyl optionally substituted independently with one or more R, or two R on the same atom 4a come together to form oxo.

[0078] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -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, or heterocycloalkyl, or two R on the same atom 4a come together to form oxo.

[0079] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)R a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom 4a come together to form oxo.

[0080] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently a halogen, -CN, -OH, or -OR a , -S(=O)R a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, or two R on the same atom 4a come together to form oxo.

[0081] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently a halogen, -S(=O)R a , C1-C6 alkyl, or C1-C6 haloalkyl, or two R on the same atom 4a come together to form oxo.

[0082] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently a halogen, -S(=O)R a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0083] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R 4a are each independently a halogen.

[0084] In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R 4a together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R on the same carbon 4a together form a cycloalkyl optionally substituted with one or more R.

[0085] In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R 4a together form a heterocycloalkyl, each optionally substituted with one or more R.

[0086] In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R 4a are taken together to form a cycloalkyl optionally substituted with one or more R. In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R on different atoms 4a are taken together to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R on different atoms 4a are taken together to form an aryl optionally substituted with one or more R. In some embodiments of compounds of Formula (I), (Ia), or (Ib), two R on different atoms 4a together form a heteroaryl optionally substituted with one or more R.

[0087] In some embodiments of the compounds of Formula (I),

[0088] [ka] teeth

[0089] [ka] is.

[0090] In some embodiments of the compounds of Formula (I),

[0091] [ka] teeth

[0092] [ka] is.

[0093] In some embodiments of the compounds of Formula (I),

[0094] [ka] teeth

[0095] [ka] is.

[0096] In some embodiments of the compounds of Formula (I),

[0097] [ka] teeth

[0098] [ka] In some embodiments of the compound of formula (I),

[0099] [ka] teeth

[0100] [ka] In some embodiments of the compound of formula (I),

[0101] [ka] teeth

[0102] [ka] In some embodiments of the compound of formula (I),

[0103] [ka] teeth

[0104] [ka] In some embodiments of the compound of formula (I),

[0105] [ka] teeth

[0106] [ka] In some embodiments of the compound of formula (I),

[0107] [ka] teeth

[0108] [ka] In some embodiments of the compound of formula (I),

[0109] [ka] teeth

[0110] [ka] In some embodiments of the compound of formula (I),

[0111] [ka] teeth

[0112] [ka] In some embodiments of the compound of formula (I),

[0113] [ka] teeth

[0114] [ka] In some embodiments of the compound of formula (I),

[0115] [ka] teeth

[0116] [ka] In some embodiments of the compound of formula (I),

[0117] [ka] teeth

[0118] [ka] In some embodiments of the compound of formula (I),

[0119] [ka] teeth

[0120] [ka] is.

[0121] As used herein, the formula (II)

[0122] [ka] Also disclosed is a compound of the formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is a halogen, R 2 is a halogen, X is N or CR X and R X are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Y is N or CR Y and R Y are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Ring A is pyrazole; R 4are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R; n is 0 to 2, R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional and may be joined by one or more R 6a is replaced by R 6a 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 Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 6b is replaced by Alternatively, two R on the same atom 6a come together to form oxo, R 6b 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 , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -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; Alternatively, two R on the same atom 6b come together to form oxo, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom together form an oxo.

[0123] In some embodiments of the compound of Formula (II), the compound has the formula (IIa):

[0124] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 4a is hydrogen or R 4 and R 4b is hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R.

[0125] In some embodiments of the compound of Formula (II), the compound has the formula (IIb):

[0126] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 4a is hydrogen or R 4 and R 4b is hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R.

[0127] In some embodiments of the compound of Formula (II), the compound has the formula (IIc):

[0128] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 4a is hydrogen or R 4 and R 4b is hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R.

[0129] In some embodiments of the compound of Formula (II), the compound has the formula (IId):

[0130] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 4a is hydrogen or R 4 and R 4b is hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R.

[0131] In some embodiments of compounds of Formula (IIa)-(IId), R 4a is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (IIa)-(IId), R4a is hydrogen.

[0132] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 1 is fluoro or chloro. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 1 is chloro.

[0133] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 2 is fluoro or chloro. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 2 is chloro.

[0134] In some embodiments of compounds of Formula (II) or (IIa)-(IId), X is CR X In some embodiments of compounds of Formula (II) or (IIa)-(IId), X is N.

[0135] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R X is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R X is hydrogen or halogen. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R X is hydrogen.

[0136] In some embodiments of compounds of Formula (II) or (IIa)-(IId), Y is CR Y In some embodiments of compounds of Formula (II) or (IIa)-(IId), Y is N.

[0137] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R Yis hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R Y is hydrogen or halogen. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R Y is hydrogen.

[0138] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 3 is hydrogen.

[0139] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 4 are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IId), R 4 are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IId), R 4are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 4 are each independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or aryl, and each alkyl, cycloalkyl, and aryl is optionally and independently substituted with one or more R. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 4 are each independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or aryl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 4 are each independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 4 are each independently aryl.

[0140] In some embodiments of a compound of Formula (II) or (IIa)-(IId), n is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa)-(IId), n is 0. In some embodiments of a compound of Formula (II) or (IIa)-(IId), n is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IId), n is 2.

[0141] In some embodiments of compounds of Formula (IIa)-(IId), R 4bis C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of compounds of Formulae (IIa)-(IId), R 4b is C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of compounds of Formulae (IIa)-(IId), R 4b is C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of compounds of Formulae (IIa)-(IId), R 4b is C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or aryl, wherein the alkyl, cycloalkyl, and aryl are each optionally independently substituted with one or more R. In some embodiments of compounds of Formulae (IIa)-(IId), R 4b is C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or aryl. In some embodiments of compounds of Formula (IIa)-(IId), R 4b is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of Formula (IIa)-(IId), R 4b is aryl.

[0142] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 5 is hydrogen.

[0143] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6 is C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional and may be joined by one or more R 6a In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6 is one or more R 6a In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6 is C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R 6a In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6 is C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), and alkylene, aryl, and heteroaryl are optionally joined by one or more R 6a In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6 is C1-C6 alkylene (aryl), and the alkylene and aryl are optionally joined by one or more R 6ais replaced by

[0144] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6a 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, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 6b is replaced by

[0145] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl, each alkyl optionally independently selected from one or more R 6b In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6a are each independently -OR a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0146] In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6b are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (II) or (IIa)-(IId), R 6b are each independently deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0147] As used herein, the formula (III)

[0148] [ka] Also disclosed is a compound of the formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 11 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 , -NR b S(=O)2R 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is 1 to 5; R 12 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; R 13 are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R; p is 0 to 3; R 14 is C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 14a is replaced by R 14a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR cR 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 , -NR b S(=O)2R 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 14b is replaced by Alternatively, two R on the same atom 14a come together to form oxo, R 14b 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 Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 14b come together to form oxo, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom together form an oxo.

[0149] In some embodiments of the compound of Formula (II), ring B is aryl or heteroaryl. In some embodiments of the compound of Formula (II), ring B is aryl. In some embodiments of the compound of Formula (II), ring B is heteroaryl. In some embodiments of the compound of Formula (II), ring B is 5- or 6-membered heteroaryl. In some embodiments of the compound of Formula (I), ring B is phenyl or pyridyl. In some embodiments of the compound of Formula (II), ring B is phenyl. In some embodiments of the compound of Formula (II), ring B is pyridyl.

[0150] In some embodiments of the compound of Formula (II), R 11 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl.

[0151] In some embodiments of the compound of Formula (II), R 11are each independently halogen, —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), R 11 are each independently a halogen or —OH.

[0152] In some embodiments of the compound of Formula (III), m is 1 to 3. In some embodiments of the compound of Formula (III), m is 2 or 3. In some embodiments of the compound of Formula (III), m is 2. In some embodiments of the compound of Formula (III), m is 3.

[0153] In some embodiments of the compound of Formula (III), the compound has the formula (IIIa):

[0154] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 15 is a halogen, R 16 is a halogen, W is N or CR W and R W are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; Z is N or CR Z and R Z are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl.

[0155] In some embodiments of the compound of Formula (IIIa), R 15is fluoro or chloro. In some embodiments of the compound of Formula (IIIa), R 15 is chloro.

[0156] In some embodiments of the compound of Formula (IIIa), R 16 is fluoro or chloro. In some embodiments of the compound of Formula (IIIa), R 16 is chloro.

[0157] In some embodiments of the compound of Formula (IIIa), W is CR W In some embodiments of the compound of Formula (IIIa), W is N.

[0158] In some embodiments of the compound of Formula (IIIa), R W is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IIIa), R W is hydrogen or halogen. In some embodiments of the compound of Formula (IIIa), R W is hydrogen.

[0159] In some embodiments of the compound of Formula (IIIa), Z is CR Z In some embodiments of the compound of Formula (IIIa), Z is N.

[0160] In some embodiments of the compound of Formula (IIIa), R Z is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IIIa), R Z is hydrogen or halogen. In some embodiments of the compound of Formula (IIIa), R Z is hydrogen.

[0161] In some embodiments of compounds of Formula (III) or (IIIa), R 12is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (III) or (IIIa), R 12 is hydrogen.

[0162] In some embodiments of compounds of Formula (III) or (IIIa), R 13 are each independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa), R 13 are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III) or (IIIa), R 13 are each independently halogen or C1-C6 alkyl. In some embodiments of compounds of Formula (III) or (IIIa), R 13 are each independently a halogen. In some embodiments of compounds of Formula (III) or (IIIa), R 13 are each independently C1-C6 alkyl.

[0163] In some embodiments of the compound of Formula (III) or (IIIa), p is 0 to 2. In some embodiments of the compound of Formula (III) or (IIIa), p is 0 or 1. In some embodiments of the compound of Formula (III) or (IIIa), p is 0. In some embodiments of the compound of Formula (III) or (IIIa), p is 1. In some embodiments of the compound of Formula (III) or (IIIa), p is 2.

[0164] In some embodiments of compounds of Formula (III) or (IIIa), R 14is C1-C6 alkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 14a In some embodiments of compounds of Formula (III) or (IIIa), R 14 is one or more R 14a In some embodiments of compounds of Formula (III) or (IIIa), R 14 is a C1-C6 alkylene (aryl) or a C1-C6 alkylene (heteroaryl), and each alkylene, aryl, and heteroaryl is optionally independently selected from one or more R 14a In some embodiments of compounds of Formula (III) or (IIIa), R 14 is a C1-C6 alkylene (aryl), and each alkylene and aryl is optionally independently selected from one or more R 14a is replaced by

[0165] In some embodiments of compounds of Formula (III) or (IIIa), R 14a 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, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally independently selected from one or more R 14b is replaced by

[0166] In some embodiments of compounds of Formula (III) or (IIIa), R 14a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl, each alkyl optionally independently selected from one or more R 14b is replaced by

[0167] In some embodiments of compounds of Formula (III) or (IIIa), R 14a are each independently -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III) or (IIIa), R 14a are each independently C1-C6 haloalkyl.

[0168] In some embodiments of compounds of Formula (III) or (IIIa), R 14b are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III) or (IIIa), R 14b are each independently deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0169] In some embodiments of the compounds disclosed herein, R aare each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. 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, or C1-C6 heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. 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, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0170] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, 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 disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen. In some embodiments of the compounds disclosed herein, R bare each independently C1-C6 alkyl.

[0171] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. 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, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R c and R dare 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. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1-C6 alkyl.

[0172] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a 5-membered heterocycloalkyl optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a 6-membered heterocycloalkyl optionally substituted with one or more R.

[0173] In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —O—C—C alkyl, —O—C—C haloalkyl, —NH, —NHC—C alkyl, —N(C—C alkyl), —C(═O)C—C alkyl, —C(═O)OH, —C(═O)O—C alkyl, —C(═O)NH, —C(═O)NHC—C alkyl, —C(═O)N(C—C alkyl), C—C alkyl, C—C haloalkyl, C—C deuterated alkyl, C—C hydroxyalkyl, C—C aminoalkyl, C—C heteroalkyl, or C—C cycloalkyl; or, two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC-C alkyl, -OC-C haloalkyl, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC-C alkyl, -OC-C haloalkyl, -NH, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, or C-C cycloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen.

[0174] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0175] Described herein are compounds selected from the compounds of Table 1a, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0176] [Table 1-1]

[0177] [Table 1-2]

[0178] [Table 1-3]

[0179] [Table 1-4]

[0180] [Table 1-5]

[0181] [Table 1-6]

[0182] [Table 1-7]

[0183] [Table 1-8]

[0184] Table 1-9

[0185] Table 1-10

[0186] Table 1-11

[0187] Table 1-12

[0188] Table 1-13

[0189] Table 1-14

[0190] Table 1-15

[0191] Table 1-16

[0192] Table 1-17

[0193] Table 1-18

[0194] [Table 1-19]

[0195] Described herein are compounds selected from the compounds of Table 1b, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0196] [Table 2]

[0197] 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 provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein contain one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived 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 enantiomer. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinctive 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 on differences in solubility. In some embodiments, the optically pure enantiomer is recovered along with the resolving agent by any practical means that does not result in racemization.

[0198] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds, such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers that are different from the atomic masses or mass numbers that are usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Isotopically labeled 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 The C isotope is particularly preferred because it is easy to prepare and detect. 2 Substitution with heavy isotopes such as H may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0199] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0200] In some embodiments, the labeled compounds described herein are used to measure the in vitro and in vivo binding of unlabeled HSD17B13 inhibitors.

[0201] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0202] In some embodiments, the compounds described herein possess acidic or basic groups and thus form pharmaceutically acceptable salts by reaction with any of a number of inorganic or organic bases, and inorganic and organic acids. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0203] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a mineral acid, organic acid, or inorganic base with a compound described herein, 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, or the like. Salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Included are 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.

[0204] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids including, but not limited to, 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-hydroxybenzoic acid), benzoic acid, ... Examples of suitable carboxylic acids include benzoyl)benzoic acid, 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, glucoheptonic 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 that are not themselves pharmaceutically acceptable, such as oxalic acid, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0205] In some embodiments, the compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, or the like, of pharmaceutically acceptable metal cations, ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4alkyl)4, etc.

[0206] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is noted that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0207] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0208] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. 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 from aqueous / organic solvent mixtures using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0209] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom, accompanied by switching between a single bond and an adjacent double bond. In bond structures that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0210] Treatment method Provided herein are methods for inhibiting the expression or activity of HSD17B13, which may be useful for treating, preventing, or ameliorating HSD17B13-associated diseases, such as NAFLD or NASH, in a subject by administering a compound that targets HSD17B13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0211] Provided herein are methods for inhibiting HSD17B13 expression or activity in a cell, the methods comprising contacting the cell with a disclosed HSD17B13 inhibitor, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, thereby inhibiting HSD17B13 expression or activity in the cell. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is in the liver. In some embodiments, the cell is in the liver of a subject having or at risk of having a disease, disorder, condition, symptom, or physiological marker associated with liver disease, metabolic disease, or cardiovascular disease or disorder. In some embodiments, the cell is an adipocyte or monocyte from a subject having or at risk of having a disease. In some embodiments, the cell is a lymphocyte from a subject having or at risk of having a disease. In some embodiments, liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, fatty liver disease, chronic liver disease, cirrhosis, fatty liver, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, non-alcoholic steatohepatitis (NASH), fulminant Wilson's disease, rapidly fibrosing hepatitis C virus injury, and decompensated portal vein hypertension.In some embodiments, liver disease, metabolic disease, or cardiovascular disease or disorder is NASH.In some embodiments, liver disease, metabolic disease, or cardiovascular disease or disorder is cholestatic liver disease.

[0212] In some embodiments, the liver disease is primary biliary cirrhosis or primary sclerosing cholangitis.

[0213] Provided herein are methods for treating, preventing, delaying the onset, slowing the progression, or ameliorating one or more diseases, disorders, conditions, symptoms, or physiological markers associated with HSD17B13, comprising administering a compound disclosed herein, or a pharmaceutically 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, condition, 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.

[0214] Provided herein are methods for reducing, improving, or modulating hepatic steatosis, liver fibrosis, triglyceride synthesis, lipid levels, liver lipids, ALT levels, NAFLD activity score (NAS), cholesterol levels, or triglyceride levels, or a combination thereof, in a subject, the methods comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, improving, or modulating hepatic steatosis in an individual. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, improving, or modulating hepatic 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 their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating lipid levels in individuals. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating liver lipids in individuals. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating ALT levels in individuals. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating NAFLD activity scores in individuals. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating cholesterol levels in individuals.In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are provided for use in reducing, improving, or regulating triglyceride levels in individuals. In some embodiments, the subject is identified as having or at risk for a disease, disorder, illness, symptom, 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.

[0215] Provided herein are methods for treating, preventing, or delaying the onset of drug-induced liver injury (DILI) in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the liver injury is steatohepatitis. Also provided herein are methods for treating, preventing, or delaying the onset of drug-induced steatohepatitis (DISH) in a subject. In some embodiments, the subject in need thereof is receiving chemotherapy for the treatment of cancer. In some embodiments, the subject in need thereof is receiving treatment for cardiovascular disease. In some embodiments, the subject in need thereof is receiving treatment for a psychiatric disorder / illness. In some embodiments, the subject in need thereof is receiving treatment for pain. In some embodiments, the subject in need thereof 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 in need thereof is receiving amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the subject in need thereof is receiving amitriptyline, clozapine, or any combination thereof, hi some embodiments, the subject in need thereof is receiving methotrexate, pirprofen, or any combination thereof.

[0216] Cholestatic disorders Provided herein are methods of treating a cholestatic disease in a subject, the methods comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0217] In some embodiments, inhibiting HSD17B13 improves bile flow.In some embodiments, inhibiting HSD17B13 is used to treat cholestatic disease.Cholestatic disease includes primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), Alagille syndrome, biliary atresia, liver damage in cystic fibrosis patients and progressive familial intrahepatic cholestasis (PFIC).

[0218] HSD17B13 protein is highly expressed in the liver and gallbladder. The gallbladder is developmentally downstream of hepatocytes via the biliary tree. Inactive HSD17B13 is associated with increased hepatic and plasma phosphatidylcholine. Phosphatidylcholine is essential for bile flow. Hepatic phosphatidylcholine is secreted into bile at a rate equivalent to the total hepatic level of phosphatidylcholine secreted within one day along with bile acids (BAs) and cholesterol. In some embodiments, inactive HSD17B13 is associated with increased plasma levels of VLDL-cholesterol. This means that cholesterol is secreted in large amounts from the liver but is not catabolized to bile acids for secretion into bile. In some embodiments, inhibition of HSD17B13 improves bile flow by increasing phosphatidylcholine. In some embodiments, HSD17B13 protects the biliary tree by preventing inflammation. In some embodiments, HSD17B13 protects the biliary tree by preventing cytotoxic bile acids from damaging the biliary tree.

[0219] In some embodiments, the cholestatic disease is primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), Alagille syndrome, biliary atresia, liver injury in cystic fibrosis patients, progressive familial intrahepatic cholestasis (PFIC), intrahepatic cholestasis of pregnancy, drug-induced cholestasis, AIDS cholangitis, IG4-associated cholangitis, biliary stricture, or hypophospholipid-associated cholestasis.

[0220] In some embodiments, the cholestatic disease is primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), Alagille syndrome, biliary atresia, liver injury in cystic fibrosis patients, or progressive familial intrahepatic cholestasis (PFIC).

[0221] In some embodiments, the cholestatic disease is primary sclerosing cholangitis (PSC).

[0222] In some embodiments, the PSC is associated with inflammatory bowel disease (IBD). In some embodiments, the PSC is associated with elevated levels of lipopolysaccharide (LPS) (endotoxemia). In some embodiments, the elevated levels of LPS are in the blood. In some embodiments, the elevated levels of LPS are in the liver. In some embodiments, the elevated levels of LPS are in the biliary tree. In some embodiments, the cholestatic disease is primary biliary cholangitis (PBC). In some embodiments, the cholestatic disease is Alagille syndrome. In some embodiments, the cholestatic disease is biliary atresia. In some embodiments, the cholestatic disease is liver damage in cystic fibrosis patients. In some embodiments, the cholestatic disease is progressive familial intrahepatic cholestasis (PFIC). In some embodiments, the PFIC is PFIC-3. In some embodiments, PFIC-3 is due to a mutation in ABCB4, which requires phosphatidylcholine for bile acid transport.

[0223] In some embodiments, the cholestatic disease is treated by improving bile flow in the subject. In some embodiments, the cholestatic disease is treated by improving cholesterol secretion from the liver in the subject.

[0224] In some embodiments, inactive HSD17B13 is associated with reduced cytokine and inflammatory gene expression. In some embodiments, hepatocytes with inactive HSD17B13 have improved hepatocyte responses to LPS. In some embodiments, inactive HSD17B13 is associated with improved autophagy in response to LPS (see Figures 1A, 1B, and 1C). In some embodiments, increased LC3B-11 in combination with increased p62 indicates autophagosome accumulation and impaired autophagy.

[0225] Liver damage caused by protein accumulation Disclosed herein is a method for treating liver damage caused by protein accumulation in a subject, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the accumulating protein is α1-antitrypsin.

[0226] Alpha-1 antitrypsin is encoded by the gene SERPINA1. The normal allele is designated M, while common SERPINA1 alleles associated with liver disease have the amino acid changes Glu264Val (designated S) and Glu342Lys (designated Z). Individuals homozygous for the Z (designated PiZZ) allele have pulmonary symptoms of their A1AT deficiency, which can be treated with enzyme replacement. However, individuals heterozygous for the Z allele, carrying either the M allele (designated PiMZ) or the S allele (designated PiSZ), show signs of liver disease. The protein resulting from translation of the Z and S alleles is a misfolded protein. This misfolded protein has been shown to polymerize, leading to cellular damage through the accumulation of misfolded and polymerized proteins. Protection against damage from accumulated misfolded proteins has been observed by increasing autophagy.

[0227] In some embodiments, HSD17B13 plays a role in autophagy. In some embodiments, autophagy is important for removing misfolded proteins and is involved in liver damage caused by α1-antitrypsin deficiency. In some embodiments, inhibiting HSD17B13 improves autophagy, thereby improving the clearance of misfolded proteins and improving liver health. In some embodiments, liver diseases associated with α1-antitrypsin deficiency include inflammation and decreased platelets. In some embodiments, inactive HSD17B13 is associated with reduced inflammation, decreased inflammatory genes including NF-kB and TGF-β, and increased platelets.

[0228] In some embodiments, the protein accumulation is eliminated via autophagy. In some embodiments, the protein is a misfolded protein. In some embodiments, the liver damage is caused by α1-antitrypsin deficiency. In some embodiments, α1-antitrypsin deficiency results in proteins that are not fully processed and accumulate as misfolded proteins in the liver. In some embodiments, the liver disease associated with α1-antitrypsin deficiency includes inflammation. In some embodiments, the liver disease associated with α1-antitrypsin deficiency includes platelet reduction.

[0229] Treatment of virus-induced damage Disclosed herein is a method for treating viral infection-induced liver injury in a subject, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0230] Also disclosed herein is a method for reducing the severity of inflammation in a subject having a viral infection, the method comprising administering to the subject a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor.

[0231] Also disclosed herein is a method for reducing the severity of an acute immune response in a subject having a viral infection, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0232] Viral infection is often associated with dysregulation of liver inflammatory response.In some embodiments, inactive HSD17B13 is associated with lower levels of genes involved in the activation of innate immune response, including cytokines.Inflammation is an important component of virus-driven injury.In some embodiments, inactive HSD17B13 protects against the rapid progression of fibrosis in HCV patients.

[0233] Because AAV-driven gene therapy is aided by autophagy for incorporation into hepatocytes, HSD17B13 inhibitors that improve autophagy and reduce inflammation could enhance efficacy and reduce side effects.

[0234] In some embodiments, the viral infection is hepatitis A. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis C.

[0235] In some embodiments, the viral infection is SARS-Cov-2.

[0236] SARS-Cov-2 Liver injury and elevated liver transaminases are common features in patients with severe SARS-CoV-2 infection. There is no clear increased risk of COVID-19 associated with liver disease, and thus, 2–11% of patients with COVID-19 have underlying liver comorbidities. In contrast, a much larger proportion of patients (14–53%) have elevated liver transaminases. Patients suspected of having COVID-19 who test positive for SARS-CoV-2 RNA have elevated ALT, AST, and decreased albumin compared with patients who test negative for viral RNA, consistent with liver injury. Among patients who died from COVID-19, 58% and 78% had elevated liver transaminases. Elevated liver transaminases were particularly pronounced in intensive care unit patients (62%) compared with 25% of patients not requiring ICU care. Patients with a CT scan-confirmed diagnosis of COVID-19 during the asymptomatic stage had a lower incidence of elevated liver transaminases compared with patients diagnosed after the onset of symptoms. Although there may be a role for the virus in causing direct liver damage, as evidenced by the observation of SARS-CoV-2 RNA in blood and feces, as well as by 2–10% of patients with diarrhea, liver damage can also result from secondary inflammatory events or the use of many different drugs during critical care.

[0237] In addition to liver injury in severe COVID-19 patients, there is a high incidence of cytokine increases, or cytokine storms, which can cause multiple organ failure and death. Therefore, preventing or treating cytokine storms may be critical for treating the most severely ill patients. Blood analysis of COVID-19 patients generally shows decreases in CD4 and CD8 cells but increases in Th17 cells. Similarly, increases in IL-6, IL-10, IL-2, and IFNγ were observed in cohorts of patients with severe disease. Overall, liver injury is seen in COVID-19 patients experiencing more widespread and more severe disease, involving multiple organs beyond the lungs. Possible reasons for this include oral uptake through the more permeable intestinal barrier in patients with comorbidities such as diabetes. The liver is exposed to the virus and, as a key mediator of the inflammatory response, may mediate either resolution of the inflammatory process or acceleration of the inflammatory process, leading to increased cytokine release and further organ damage.

[0238] Genetic evidence for the gene encoding the enzyme HSD17B13, which is associated with hepatic transaminase levels and liver disease, is rapidly growing. Herein, genetic evidence includes numerous studies of genetic and disease information from over 200,000 individuals. Lack of HSD17B13 activity has been shown to be protective against liver disease caused by overnutrition, excessive and chronic alcohol consumption, toxins such as copper, and viruses such as HCV. The highly reproducible association of HSD17B13 with multiple forms of liver disease, elevated hepatic transaminases, and liver injury has inspired efforts to develop inhibitors of this enzyme to prevent and treat liver injury. The diversity of toxins and damage prevented by loss of HSD17B13 function is such that we propose here that it prevents liver injury in severe COVID-19.

[0239] HSD17B13 activity has been shown to be involved in inflammation and inflammatory responses. Loss of HSD17B13 function has recently been associated with decreased gene expression and protein levels of immune response genes involved in adverse events, including IL-6, IL-10, and IL-1β. An enzymatically inactive polymorph of HSD17B13 is associated with lower ALT levels and lower severity of histopathological endpoints of inflammation in patients with nonalcoholic fatty liver disease.

[0240] In some embodiments, HSD17B13 inhibitors prevent and treat liver injury and reduce the severity of inflammation and acute immune responses in patients with COVID-19.

[0241] In some embodiments, the viral infection is associated with dysregulated inflammatory responses in the liver. In some embodiments, administration results in a decrease in the level of immune response-activating genes. In some embodiments, administration results in a decrease in inflammation. In some embodiments, the subject has elevated levels of alanine aminotransferase (ALT). In some embodiments, the subject has elevated levels of aspartate aminotransferase (AST). In some embodiments, the subject has reduced levels of albumin.

[0242] Malignant lesions Disclosed herein is a method for treating a malignancy selected from hepatocellular carcinoma (HCC), hepatobiliary adenoma, cholangiocarcinoma, gallbladder adenocarcinoma, and bile duct malignancies in a subject, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0243] Inactive HSD17B13 is associated with a lower rate of HCC. However, HSD17B13 expression is low in tumor tissue but normal in the peritumoral space. High protein levels in the peritumoral space are associated with improved survival and tumor-free survival. This apparent contradiction supports the use of small molecules that inhibit HSD17B13 but maintain the protein available to support autophagy activity. Autophagy is important for maintaining killer T-cell responses and using the body's own immune system to fight tumors. By inhibiting HSD17B13, surrounding tissues can undergo effective autophagy, enabling a killer T-cell response.

[0244] HSD17B13 is highly expressed in normal gallbladder cells. Inactive HSD17B13 is associated with increased phosphotidylcholine, which is essential for sequestering cytotoxic bile acids for excretion and bile flow. These factors, along with improved killer T cell responses and reduced inflammation and fibrosis, are mechanisms by which HSD17B13 inhibitors can be used to treat hepatobiliary adenomas and gallbladder adenocarcinomas.

[0245] In some embodiments, the malignant tumor is hepatocellular carcinoma (HCC). In some embodiments, the malignant tumor is hepato-biliary adenoma. In some embodiments, the malignant tumor is cholangiocarcinoma. In some embodiments, the malignant tumor is gallbladder adenocarcinoma. In some embodiments, the HSD17B13 receptor is expressed in the peritumoral space.

[0246] Hemochromatosis A method for treating hemochromatosis in a subject, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the hemochromatosis is primary hemochromatosis. In some embodiments, the hemochromatosis is secondary hemochromatosis. In some embodiments, the hemochromatosis is caused by liver disease. In some embodiments, the hemochromatosis is drug-induced hemochromatosis.

[0247] Lysosomal acid lipase deficiency (LAL-D) Disclosed herein are methods for treating lysosomal acid lipase deficiency (LAL-D) in a subject, the methods comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by a mutation in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes Wolman disease. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes cholesteryl ester storage disease. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) is caused by a mutation in the LIPA gene. In some embodiments, the lysosomal acid lipase deficiency (LAL-D) causes the accumulation of fatty substances in the cells and tissues of the body.

[0248] Bleeding / clotting disorder Disclosed herein are methods for treating a bleeding disorder in a subject, the methods comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the bleeding disorder is hemophilia A or hemophilia B.

[0249] Disclosed herein are methods for treating a coagulation factor disorder in a subject, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the coagulation factor disorder is von Willebrand disease.

[0250] In some embodiments, diseases treated by inhibition of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) are listed in the table below.

[0251] [Table 3]

[0252] Also disclosed herein are methods for selectively inhibiting HSD17B13, comprising administering a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound selectively inhibits HSD17B13 over HSD17B2, HSD17B14, or any combination thereof. In some embodiments, inhibition of HSD17B2 is associated with disruption of normal endocrine function in multiple tissues. In some embodiments, inhibition of HSD17B2 is associated with weight loss. In some embodiments, inhibition of HSD17B2 is associated with muscle loss. In some embodiments, inhibition of HSD17B14 is associated with disruption of normal endocrine function in multiple tissues.

[0253] dosage In certain embodiments, compositions containing the compounds described herein are administered for preventive 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 prevent at least one symptom of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0254] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will vary depending on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in remission, to prevent the recurrence of the disease or condition. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal having 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 recently been identified as a major determinant of liver fat content. Several studies have confirmed that the I148M variant predisposes to the full range of liver damage associated with fatty liver, from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant is a major determinant of the progression of alcohol-related steatohepatitis to cirrhosis, and represents a major determinant affecting fibrogenesis and associated clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis, and primary sclerosing cholangitis. In some embodiments, PNPLA3 polymorphisms are used to predict liver disease progression.

[0255] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0256] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon recurrence of symptoms.

[0257] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., 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.

[0258] In general, however, dosages used for adult human treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, dosages utilized for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is suitably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0259] In one embodiment, a suitable daily dosage of a compound described herein or a pharmaceutically acceptable salt 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 a dosage form will be less than or greater than the ranges set forth herein, depending 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 requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0260] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD10 and ED90. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between the LD50 and ED50. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein lies within a range of circulating concentrations that includes the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dosage will vary within this range depending on the dosage form used and the route of administration utilized.

[0261] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharmaceutically 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 topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0262] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0263] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, intravaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection, as well as intramuscular, subcutaneous, intravenous, and intramedullary injection.

[0264] In certain embodiments, the compounds described herein are administered locally rather than systemically, often as depot or sustained-release preparations, for example, via injection of the compound directly into an organ. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is selectively taken up by the organ. In still 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 still other embodiments, the compounds described herein are administered locally.

[0265] Pharmaceutical Compositions / Formulations The compounds described herein can be administered to subjects according to standard pharmaceutical practice alone or in pharmaceutical compositions, combined with pharmaceutically acceptable carriers, excipients or diluents.In one embodiment, the compounds of the present invention can be administered to animals.The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration routes.

[0266] In another aspect, the present invention provides a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner, using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutically usable preparations.Suitable formulation depends on the route of administration selected. Summary summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, 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.

[0267] In some embodiments, the pharmaceutically acceptable excipient is selected from a carrier, a binder, 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 penetration enhancer, a humectant, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0268] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. 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, pulsatile-release formulations, multiparticulate formulations, and mixed immediate and controlled-release formulations.

[0269] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0270] Orally administered pharmaceutical compositions can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and optionally adding suitable excipients to obtain tablets or dragee cores, followed by processing the granular mixture. Suitable excipients include, for example, 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 other materials such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Optionally, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, for example, sodium alginate, are added. In some embodiments, dyes or pigments are added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0271] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and sealed soft 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 compound is dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0272] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the compounds described herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent the growth of microorganisms.

[0273] combination Disclosed herein are methods of treating hepatic, metabolic, or cardiovascular diseases using the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, in combination with an additional therapeutic agent.

[0274] In some embodiments, the additional therapeutic agent is used in the treatment of diabetes or a diabetes-related disorder or disease.

[0275] In some examples, the additional therapeutic agent is a statin, an insulin sensitizer, an insulin secretagogue, an α-glucosidase inhibitor, a GLP agonist, a GIP agonist, a THRβ agonist, a PDE inhibitor, a DPP-4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, gemigliptin, or dutogliptin), a catecholamine (e.g., epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor agonist (e.g., vasodilator, vasodilator-activated receptor agonist ... Examples of additional therapeutic agents include a peroxisome proliferator-activated receptor (PPAR)-γ agonist (e.g., a thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar, farglitazar, muraglitazar, or tesaglitazar), a peroxisome proliferator-activated receptor (PPAR)-α agonist, a peroxisome proliferator-activated receptor (PPAR)-δ 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 includes fish oil, a fibrate, a vitamin such as niacin, retinoic acid (e.g., 9-cis-retinoic acid), nicotinamide ribonucleoside, or an analog thereof, or a combination thereof. In other examples, the additional therapeutic agent comprises an ACC inhibitor, an FGF19 and FGF21 mimetic, a CCR2 / CCR5 antagonist, or a combination thereof.

[0276] In some embodiments, the additional therapeutic agent is vivitrol.

[0277] In some embodiments, the additional therapeutic agent is a statin, e.g., an HMG-CoA reductase inhibitor, fish oil, a fibrate, niacin, or a combination thereof. In other examples, the additional therapeutic agent is a lipid-lowering drug that interferes with lipid absorption, such as orlistat.

[0278] 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 lowering blood glucose levels elevated by food intake.

[0279] 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 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 slipro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, and glucagon-like peptide 1, and any combination thereof. In some embodiments, the additional therapeutic agent is a lipid-lowering agent.

[0280] 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.

[0281] 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. [Example]

[0282] Example 1: Synthesis of 4,6-dichloro-5-hydroxy-N-(4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0283] [ka]

[0284] Step 1: Synthesis of 3-amino-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0285] To a stirred solution of methyl 3-amino-1H-pyrazole-4-carboxylate (0.6 g, 4.25 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.745 g, 4.25 mmol) in toluene (3 mL) was added 2 M trimethylaluminum in toluene (2.04 mL, 21.3 mmol) at 0 °C. The resulting reaction mixture was stirred at 100 °C for 32 hours. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (15 × 2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give 3-amino-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (0.520 g, 43%) as a brown solid. LCMS(ES):m / z calculated for C12H11F3N4O,284.24;found,285.1(M+H).

[0286] Step 2: Synthesis of 4,6-dichloro-5-hydroxy-N-(4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0287] To a stirred solution of 3-amino-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.5 g, 1.76 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.439 g, 2.11 mmol) in acetonitrile (5 mL, 76.6 mmol) was added phosphorus trichloride (0.164 mL, 1.76 mmol) at ambient temperature. The resulting reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with ice water (20 mL). The precipitated solid was filtered and dried under reduced pressure to give a crude solid. The crude product was purified by reverse-phase preparative HPLC to give 4,6-dichloro-5-hydroxy-N-(4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide (0.093 g, 11%) as an off-white solid. LCMS (ES): m / z calculated for C18H12Cl2F3N5O3; 473.03 found, 472.1 (MH); 1 H NMR (400MHz, DMSO d6):δ 11.71(s,1H),8.83(t,J=5.2Hz,1H),8.21-8.16(m,1H),8.10(s,1H),7.75 (d,J=7.6Hz,1H),7.70-7.66(m,1H),7.55-7.48(m,2H),4.73-4.63(m,2H).

[0288] Example 2: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0289] [ka]

[0290] Step 1: Synthesis of 3-amino-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0291] To a stirred solution of methyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (0.4 g, 2.58 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.45 g, 2.58 mmol) in toluene (4 mL) was added 2 M trimethylaluminum in toluene (2.47 mL, 25.8 mmol) at 0 °C. The resulting reaction mixture was stirred for 32 h at 100 °C. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (15 × 2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography to give 3-amino-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.5 g, 65.05%) as a brown solid. LCMS (ES): m / z calculated for C13H13F3N4O, 298.27; found, 299.1 (M+H).

[0292] Step 2: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0293] To a stirred solution of 3-amino-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.5 g, 1.68 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.42 g, 2.01 mmol) in acetonitrile (5 mL) was added phosphorus trichloride (0.157 mL, 1.68 mmol) at ambient temperature. The resulting reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with ice-cold water (20 mL). The precipitated solid was filtered and dried under reduced pressure to give the crude product. The resulting crude product was purified by reverse-phase preparative HPLC to give 4,6-dichloro-5-hydroxy-N-[1-methyl-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1H-pyrazol-3-yl]pyridine-2-carboxamide (0.073 g, 9%) as a pale yellow solid. LCMS (ES): m / z calculated for C19H14Cl2F3N5O3, 487.04; found, 486.1 (MH); 1 H NMR(400MHz,DMSO-d6):δ 11.47 s, 1H),8.77(t,J=6.0Hz,1H),8.27(s,1H),8.05(s,1H),7.75(d,J=8.0Hz,1 H),7.95-7.68(m,1H),7.54-7.47(m,2H),4.68-4.58(m,2H),3.86(s,3H).

[0294] Example 3: Synthesis of 3-(3,5-dichloro-4-hydroxybenzamido)-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0295] [ka]

[0296] To a stirred solution of 3-amino-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.15 g, 0.528 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (0.12 g, 0.580 mmol) in acetonitrile (3 mL) was added phosphorus trichloride (0.013 mL, 0.158 mmol) dropwise at room temperature. The resulting reaction mixture was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with ice-cold water (15 mL), and the resulting solid was collected by filtration, washed with diethyl ether (5 mL), and dried under reduced pressure to give the crude product as an off-white solid. The crude product was purified by preparative HPLC (Column: XBridge C18 (250 mm × 4.6 mm × 5 μm); Mobile phase (A): 0.1% TFA in water; Mobile phase (B): acetonitrile; Flow rate: 1.0 mL / min) to give 3-(3,5-dichloro-4-hydroxybenzamido)-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (0.058 g, 23%) as a white solid. LCMS (ES) m / z calculated for C19H13Cl2F3N4O3 is 472.03; found, 473.1 (M+H), 98.63% at 254 nm. 1 H NMR(400MHz,DMSO d6 at 90℃) δ 8.4(bs,1H),8.13(bs,1H),7.85(s,2H),7.70(d,J=7.6Hz,1H),7.62-7.57(m,2H),7.49-7.47(m,1H),4.63(d,J=24.8Hz,2H).

[0297] Example 4: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-3-((2-(trifluoromethoxy)benzyl)carbamoyl)-1H-pyrazol-4-yl)picolinamide

[0298] [ka]

[0299] Step 1: Synthesis of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate

[0300] To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (3 g, 17.5 mmol) in anhydrous dimethylformamide (25 mL) was added potassium carbonate (2.91 g, 21 mmol) at 0° C., followed by slow addition of iodomethane (2.99 g, 21 mmol) over 15 minutes. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×30 mL), brine (2×20 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by flash chromatography to give methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.87 g, 58%) as an off-white solid and methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (0.92 g, 28%) as a yellow sticky solid. LCMS (ES) m / z calculated for C6H7N3O4 is 185.04; found, 186.1 (M+H).

[0301] Step 2: Synthesis of methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate

[0302] To a stirred solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.87 g, 10.1 mmol) in methanol (30 mL) was added Pd / C (0.45 g, 2.11 mmol), followed by stirring at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a pad of Celite and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give the crude compound, which was triturated with n-pentane (10 mL) and diethyl ether (10 ml) to give methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate (1.2 g, 77%) as a black solid.

[0303] Step 3: Synthesis of 4-amino-1-methyl-N-(2-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxamide

[0304] To a stirred solution of methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate (0.25 g, 1.61 mmol) and 1-[2-(trifluoromethoxy)phenyl]methanamine (0.30 g, 1.61 mmol) in toluene (5 mL) was added 2 M trimethylaluminum in toluene (0.46 mL, 4.83 mmol) at 0 °C. The resulting reaction mixture was stirred for 2 h at 100 °C. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (15 × 2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography to give 4-amino-1-methyl-N-(2-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxamide (0.17 g, 35%) as a pale yellow liquid. LCMS (ES) m / z calculated for C13H13F3N4O2 is 314.10; found, 315.1 (M+H).

[0305] Step 4: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-3-((2-(trifluoromethoxy)benzyl)carbamoyl)-1H-pyrazol-4-yl)picolinamide

[0306] To a stirred solution of 4-amino-1-methyl-N-(2-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxamide (0.14 g, 0.445 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.1 g, 0.490 mmol) in chlorobenzene (0.8 mL) was added phosphorus trichloride (0.011 mL, 0.134 mmol) dropwise at room temperature. The resulting reaction mixture was heated to 100° C. for 6 hours. The reaction mixture was cooled to ambient temperature and quenched with ice-cold water (15 mL), and the resulting solid was collected by filtration, washed with diethyl ether (5 mL), and dried under reduced pressure to give the crude product as an off-white solid. The crude product was purified by preparative HPLC to give 4,6-dichloro-5-hydroxy-N-(1-methyl-3-((2-(trifluoromethoxy)benzyl)carbamoyl)-1H-pyrazol-4-yl)picolinamide (0.067 g, 30%) as an off-white solid. LCMS (ES) m / z calculated for C19H14Cl2F3N5O4 is 503.04; found, 504.1 (M+H). 1 H NMR(400MHz,DMSO d6) δ 11.13(s,1H),8.98(t,J=6.0Hz,1H),8.43(s,1H),8.07(s,1H),7.43-7.36(m,4H),4.55(d,J=6.0Hz,2H),3.96(s,3H).

[0307] Example 5: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-5-((2-(trifluoromethoxy)benzyl)carbamoyl)-1H-pyrazol-4-yl)picolinamide

[0308] The title compound was synthesized as described above. LCMS (ES) m / z calculated for C19H14Cl2F3N5O4 is 503.04; found, 504.1 (M+H). 1H NMR(400MHz,DMSO d6) δ 11.13(s,1H),8.94(t,J=6.0Hz,1H),8.43(s,1H),8.07(s,1H),7.43-7.36(m,4H) 4.55(d,J=6.0Hz,2H),3.96(s,3H).

[0309] Example 6: Synthesis of 3-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0310] [ka]

[0311] Step 1: Synthesis of 3-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0312] To a stirred solution of 3,5-dichloro-4-methoxybenzoic acid (0.22 g, 1.01 mmol) in pyridine (2 mL) at 0 °C, phosphoroyl trichloride (0.094 mL, 1.01 mmol) was added and stirred at room temperature for 10 minutes. 3-Amino-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.3 g, 1.01 mmol) was then added and stirred for 30 minutes. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 mL × 2). The combined organic layers were washed with water (2 mL × 2), brine (2 mL × 2), and dried over sodium sulfate to give the crude compound, which was purified by flash column chromatography to give 3-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.2 g, 40%) as a white solid. LCMS (ES) m / z calcd, For C21H17Cl2F3N4O3, 500.06; found, 501.1 (M+H).

[0313] Step 2: Synthesis of 3-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0314] To a stirred solution of 3-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.110 g, 0.219 mmol) in dichloromethane (0.5 mL) was added boranetribromide in dichloromethane (0.167 mL, 1.76 mmol) at 0° C., and the reaction was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water and then extracted with DCM (3×5 mL). The combined organic layers were washed with water (3 mL×2), brine (2 mL×2), and dried over sodium sulfate to give the crude compound, which was purified by flash column chromatography to give an off-white solid. The solid material was further purified by reverse-phase preparative HPEC to give pure 3-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide as a white solid (31 mg, 29%). LCMS (ES) m / z calculated for C20H15Cl2F3N4O3, 486.05; found, 487.1 (M+H). 1 H NMR(400MHz,DMSO-d6) δ 10.98(s,1H),10.51(s,1H),8.51(t,J=5.6Hz,1H),8.22(s,1H),7.83(s,2H),7.70( d,J=7.6Hz,1H),7.61(t,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.46(t,J=7.6Hz,1H) 4.58(d,J=5.6Hz,2H),3.85(s,3H).

[0315] Example 7: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0316] [ka]

[0317] Step 1: Synthesis of 5-amino-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0318] To a solution of methyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (0.4 g, 2.58 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.358 mL, 2.58 mmol) in toluene (5 mL, 42.3 mmol) was added 2 M trimethylaluminum in toluene (0.741 mL, 3 equivalents, 7.73 mmol) at 0 °C. The reaction mixture was then stirred at 120 °C for 12 hours. The reaction mixture was cooled to ambient temperature and poured into cold water. The resulting solid material was filtered, and the filtrate was extracted with DCM (3 mL × 2). The combined organic phases were washed with water (2 mL × 2), brine (2 mL × 2), dried over sodium sulfate, and evaporated under reduced pressure to give 5-amino-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.77 g, quantitative). LCMS(ES)m / z calcd, For C13H13F3N4O,298.10;found,299.1(M+H).

[0319] Step 2: Synthesis of 5-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0320] To a stirred solution of 3,5-dichloro-4-methoxybenzoic acid (0.0593 g, 0.268 mmol) in pyridine (1 mL) at 0 °C, phosphoroyl trichloride (0.025 mL, 0.268 mmol) was added and stirred for 10 minutes at room temperature. To this stirred solution, 5-amino-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.08 g, 0.268 mmol) was added and stirred for an additional 30 minutes. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 mL × 2). The combined organic layers were washed with water (2 mL × 2), brine (2 mL × 2), and dried over sodium sulfate to give the crude compound, which was purified by flash column chromatography to give 5-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide as a white solid (0.11 g, 82%). LCMS (ES) m / z calcd, For C21H17Cl2F3N4O3, 500.06; found, 501.0 (M+H).

[0321] Step 3: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0322] To a stirred solution of 5-(3,5-dichloro-4-methoxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (0.1 g, 0.199 mmol) in dichloromethane (0.556 mL) was added (0.151 mL, 1.6 mmol) at 0° C., and the reaction was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with DCM (3×5 mL). The combined organic layers were washed with water (3 mL × 2), brine (2 mL × 2), and dried over sodium sulfate to give the crude compound, which was purified by flash column chromatography to give an off-white solid, which was further purified by reverse-phase preparative HPLC to give 5-(3,5-dichloro-4-hydroxybenzamido)-1-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-4-carboxamide (5 mg, 5%) as a white solid. LCMS (ES) m / z calculated for C20H15Cl2F3N4O3, 486.05; found, 487.1 (M+H); 1 H NMR(400MHz,DMSO-d6) δ 11.01(s,1H),10.31(bs,1H),8.55(t,J=5.6Hz,1H),8.00(d,J=6.4Hz,3H),7.70(d,J= 8Hz,1H),7.61(t,J=7.6Hz,1H),7.52-7.43(m,2H),4.57(d,J=5.6Hz,2H),3.65(s,3H).

[0323] Example 8: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-phenyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0324] [ka]

[0325] Step 1: Synthesis of methyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate

[0326] To a stirred solution of methyl 3-amino-1H-pyrazole-4-carboxylate (0.3 g, 2.13 mmol) in DMF (10 mL) was added iodobenzene (0.35 mL, 3.19 mmol), cesium carbonate (693 mg, 2.13 mmol), and copper bromide (30.5 mg, 0.213 mmol), and the reaction mass was heated to 150° C. in a MW oven for 45 minutes. After completion of the reaction, the reaction mass was quenched with water (20 mL), extracted with ethyl acetate (20 mL), the organic layer was collected and washed with water (20 mL), brine solution (20 mL), the organic layer was dried over sodium sulfate, filtered, and evaporated to give the crude product, which was purified by flash column chromatography to give pure methyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (0.3 g, 65%) as an off-white solid. LCMS(ES)m / z calculated for C11H11N3O2, 217;found,218(M+H).

[0327] Step 2: Synthesis of methyl 3-(4,6-dichloro-5-hydroxypicolinamido)-1-phenyl-1H-pyrazole-4-carboxylate

[0328] To a stirred solution of methyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (250 mg, 1.15 mmol) in chlorobenzene (5 mL), 4,6-dichloro-5-hydroxypicolinic acid (311 mg, 1.5 mmol), PCl3 (158 mg, 1.15 mmol) were added, and the reaction mass was heated to 130 °C for 4 hours. After completion of the reaction, the reaction mass was cooled to room temperature, quenched with ice water (10 mL), extracted with ethyl acetate (10 mL), and the organic layer was collected and washed with water (10 mL) and brine solution (10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give the crude product, which was purified by flash column chromatography to give the title product, methyl 3-(4,6-dichloro-5-hydroxypicolinamido)-1-phenyl-1H-pyrazole-4-carboxylate (250 mg, 53%) as an off-white solid. LCMS(ES)m / z calculated for C17H12Cl2N4O4, 406;found,407(M+H).

[0329] Step 3: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-phenyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-3-yl)picolinamide

[0330] To a stirred solution of methyl 3-(4,6-dichloro-5-hydroxypicolinamido)-1-phenyl-1H-pyrazole-4-carboxylate (220 mg, 0.540 mmol) in toluene (5 mL) was added (2-(trifluoromethyl)phenyl)methanamine (0.076 mL, 0.540 mmol), the reaction mass was cooled to 0° C., trimethylaluminum 2.0 M in toluene (0.81 mL, 1.62 mmol) was added and the reaction mass was heated to 100° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS, after completion of the reaction the reaction mass was cooled to room temperature, quenched with ice water (10 mL), extracted with ethyl acetate (20 mL) and dried over sodium sulfate to give the crude product which was purified by flash column chromatography, the fractions were collected and dried to give the crude product which was further purified by preparative HPLC. LCMS(ES)m / z calculated for C24H16Cl2F3N5O3, 549.0;found,550(M+H). 1 H NMR(400MHz,DMSO-d6):δ 10.53(s,1H),8.70-8.62(m,1H),8.28(s,1H),7.91(s,1H),7.71(d,J=8.0Hz,1H),7.63-7. 60(m,1H),7.56-7.53(m,3H),7.49-7.45(m,3H),7.40-7.38(m,1H),4.60(d,J=5.2Hz,2H).

[0331] Example 9: Synthesis of 3-(3,5-dichloro-4-hydroxybenzamido)-1-phenyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0332] The title compound was synthesized as described above. LCMS (ES): m / z calculated for C25H17Cl2F3N4O3, 548.0; found, 549 (M+H). 1H NMR(400MHz,DMSO-d6):δ 11.00(bs,1H),10.73(s,1H),9.01(s,1H),8.66(t,J=5.6Hz,1H),7.94(s,2H),7.87-7.80(m,2H),7.73-7.6 8(m,1H),7.64-7.62(m,2H),7.61-7.57(m,2H),7.50-7.47(m,1H),7.40-7.37(m,1H),4.63(d,J=5.2Hz,2H).

[0333] Example 10: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-5-yl)picolinamide

[0334] [ka]

[0335] Step 1: Synthesis of 5-amino-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide

[0336] To a solution of methyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (0.4 g, 2.58 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.358 mL, 2.58 mmol) in toluene (5 mL, 42.3 mmol), trimethylalumane (0.741 mL, 3 equiv., 7.73 mmol) was added dropwise under nitrogen at 0°C and stirred for a while. The resulting reaction mixture was then stirred at 120°C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice blocks, and the formed solid was filtered. The aqueous layer was extracted with DCM (3 mL × 2). The combined organic layers were washed with water (2 mL × 2), brine (2 mL × 2), dried over sodium sulfate, and evaporated under reduced pressure to give 5-amino-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (0.77 g, 2.58 mmol). LCMS (ES) m / z calcd, For C13H13F3N4O, 298.10; found, 299.1 (M+H).

[0337] Step 2: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-5-yl)picolinamide

[0338] To a stirred solution of 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.174 g, 0.838 mmol) in pyridine (2 mL), PCl3 (0.157 mL, 1.68 mmol) was added at 0 °C and stirred for 15 minutes at room temperature. Then, 5-amino-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (0.25 g, 0.838 mmol) was added thereto and stirred for 30 minutes. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (5 mL × 2). The combined organic layer was washed with water (3 mL × 2), brine (4 mL × 2), and dried over sodium sulfate to give the crude compound, which was purified by Combi flash chromatography. Pure fractions were collected and concentrated to give the title compound, which was further purified by reverse-phase preparative HPLC. Pure fractions were collected and concentrated to give pure 4,6-dichloro-5-hydroxy-N-(1-methyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)-1H-pyrazol-5-yl)picolinamide (0.012 g, 0.0246 mmol) as a white solid. LCMS (ES) m / z calculated for C19H14Cl2F3N5O3, 487.04; found, 488.00 (M+H), 99.6% at 254 nm. 1 H NMR(400MHz,DMSO-d6) δ 10.41(s,1H),8.59-8.57(m,1H),7.99(d,J=17.6Hz,2H),7.67(d,J=8Hz,1H ),7.56-7.47(m,1H),7.48-7.42(m,2H),4.54(d,J=4.4Hz,2H),3.66(s,3H).

[0339] Example 11: Synthesis of 3,5-dichloro-4-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)benzamide

[0340] [ka]

[0341] Step 1: Synthesis of 2-amino-6-bromo-3-methyl-N-(2-(trifluoromethyl)benzyl)benzamide

[0342] To a stirred solution of 2-amino-6-bromo-3-methylbenzoic acid (2 g, 8.69 mmol) in N,N-dimethylformamide (10 mL), 1-[2-(trifluoromethyl)phenyl]methanamine (1.23 mL, 8.69 mmol), triethylamine (4.24 mL, 30.4 mmol), HATU (3.97 g, 10.4 mmol), and N,N-dimethylpyridin-4-amine (0.106 g, 0.869 mmol) were added and stirred at room temperature for 2 hours. The reaction was monitored by TLC. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 2-amino-6-bromo-3-methyl-N-(2-(trifluoromethyl)benzyl)benzamide (2 g, 59%) as an off-white solid. LCMS (ES): m / z calculated for C16H14BrF3N2O, 386.02; found, 387.2

[0343] Step 2: Synthesis of 5-bromo-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one

[0344] Sodium nitrite (2.89 g, 41.8 mmol) was added portionwise to a stirred solution of 1 M hydrogen chloride (72 mL) at 0° C. and stirred for 20 minutes. Then, 2-amino-6-bromo-3-methyl-N-(2-(trifluoromethyl)benzyl)benzamide (5.4 g, 13.9 mmol) in N,N-dimethylformamide (4 mL) was added at 0° C. and stirred for 1 hour. The reaction was monitored by TLC. After adjusting the pH to approximately 9 with concentrated ammonia, the reaction mixture was stirred for 20 minutes. The pH was then adjusted to approximately 2 with concentrated hydrochloric acid and stirring was continued for an additional 20 minutes. The precipitated solid was filtered, washed with hexane (25 mL), and dried to give 5-bromo-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (3.4 g, 61%) as an orange solid. LCMS(ES):m / z calculated for C16H11BrF3N3O,397.18;found,398.

[0345] Step 3: Synthesis of tert-butyl (8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate

[0346] A suspension of 5-bromo-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (3.4 g, 8.54 mmol), tert-butyl carbamate (1.10 g, 9.39 mmol), and cesium carbonate (8.35 g, 25.6 mmol) in 1,4-dioxane (80 mL, 1.04 mmol) was degassed with nitrogen, and Xantphos (0.49 g, 0.854 mmol) and Pd(dba) (0.491 g, 0.854 mmol) were added at room temperature and stirred in a sealed tube at 100 °C for 16 h. The reaction progress was monitored by LCMS and TLC. Upon completion, the reaction mixture was quenched with water, and the compound was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give a crude solid. The crude was purified by flash column chromatography to give tert-butyl (8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate (2.1 g, 56%) as an off-white solid. LCMS (ES): m / z calcd. C21H21F3N4O3, 434.42; found, 435.1

[0347] Step 4: Synthesis of 5-amino-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one.

[0348] To a suspension of tert-butyl (8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate (2 g, 4.76 mmol) in methanol (3.12 m, 77.1 mmol) was added 4 M HCl in dioxane (0.826 mL, 23.8 mmol) at room temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-amino-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (1.4 g, 92%) as a yellow solid. LCMS(ES):m / z calculated for C16H13F3N4O,334.30;found,335.1.

[0349] Step 5: Synthesis of 3,5-dichloro-4-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)benzamide

[0350] To a suspension of 5-amino-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1.2.3]triazin-4(3H)-one (0.350 g, 1.05 mmol) in acetonitrile (5 mL) was added 3,5-dichloro-4-hydroxybenzoic acid (0.238 g, 1.15 mmol) and phosphorus trichloride (0.916 mL, 1.05 mmol) at ambient temperature. The resulting reaction mixture was heated to 130° C. for 3 hours. The reaction mixture was cooled to ambient temperature and then poured into ice-cold water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 3,5-dichloro-4-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)benzamide (0.010 g, 2%) as a white solid. LCMS (ES): m / z calculated for C23H15Cl2F3N4O3, 522.05; found 521.1 (MH); 1 H NMR(400MHz,DMSO-d6):δ 12.29(s,1H),11.15(bs,1H),8.86(d,J=8.4Hz,1H),8.00(d,J=8.4Hz,1H),7.84 -7.80(m,3H),7.62-7.52(m,2H),7.31(d,J=8Hz,1H),5.78(s,2H),2.72(s,3H).

[0351] Example 12: Synthesis of 4,6-dichloro-5-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)picolinamide

[0352] [ka]

[0353] To a suspension of 5-amino-8-methyl-3-(2-(trifluoromethyl)benzyl)benzo[d][1.2.3]triazin-4(3H)-one (0.35 g, 1.05 mmol) in acetonitrile (5 mL) was added 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.240 g, 1.15 mmol) and phosphorus trichloride (0.09 mL, 1.05 mmol) at ambient temperature. The resulting reaction mixture was heated to 130° C. for 3 hours. The reaction mixture was cooled to ambient temperature and then poured into ice-cold water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4,6-dichloro-5-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)picolinamide (0.006 g, 1.8%) as a white solid. LCMS (ES): m / z calculated for C22H14Cl2F3N5O3, 523.04; found 524.1 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 13.05(s,1H),9.0(d,J=8.4Hz,1H),8.09(s,1H),7.97(d,J=8.8Hz,1H),7.82(t, J=7.6Hz,1H),7.61-7.51(m,2H),7.30(d,J=8Hz,1H),5.76(s,2H),2.71(s,3H).

[0354] Example 13: Synthesis of 4,6-dichloro-N-(8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)-5-hydroxypicolinamide

[0355] [ka]

[0356] Step 1: Synthesis of 2-amino-6-bromo-3-fluoro-N-(2-(trifluoromethyl)benzyl)benzamide

[0357] To a stirred solution of 2-amino-6-bromo-3-fluorobenzoic acid (1 g, 4.27 mmol) in DMF (15 mL), 1-[2-(trifluoromethyl)phenyl]methanamine (0.604 mL, 4.27 mmol), triethylamine (2.08 mL, 15 mmol), HATU (1.95 g, 5.13 mmol), and N,N-dimethylpyridin-4-amine (0.052 g, 0.427 mmol) were added and stirred for 16 hours at room temperature. The reaction was monitored by TLC. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 2-amino-6-bromo-3-fluoro-N-(2-(trifluoromethyl)benzyl)benzamide (1.5 g, 89.74%) as an off-white solid. LCMS (ES): m / z calculated for C15H11BrF4N2O, 390.0; found, 391.0.

[0358] Step 2: Synthesis of 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one

[0359] To a stirred solution of sodium nitrite (1.06 g, 15.3 mmol), a 1 M solution of HCl (25 mL) was added dropwise at 0° C. and stirred for 20 minutes. Then, 2-amino-6-bromo-3-fluoro-N-{[2-(trifluoromethyl)phenyl}methyl[benzamide] (2 g, 5.11 mmol) dissolved in DMF (10 mL) was added and stirred for 1 hour at 0° C. The reaction was monitored by TLC. The pH was adjusted to approximately 9 with concentrated ammonia and stirred for 20 minutes. The pH was then adjusted to approximately 2 with concentrated hydrochloric acid and stirring was continued for 20 minutes. After the reaction was complete, the mixture was suction filtered, and the filter cake was washed with a small amount of hexane and dried to give 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (0.6 g, 29%) as an orange solid. LCMS(ES):m / z calculated for C15H8BrF4N3O,400.98;found,402.0.

[0360] Step 3: Preparation of tert-butyl (8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate

[0361] A suspension of 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (0.2 g, 0.497 mmol), tert-butyl carbamate (0.117 g, 0.995 mmol), and cesium carbonate (0.486 g, 1.49 mmol) in 1,4-dioxane (5.15 mL, 60.4 mmol) was degassed with nitrogen, and Xantphos (0.0288 g, 0.0497 mmol) and Pd(dba) (0.0286 g, 0.0497 mmol) were added at room temperature and stirred in a sealed tube at 100 °C for 16 h. The reaction progress was monitored by LCMS and TLC. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (10 mL), brine (3 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give tert-butyl (8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate (0.130 g, 59.6%) as a colorless liquid. LCMS (ES): m / z calcd. C20H18F4N4O3, 438.34; found, 439.1.

[0362] Step 4: Synthesis of 5-amino-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one

[0363] To a suspension of tert-butyl (8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)carbamate (0.130 g, 0.297 mmol) in methanol (5 ml) was added 4 M HCl in dioxane (0.0515 mL, 1.48 mmol) and stirred for 16 hours at room temperature. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (10 mL), brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 5-amino-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (0.095 g, 94%). LCMS(ES):m / z calculated for C15H10F4N4O,338.27;found,339.1

[0364] Step 5: Synthesis of 4,6-dichloro-5-hydroxy-N-(8-methyl-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)picolinamide

[0365] A suspension of 5-amino-8-fluoro-3-(2-(trifluoromethyl)benzyl)benzo[d][1,2,3]triazin-4(3H)-one (0.130 g, 0.384 mmol) in acetonitrile (5 ml) was stirred with 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.0879 g, 0.423 mmol) and phosphorus trichloride (33.6 μL, 0.384 mmol) for 3 hours at 120° C. The reaction was monitored by TLC. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phase was washed with water (10 mL), brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC. The pure fractions were collected and concentrated to give 4,6-dichloro-N-(8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)-5-hydroxypicolinamide (0.007 g, 3.45%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.90(s,1H),9.14-9.10(m,1H),8.10-8.04(m,2H),7.86(d,J=7.6Hz,1H),7.64-7.54(m,2H),7.38(d,J=8Hz,1H),5.80(s,2H).LCMS(ES)m / z calculated for C21H11Cl2F4N5O3, 527.02; found 528.1(M+H).

[0366] Example 14: Synthesis of 3,5-dichloro-N-(8-fluoro-4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)-4-hydroxybenzamide

[0367] The title compound was synthesized as described above. LCMS (ES) m / z calculated for C22H12Cl2F4N4O3, 526.02; found, 527.0 (M+H); 1H NMR(400MHz,DMSO-d6) δ 12.03(s,1H),11.22(s,1H),8.90(d,J=9.2Hz,1H),8.07(t,J=9.6Hz,1H) ,7.85-7.81(m,3H),7.61-7.51(m,2H),7.36(d,J=8Hz,1H),5.78(s,2H).

[0368] Example 15: Synthesis of 4,6-dichloro-N-(8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)-5-hydroxypicolinamide

[0369] [ka]

[0370] Step 1: Synthesis of 2-amino-6-bromo-3-fluoro-N-((1S,2R)-2-phenylcyclobutyl)benzamide

[0371] To a stirred solution of 2-amino-6-bromo-3-fluorobenzoic acid (0.5 g, 2.14 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.89 mL, 6.41 mmol), HATU (0.75 g, 3.2 mmol), and (1S,2R)-2-phenylcyclobutan-1-amine (315 mg, 2.14 mmol) at room temperature. The resulting reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with water (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 2-amino-6-bromo-3-fluoro-N-((1S,2R)-2-phenylcyclobutyl)benzamide (0.62 g, 80%) as an off-white solid. LCMS(ES)m / z calculated for C17H16BrFN2O,362.04; found,363.0(M+2H).

[0372] Step 2: Synthesis of 5-bromo-8-fluoro-2-methyl-3-((1S,2R)-2-phenylcyclobutyl)quinazolin-4(3H)-one

[0373] To a stirred solution of 2-amino-6-bromo-3-fluoro-N-[(1S,2R)-2-phenylcyclobutyl]benzamide (619 mg, 1.7 mmol) in toluene (6 mL), p-TSA (58.7 mg, 0.341 mmol) and pentane-2,4-dione (0.192 mL, 1.87 mmol) were added at room temperature. The resulting reaction mixture was heated to 120° C. in a sealed tube for 16 hours. Upon completion, the reaction mixture was quenched with water (25 mL) and extracted into ethyl acetate (2×50 mL). The combined organics were washed with water (20 mL) and brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give crude 5-bromo-8-fluoro-2-methyl-3-((1S,2R)-2-phenylcyclobutyl)quinazolin-4(3H)-one (0.62 g, 94%) as a brown solid. LCMS (ES) m / z calculated for C19H16BrFN2O, 387.05; found, 389.1 (M+2H).

[0374] Step 3: Synthesis of tert-butyl (8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)carbamate

[0375] To a stirred solution of 5-bromo-8-fluoro-2-methyl-3-[(1S,2R)-2-phenylcyclobutyl]-3,4-dihydroquinazolin-4-one (0.5 g, 1.29 mmol) in 1,4-dioxane (3 mL) was added tert-butyl carbamate (454 mg, 3.87 mmol) and cesium carbonate (1.26 g, 3.87 mmol). The mixture was purged with N for 10 min, after which Xantphos (0.15 g, 0.258 mmol) and Pd(dba) (74.2 mg, 0.129 mmol) were added and heated to 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite, washed with ethyl acetate (30 mL), and the filtrate was evaporated to give a crude product that was purified by flash column chromatography to give tert-butyl (8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)carbamate (0.33 g, 60%) as an off-white solid. LCMS (ES) m / z calculated for C24H26FN3O3, 423.20; found, 424.2 (M+H).

[0376] Step 4: Synthesis of 5-amino-8-fluoro-2-methyl-3-((1S,2R)-2-phenylcyclobutyl)quinazolin-4(3H)-one

[0377] To solid tert-butyl N-{8-fluoro-2-methyl-4-oxo-3-[(1S,2R)-2-phenylcyclobutyl]-3,4-dihydroquinazolin-5-yl}carbamate (0.33 g, 0.779 mmol) was added 4 M HCl in dioxane (1.95 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was heated to 80° C. for 2 hours. Upon completion, the reaction mixture was evaporated to dryness under reduced pressure to give a solid, which was further triturated with n-pentane (20 mL) and dried to give 5-amino-8-fluoro-2-methyl-3-((1S,2R)-2-phenylcyclobutyl)quinazolin-4(3H)-one (0.2 g, 79%) as a white solid. LCMS(ES)m / z calculated for C19H18FN3O,323.14; found,324.1(M+H).

[0378] Step 5: Synthesis of 4,6-dichloro-N-(8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)-5-hydroxypicolinamide

[0379] To a stirred solution of hydroxypyridine 5-amino-8-fluoro-2-methyl-3-[(1S,2R)-2-phenylcyclobutyl]-3,4-dihydroquinazolin-4-one (150 mg, 0.464 mmol) in acetonitrile (2 mL) was added 4,6-dichloro-5-2-carboxylic acid (0.092 g, 0.18 mmol) and phosphorus trichloride (0.041 mL, 0.464 mmol). The resulting reaction mixture was heated to 100 °C in a sealed tube for 3 hours. Upon completion, the reaction mixture was quenched with ice-cold water (15 mL), stirred for 5 minutes, and the resulting solid was collected by filtration. The solid material was washed with n-pentane (10 mL) and acetonitrile (10 mL) and dried under reduced pressure to give 4,6-dichloro-N-(8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)-5-hydroxypicolinamide (0.092 g, 39%) as an off-white solid. LCMS(ES)m / z calculated for C25H19Cl2FN4O3, 512.08; found,513.1(M+H). HNMR(400MHz,DMSO-d6) δ 13.54(s,1H),8.72-8.68(m,2H),8.12(s,1H),7.70-7.65(m,1H),7.35-7.28(m,4H),7.22-7.19( m,1H),4.95-4.90(m,1H),4.81-4.76(m,1H),2.40(s,3H),2.36-2.25(m,2H),2.01-1.96(m,2H).

[0380] Example 16: Synthesis of 3,5-dichloro-N-(8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0381] [ka]

[0382] To a stirred solution of 5-amino-8-fluoro-2-methyl-3-[(1S,2R)-2-phenylcyclobutyl]-3,4-dihydroquinazolin-4-one (90 mg, 0.278 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (69.1 mg, 0.334 mmol) in chlorobenzene (3.0 mL) was added phosphorus trichloride (0.024 mL, 0.278 mmol) at 0° C. under a nitrogen atmosphere. The resulting reaction mass was heated to 130° C. for 12 hours. The reaction mixture was quenched with ice-cold water (10 mL), stirred for 5 minutes, and the resulting solid was collected by filtration. The solid was washed with n-pentane (10 ml) and dried under reduced pressure to give the crude product as a pale yellow solid. The crude material was purified by preparative HPLC to give 3,5-dichloro-N-(8-fluoro-2-methyl-4-oxo-3-((1S,2R)-2-phenylcyclobutyl)-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide (0.030 g, 21%) as an off-white solid. LCMS(ES)m / z calculated for C26H20Cl2FN3O3, 511.09; found,512.1(M+H). HNMR(400MHz,DMSO-d6) δ 12.73(s,1H),11.17(s,1H),8.56-8.53(m,1H),7.93(s,2H),7.70-7.65(m,1H),7.34-7.18(m,5H),4.97 -4.93(m,1H),4.76-4.69(m,1H),3.25-3.15(m,2H),2.42(s,3H),2.38-2.25(m,2H),1.99-1.94(m,1H).

[0383] Example 17: Preparation of 3,5-dichloro-N-(2,8-dimethyl-4-oxo-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0384] [ka]

[0385] Step 1: Preparation of 1-(cyclopropylidenemethyl)-2-(trifluoromethyl)benzene

[0386] To a stirred solution of 2-(trifluoromethyl)benzaldehyde (10 g, 57.4 mmol) (1) in tetrahydrofuran (150 mL), (3-bromopropyl)triphenylphosphonium bromide (29.3 g, 63.2 mmol) was added, followed by potassium tert-butoxide (19.3 g, 172 mmol), and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to ambient temperature, poured into cold water (50 mL), and extracted with ethyl acetate (3 × 45 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography to give 1-(cyclopropylidenemethyl)-2-(trifluoromethyl)benzene as a yellowish oil (2.5 g, 22%). 1 H NMR(400MHz,CDCl3): δ 7.96(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.48(t,J=7.6Hz,1H),7.32-7.25(m,1H),7.12(s,1H),1.2-1.5(m,4H).

[0387] Step 2: Synthesis of 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one

[0388] To a stirred solution of 1-(cyclopropylidenemethyl)-2-(trifluoromethyl)benzene (1.2 g, 6.05 mmol) in dichloromethane (10 mL) was added m-CPBA (1.25 g, 7.27 mmol) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with cold water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (25 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography to give 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one as a yellowish oil (0.5 g, 39% yield). 1H NMR (400MHz, CDCl3): δ7.67(d,J=8.0Hz,1H),7.43-7.58(m,2H),7.38(t,J=7.6Hz,1H),4.9 0(t,J=8.8Hz,1H),3.25-3.4(m,1H),3.12-3.18(m,1H),2.6-2.7(m,1H),2.08-2.2(m,1H).

[0389] Step 3: Synthesis of 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one oxime

[0390] To a stirred solution of 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one (4) (0.365 g, 1.7 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (0.355 g, 5.11 mmol) and potassium carbonate (0.707 g, 5.11 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one oxime (0.4 g, 102% yield) as a crude yellow solid. LCMS (ES) m / z calculated for C11H10F3NO, 229.07; found 230.1 (M+H);

[0391] Step 4: Synthesis of 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-amine

[0392] To a stirred solution of 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-one oxime (0.4 g, 1.75 mmol) in THF:MeOH (4:1) (12 mL) was added nickel chloride hexahydrate (0.083 mg, 0.349 mmol), followed by the dropwise addition of sodium borohydride (0.330 mg, 8.73 mmol) in additional portions at 0 °C under an inert atmosphere. After the addition was complete, the reaction was stirred at ambient temperature for 1 h. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-amine (6) as a yellow sticky solid (0.215 g, 57%). LCMS(ES)m / z calculated for C11H12F3N, 215.09; found 216.1(M+H).

[0393] Step 5: Synthesis of 2-amino-6-bromo-3-methyl-N-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)benzamide

[0394] To a stirred solution of 2-amino-6-bromo-3-methylbenzoic acid 7 (0.2 g, 0.869 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (0.422 mL, 3.04 mmol), followed by HATU (0.661 g, 1.74 mmol) under an inert atmosphere at 0° C. and stirring for 5 minutes. To this solution was then added 2-(2-(trifluoromethyl)phenyl)cyclobutan-1-amine 6 (0.187 g, 0.869 mmol) and stirred for 16 hours at room temperature. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified by flash column chromatography to give 2-amino-6-bromo-3-methyl-N-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)benzamide as a yellow sticky solid (0.1 g, 26.92%). LCMS (ES) m / z calculated for C19H18BrF3N2O, 426.06; found 427.0 (M+H).

[0395] Step 6: Synthesis of 5-bromo-2,8-dimethyl-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)quinazolin-4(3H)-one

[0396] To a stirred solution of 2-amino-6-bromo-3-methyl-N-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)benzamide (0.090 g, 0.211 mmol) in toluene (1 mL) was added pentane-2,4-dione (0.031 g, 0.316 mmol) and p-TSA (0.008 g, 0.042 mmol). The resulting reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), and then the organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 5-bromo-2,8-dimethyl-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)quinazolin-4(3H)-one (0.090 g, 95% yield) as a yellow sticky solid. LCMS(ES)m / z calculated for C21H18BrF3N2O,450.06; found 451.1(M+H).

[0397] Step 7: Preparation of 3,5-dichloro-N-(2,8-dimethyl-4-oxo-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide

[0398] To a stirred solution of 5-bromo-2,8-dimethyl-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)quinazolin-4(3H)-one (9) (0.075 g, 0.166 mmol) in 1,4-dioxane (7.5 mL) was added 3,5-dichloro-4-hydroxybenzamide (10) (0.034 mg, 0.166 mmol) and potassium t-butoxide (0.056 g, 0.499 mmol). The reaction mixture was degassed using argon gas for 10 minutes, after which Xantphos (0.0192 g, 0.033 mmol) and bis(dibenzylideneacetone)palladium(0) (0.0191 g, 0.033 mmol) were added to the solution at room temperature. The resulting reaction mixture was heated to 100° C. for 1 hour. The reaction mixture was cooled to room temperature, ice-cold water (15 mL) was added, and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography to give 3,5-dichloro-N-(2,8-dimethyl-4-oxo-3-(2-(2-(trifluoromethyl)phenyl)cyclobutyl)-3,4-dihydroquinazolin-5-yl)-4-hydroxybenzamide as an off-white solid (0.008 g, 8%). LCMS (ES) m / z calculated for C28H22Cl2F3N3O3, 575.10; found 576.2 (M+H); 1 H NMR(400MHz,DMSO-d6) δ 12.41(s,1H),11.1(s,1H),8.36(d,J=8.4Hz,1H),7.65-7.8(m,2H),7.53( dJ=8.4Hz,1H),7.37(d,J=8.0Hz,2H),7.26(t,J=7.2Hz,1H),7.16(t,J=7. 6Hz,1H),5.41-5.45(m,1H),4.60-4.64(m,1H),3.0-3.10(m,1H),2.65-2. 8(m,1H),2.57(s,3H),2.37(s,3H),1.2-1.3(m,1H),1.15(t,J=7.2Hz,1H).

[0399] Example 18: Synthesis of 4,6-dichloro-N-(1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide

[0400] [ka]

[0401] Step 1: Synthesis of 5-bromo-3-{[2-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0402] To a solution of 5-bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (5 g, 20.7 mmol) in THF (40 mL) was added (2-(trifluoromethyl)phenyl)methanamine (3.62 g, 20.7 mmol) and triethylamine (6.7 mL, 2.5 equiv., 51.6 mmol) at ambient temperature. The resulting reaction mixture was heated to 80 °C for 1 h, cooled to room temperature, diluted with ethyl acetate (50 mL) and water (30 mL), and extracted into ethyl acetate. The organic layer was dried over NaSO and concentrated to give a brown oil. The viscous compound was dissolved in THF (10 mL) and cooled to 0 °C. Then, triphosgene (3.07 g, 0.5 equiv., 10.3 mmol) was added and stirred for 30 minutes at ambient temperature. Triethylamine was then added to the stirred solution, stirring was continued for an additional 2 hours, and the solid material was removed from the reaction mixture by filtration. The filtrate was concentrated and dried to give a brown solid, which was triturated with diethyl ether (10 mL) to give 5-bromo-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione as an off-white solid (5 g, 60% yield). LCMS (ES) m / z calculated for C16H10BrF3N2O2 397.99 found, 399.0.

[0403] Step 2: Synthesis of 5-bromo-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione

[0404] To a solution of 5-bromo-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.5 g, 1.25 mmol) in 5 mL of dimethylformamide was added potassium carbonate (0.26 g, 1.88 mmol), potassium iodide (0.05 g, 0.301 mmol), and bromoethane (0.13 g, 1.25 mmol). The resulting reaction mixture was heated to 120°C for 16 h, cooled to room temperature, diluted with ethyl acetate (30 mL) and water (20 mL), and extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with diethyl ether (20 mL) to give pure 5-bromo-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.5 g, 93%) as an off-white solid. LCMS (ES) m / z calculated for C18H14BrF3N2O2 426.0; found 427.0.

[0405] Step 3: Synthesis of tert-butyl (1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate

[0406] A stirred solution of 5-bromo-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (1 g, 2.34 mmol) and tert-butyl carbamate (0.27 g, 2.34 mmol) in 1,4-dioxane (5 mL) and cesium carbonate (1.53 g, 4.68 mmol) was degassed with nitrogen for 10 minutes, after which Pd(dba) (0.067 g, 0.117 mmol) and Xantphos (0.13 g, 0.234 mmol) were added. The resulting reaction mixture was stirred for 5 hours at 100 °C. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was diluted with ethyl acetate (50 mL) and washed with water (30 mL), the organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with diethyl ether (20 mL) to give pure tert-butyl (1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate (0.6 g, 55%). LCMS (ES) m / z calculated for C23H24F3N3O4 463.17; found, 364.1 (M-Boc).

[0407] Step 4: Synthesis of 5-amino-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione

[0408] A stirred solution of tert-butyl (1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate (0.6 g, 1.29 mmol) in dichloromethane (5 mL) was cooled to 0 °C, HCl in dioxane (5 mL) was added, and the reaction was stirred for 2 hours at ambient temperature. The reaction progress was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was concentrated and triturated with diethyl ether (10 mL) to give pure 5-amino-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (450 mg, 95% yield) as an off-white solid. LCMS (ES) m / z calculated for C18H16F3N3O2 363.2; found 364.1 (M+H).

[0409] Step 5: Synthesis of 4,6-dichloro-N-(1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide

[0410] To a solution of 5-amino-1-ethyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.2 g, 0.55 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.11 g, 0.55 mmol) in chlorobenzene (2 mL) was added PCl3 (0.075 g, 0.550 mmol). The reaction mixture was heated at 120 °C for 3 h. The reaction progress was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL × 2), aqueous bicarbonate (10 mL), and the combined organic layers were concentrated to give a residue that was purified by reverse-phase preparative HPLC. The pure fractions were collected and concentrated to give 4,6-dichloro-N-(1-ethyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide (54 mg, 18% yield) as a white solid. LCMS (ES) m / z calculated for C24H17Cl2F3N4O4 553.36; found 553.1 (M+H). 1 H NMR(400MHz,DMSO-d6) δ 13.54(s,1H),8.64(d,J=8Hz,1H),8.08(s,1H),7.82-7.7.5(m,2H),7.53(t,J=7.6Hz,1H),7.45(t,J=8Hz ,1H),7.30-7.22(m,1H),7.21(d,J=9.2Hz,1H),5.33(s,2H),4.17(q,J=6.8Hz,2H),1.23(t,J=6.8Hz,3H).

[0411] Example 19: Synthesis of 4,6-dichloro-N-(8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide

[0412] [ka]

[0413] Step 1: Synthesis of 5-bromo-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0414] To a stirred solution of 2-amino-6-bromo-3-fluorobenzoic acid (0.5 g, 2.14 mmol) in THF (6 mL) was added triphosgene (0.63 g, 2.14 mmol) at −10° C. for 30 min, which was then stirred at −10° C. to −5° C. for 1 h, followed by stirring at room temperature for 16 h. Upon completion, the reaction mixture was evaporated under reduced pressure to a residue to which diethyl ether (3×50 mL) was added, stirred for 5 min, and the resulting solid was collected by filtration. The solid was triturated with diethyl ether (25 mL) and evaporated to dryness to give 5-bromo-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (0.4 g, 72%) as a pale yellow solid. LCMS(ES)m / z calcd, For C8H3BrFNO3, 258.93; found,259.9(M+H).

[0415] Step 2: Synthesis of 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione

[0416] To a solution of 5-bromo-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (0.4 g, 1.54 mmol) in tetrahydrofuran (10 mL) was added 1-[2-(trifluoromethyl)phenyl]methanamine (0.21 mL, 1.54 mmol) and triethylamine (0.24 mL) dropwise. The reaction mixture was heated at 80° C. for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (10 mL) and brine solution (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a brown oil. The oil was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C., after which triphosgene (0.22 g, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then triethylamine (0.24 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated to dryness to give 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.6 g, 93.5%) as a yellow solid. LCMS (ES) m / z calcd, For C16H9BrF4N2O2, 415.98; found, 417.0 (M+H).

[0417] Step 3: Synthesis of 5-bromo-8-fluoro-1-methyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione

[0418] To a stirred solution of 5-bromo-8-fluoro-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.7 g, 1.68 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (0.69 g, 5.03 mmol) and stirred for 15 minutes at room temperature. Iodomethane (0.15 mL, 2.52 mmol) was then added to the reaction mixture and stirred for 1 hour at room temperature. After completion, water (25 mL) was added, and it was extracted with ethyl acetate (3 × 25 mL). The combined organics were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford 5-bromo-8-fluoro-1-methyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.5 g, 69.1%) as an off-white solid. LCMS(ES)m / z calcd, For C17H11BrF4N2O2, 431.2; found,432.0(M+H).

[0419] Step 4: Synthesis of tert-butyl (8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate

[0420] To a stirred solution of 5-bromo-8-fluoro-1-methyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.2 g, 0.464 mmol) and tert-butyl carbamate (0.16 g, 1.39 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (0.45 g, 1.39 mmol). The reaction mixture was degassed with nitrogen, and Xantphos (0.053 g, 0.92 mmol) and Pd(dba) (0.026 g, 0.46 mmol) were added. The reaction mixture was heated to 100 °C for 12 h. The reaction mixture was filtered through a pad of Celite, washing with ethyl acetate (2 × 50 mL), and the filtrate was evaporated under reduced pressure to give crude tert-butyl (8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate (0.5 g, 92%) as an off-white solid. LCMS (ES) m / z calcd, For C22H21F4N3O4, 467.15; found, 368.1 (M-Boc H).

[0421] Step 5: Synthesis of 5-amino-8-fluoro-1-methyl-3-(2(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione

[0422] To a stirred solution of tert-butyl (8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)carbamate (0.5 g, 1.07 mmol) in 1,4-dioxane was added 4 M HCl in 1,4-dioxane (5 mL) at room temperature, followed by stirring at the same temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give a yellow solid, which was triturated with diethyl ether (25 mL) and evaporated to dryness to give 5-amino-8-fluoro-1-methyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.3 g, 76%) as a pale yellow solid. LCMS(ES)m / z calcd, For C17H13F4N3O2, 367.09; found,368.1(M+H).

[0423] Step 6: Synthesis of 4,6-dichloro-N-(8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide

[0424] To a stirred solution of 5-amino-8-fluoro-1-methyl-3-(2-(trifluoromethyl)benzyl)quinazoline-2,4(1H,3H)-dione (0.15 g, 0.408 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.084 mg, 0.40 mmol) in chlorobenzene (2 mL) was added trichlorophosphane (0.025 mL, 0.286 mmol) at 0° C. under a nitrogen atmosphere and heated to 130° C. for 3 hours. After completion, the reaction mass was quenched with ice-cold water (15 mL), stirred for 5 minutes, and the resulting solid was collected by filtration, washed with diethyl ether (2×15 mL), and dried under reduced pressure to give the crude product as a yellow solid. The crude solid material was purified by preparative purification. The collected fractions were lyophilized to give 4,6-dichloro-N-(8-fluoro-1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-5-hydroxypicolinamide (0.045 g, 20%) as an off-white solid. LCMS (ES) m / z calcd, For C23H14Cl2F4N4O4, 556.03; found, 555.1 (MH); 1 H NMR(400MHz,DMSO-d6) δ13.42(s,1H),8.65-8.61(m,1H),8.07(s,1H),7.77-7.72(m,2H),7.56-7.52(m ,1H),7.48-7.44(m,1H),7.31-7.29(m,1H),5.31(s,2H),3.68(d,J=9.2Hz,3H).

[0425] Example 20: Synthesis of 4,6-dichloro-5-hydroxy-N-(1-methyl-2,4-dioxo-3-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinazolin-5-yl)-picolinamide

[0426] The title compound was synthesized as described above. LCMS (ES) m / z calculated for C23H15Cl2F3N4O4 calculated for 538.04; found 539.1 (M+H). 1H NMR(400MHz,DMSO-d6) δ 13.52(s,1 H),8.65(d,J=8.4Hz,1H),8.08(s,1H),7.83-7.75(m,2H),7.55-7.40(m,2H),7.25-7.22(m,2H),5.33(s,2 H),3.54(s,3H).

[0427] Example 21: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0428] [ka]

[0429] Step 1: Synthesis of 5-amino-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0430] To a stirred solution of 5-amino-2-methylthiazole-4-carboxylic acid (0.5 g, 3.16 mmol) in tetrahydrofuran (5 mL) was added HATU (2.4 g, 6.32 mmol), triethylamine (2.2 mL, 15.8 mmol), and (2-(trifluoromethoxy)phenyl)methanamine (0.6 g, 3.16 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound, which was purified by flash column chromatography to give 5-amino-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide as a yellow liquid (0.88 g, 84%). LCMS (ES) m / z calcd. C13H12F3N3O2S, 331.0; found, 332.1 (M+1).

[0431] Step 2: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0432] To a stirred solution of 5-amino-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide (0.4 g, 1.21 mmol) in chlorobenzene (5 mL), phosphorus trichloride (52.8 μL, 0.604 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (275 mg, 1.33 mmol) were added and stirred at 130° C. for 2 hours. The reaction progress was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and filtered to give the crude compound, which was purified by flash column chromatography to give an off-white solid. The solid was further triturated with hot methanol (10 mL) to give 5-(3,5-dichloro-4-hydroxybenzamido)-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide as a white solid (0.05 g, 8%). LCMS (ES) m / z calcd. C20H14Cl2F3N3O4S, 519.0; found, 520.1 (M+1). 1 H NMR(400MHz,DMSO d6) δ 12.31(s,1H),11.32(s,1H),9.11(t,J=8.0Hz,1H),7.82(s,2H),7.45-7.35(m,4H),4.59(d,J=4.0Hz,2H),2.65(s,3H).

[0433] Example 22: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide

[0434] [ka]

[0435] To a solution of 5-amino-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide (0.4 g, 1.21 mmol) in chlorobenzene (5 mL) were added phosphorus trichloride (52.8 μL, 0.604 mmol) and 4,6-dichloro-5-hydroxypicolinic acid (0.27 g, 1.33 mmol) at ambient temperature. The resulting reaction mixture was heated to 130° C. for 2 hours. The progress of the reaction was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (20 mL). The precipitated solid was filtered and dried to give a white solid. The solid material was purified by flash column chromatography to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-methyl-N-(2-(trifluoromethoxy)benzyl)thiazole-4-carboxamide as a white solid (0.051 g, 8%). LCMS (ES) m / z calcd. C19H13Cl2F3N4O4S, 520.00; found, 521.1 (M+1); 1 H NMR(400MHz,DMSO d6) δ 12.64(s,1H),9.0(t,J=4Hz,1H),8.09(s,1H),7.40-7.32(m,4H),4.55(d,J=8.0Hz,2H),2.62(s,3H).

[0436] Example 23: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-phenyl-N-(2(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0437] [ka]

[0438] Step 1: Synthesis of ethyl 2-amino-2-cyanoacetate

[0439] To a stirred solution of (£)-(ethyl cyano(hydroxyimino)formate) (5 g, 35.2 mmol) in acetic acid (50 mL) was added zinc (11.5 g, 5 equivalents, 176 mmol) in portions at ambient temperature. The reaction mixture was stirred for 30 minutes at ambient temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through Celite and washed with dichloromethane (200 mL). The filtrate was evaporated under reduced pressure to give ethyl 2-amino-2-cyanoacetate (4 g) as an orange sticky solid. The crude compound was used in the next step without further purification.

[0440] Step 2: Synthesis of ethyl 2-cyano-2-(phenylformamido)acetate

[0441] To a stirred solution of ethyl 2-amino-2-cyanoacetate (4 g, 31.2 mmol) in dichloromethane (50 mL) was added benzoyl chloride (4.83 g, 34 mmol) and triethylamine (7.9 g, 78 mmol) at 0 °C. The reaction was stirred at ambient temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL) and brine solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product. Purification by flash chromatography gave ethyl 2-cyano-2-(phenylformamido)acetate as a yellow solid (1 g, 13% yield). LCMS (ES) m / z calculated for C12H12N2O3 232.08; found 233.1.

[0442] Step 3: Synthesis of ethyl 5-amino-2-phenyl-1,3-thiazole-4-carboxylate

[0443] To a stirred solution of ethyl 2-cyano-2-(phenylformamido)acetate (1 g, 4.31 mmol) in toluene (20 mL) was added Lawesson's reagent (5.22 g, 3 equiv., 12.9 mmol). The resulting reaction mixture was heated at reflux for 18 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue that was purified by flash chromatography to give ethyl 5-amino-2-phenyl-1,3-thiazole-4-carboxylate (400 mg, 37%) as a yellow solid. LCMS (ES) m / z calculated for C12H12N2O2S 248.06; found 249.1.

[0444] Step 5: Synthesis of 5-amino-2-phenyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide

[0445] To a stirred solution of ethyl 5-amino-2-phenyl-1,3-thiazole-4-carboxylate (0.25 g, 1.01 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.21 g, 1.21 mmol) in toluene (1 mL) was added 2 M trimethylaluminum in toluene (2 mL, 4 mmol). The reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (15 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give a crude brown solid, which was triturated with diethyl ether (10 mL) to give 5-amino-2-phenyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.2 g, 52% yield). LCMS(ES)m / z calculated for C18H14F3N3OS 377.3; found,378.1

[0446] Step 6: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-phenyl-N-(2(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0447] To a stirred solution of 5-amino-2-phenyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.2 g, 0.53 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (110 mg, 0.53 mmol) in chlorobenzene (2 mL) was added phosphorus trichloride (72.8 mg, 0.53 mmol) at ambient temperature. The resulting reaction mixture was heated at 120° C. for 3 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), and washed with water (10 mL×2) and aqueous bicarbonate (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue that was purified by reverse-phase preparative HPLC to give 4,6-dichloro-5-hydroxy-N-[2-phenyl-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]pyridine-2-carboxamide as a pale yellow solid (0.07 g, 22% yield). LCMS (ES) m / z calculated for C24H15Cl2F3N4O3S 566.02 found, 565.1 (MH). 1 H NMR(400MHz,DMSO d6) δ 12.73(s,1H),9.25(d,J=6Hz,1H),8.13(s,1H),8.04(d,J=7.2Hz,2H),7.74 (d,J=8Hz,1H),7.66-6.63(m,1H),7.54-7.47(m,5H),4.75(d,J=4.8Hz,2H).

[0448] Example 24: 5-(4,6-dichloro-5-hydroxypicolinamido)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)thiazole-4-carboxamide

[0449] [ka]

[0450] Step 1: Synthesis of 1-(2-(trifluoromethyl)phenyl)cyclopropan-1-amine

[0451] To a stirred solution of 2-(trifluoromethyl)benzonitrile (5 g, 29.2 mmol) and titanium tetraisopropoxide (13.3 mL, 43.8 mmol) in diethyl ether (50 mL, 481 mmol) was added 1 M ethylmagnesium bromide in diethyl ether (73 mL, 73 mmol) at −78° C. under a nitrogen atmosphere, and the reaction mixture was then allowed to warm slowly to 0° C. for 1 hour. To this was added boron trifluoride diethyl etherate (9.02 mL, 73 mmol) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then cooled to 0° C., and 4 N HCl (50 mL) was added and stirred at ambient temperature for an additional 1 hour. The reaction mixture was then cooled to 0° C., diluted with diethyl ether (100 mL), and 20% aqueous NaOH (80 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour. The layers were separated, and the organic layer was washed with cold 4N HCl (2×25 mL). The aqueous layer was basified using cold 20% aqueous NaOH (pH=10) and extracted with diethyl ether (2×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at ambient temperature to give 1-[2-(trifluoromethyl)phenyl]cyclopropan-1-amine (3 g, 14.9 mmol) as a yellow liquid. LCMS (ES) m / z calcd, For C10H10F3N, 201.08; found, 202.1 (M+H).

[0452] Step 2: Synthesis of 5-amino-N-(1-(2-trifluoromethyl)phenyl)cyclopropyl)thiazole-4-carboxamide

[0453] To a stirred solution of 5-amino-1,3-thiazole-4-carboxylic acid (0.2 g, 1.39 mmol), 1-[2-(trifluoromethyl)phenyl]cyclopropan-1-amine (279 mg, 1.39 mmol), and triethylamine (0.5 mL, 4.16 mmol) in tetrahydrofuran (4 mL) was added HATU (633 mg, 1.66 mmol). The reaction mixture was stirred for 3 hours at ambient temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL) and brine solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product. This was purified by flash column chromatography, the collected fractions judged by TLC, and the pure fractions were combined and evaporated under reduced pressure to give 5-amino-N-{1-[2-(trifluoromethyl)phenyl]cyclopropyl}-1,3-thiazole-4-carboxamide (0.3 g) as an off-white solid. LCMS (ES) m / z calcd, For C14H12F3N3OS, 327.07; found, 328.1 (M+H).

[0454] Step 3: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-N-(1-(2-(trifluoromethyl)phenyl)cyclopropyl)thiazole-4-carboxamide

[0455] To a stirred suspension of 5-amino-N-{1-[2-(trifluoromethyl)phenyl]cyclopropyl}-1,3-thiazole-4-carboxamide (0.1 g, 0.306 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (95.3 mg, 1.5 equiv., 0.458 mmol) in acetonitrile (5 mL) under a nitrogen atmosphere at 0° C., phosphorus trichloride (42 mg, 0.306 mmol) was added. The reaction mixture was heated to 100° C. for 16 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (20 mL), water (20 mL), and brine solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product. Purification by preparative HPLC gave 4,6-dichloro-5-hydroxy-N-[4-({1-[2-(trifluoromethyl)phenyl]cyclopropyl}carbamoyl)-1,3-thiazol-5-yl]pyridine-2-carboxamide (0.05 g, 31%) as a white solid. LCMS (ES) m / z calcd, For C20H13Cl2F3N4O3S, 516.00; found, 515.1 (MH); 1 H NMR(400MHz,DMSO-d6) δ 12.49(s,1H),8.67(s,1H),8.34(s,1H),8.12(s,1H),8.05(d,J=7.6Hz,1H),7.71-7.67(m,2H),7.53-7.49(m,1H),1.45(m,2H),1.33(m,2H).

[0456] Example 25: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-N-methyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0457] [ka]

[0458] Step 1: Synthesis of tert-butyl (2-(trifluoromethyl)benzyl)carbamate

[0459] To a stirred solution of 2-(trifluoromethyl)benzaldehyde (1 g, 5.74 mmol) in methanol (10 mL, 247 mmol) was added methanamine (3.19 mL, 28.7 mmol) and stirred at room temperature for 30 minutes. After 30 minutes, the reaction mass was cooled to 0 °C, and sodium borohydride (0.43 g, 11.5 mmol) was added portionwise and stirred at room temperature for 2 hours. Triethylamine (2.4 mL, 17.2 mmol), N,N-dimethylpyridin-4-amine (0.14 g, 1.15 mmol), and di-tert-butyl dicarbonate (1.98 mL, 8.61 mmol) were added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was quenched with water (50 mL) and extracted into ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure to give crude tert-butyl (2-(trifluoromethyl)benzyl)carbamate (0.8 g, 48%) as a gummy solid. LCMS (ES) m / z calculated for C13H16F3NO2 is 275.11; found 275.1 (M+H).

[0460] Step 2: Synthesis of N-methyl-1-(2-(trifluoromethyl)phenyl)methanamine

[0461] A stirred solution of tert-butyl (2-(trifluoromethyl)benzyl)carbamate (0.8 g, 2.77 mmol) in 4 M HCl in 1,4 dioxane (1.01 g, 10 equiv., 27.7 mmol) was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether (10 mL) to give N-methyl-1-(2-(trifluoromethyl)phenyl)methanamine (0.6 g, 92%) as an off-white solid. LCMS (ES) m / z calculated for C9H11ClF3N is 225.05; found 190.1 (M+H).

[0462] Step 3: Synthesis of 5-amino-N-methyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0463] To a stirred solution of methyl 5-amino-1,3-thiazole-4-carboxylate (0.25 g, 1.58 mmol), methyl({[2-(trifluoromethyl)phenyl]methyl})amine hydrochloride (0.428 g, 1.9 mmol), and triethylamine (0.22 mL, 1.58 mmol) in toluene (2 mL, 16.9 mmol) was added. The mixture was cooled to 0 °C, and trimethylalmane (0.455 mL, 4.74 mmol) was added. The resulting reaction mixture was heated to 100 °C for 2 h. The reaction mixture was cooled to ambient temperature, quenched with water (15 mL), and extracted into ethyl acetate (2 × 30 mL). The combined organics were washed with brine solution (2 × 10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by Combi flash chromatography to give 5-amino-N-methyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.24 g, 48%) as an off-white solid. LCMS (ES) m / z calculated for CHFNOS is 315.07; found 316.1 (M+H).

[0464] Step 4: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-N-methyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0465] To a stirred solution of 5-amino-N-methyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.220 g, 0.698 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.16 g, 0.767 mmol) in chlorobenzene (4 mL), trichlorophosphane (0.018 mL, 0.209 mmol) was added dropwise to the reaction mixture at room temperature. The reaction was then stirred at 130° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched into ice-cold water (10 mL), and the resulting mixture was extracted into ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (3 mL × 2), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 5-(4,6-dichloro-5-hydroxypicolinamido)-N-methyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.048 g, 13%) as a white solid. LCMS (ES) m / z calculated for C19H13Cl2F3N4O3S is 504.00; found 505.1 (M+H). 1 H NMR(400MHz,DMSO d6 at 90℃) δ 12.78(bs,1H),8.61(s,1H),8.09(s,1H),7.76(d,J=7.6Hz,1H),7.66(t,J=7.6Hz,1H),7.52-7.46(m,3H),5.34 (bs,2H),3.05(s,3H).

[0466] The following compounds were synthesized as described above:

[0467] [Table 4-1]

[0468] [Table 4-2]

[0469] [Table 4-3]

[0470] [Table 4-4]

[0471] Example 59: Synthesis of 2-cyclopropyl-5-(4,6-dichloro-5-hydroxypicolinamido)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide)

[0472] [ka]

[0473] Step 1: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-cyclopropylthiazole-4-carboxylate

[0474] To a stirred solution of methyl 5-bromo-2-cyclopropylthiazole-4-carboxylate (0.5 g, 1.91 mmol) and tert-butyl carbamate (0.223 g, 1.91 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (1.24 g, 3.82 mmol), degassed with nitrogen for 10 minutes, and then Pd(dba) (0.054 g, 0.095 mmol) and Xantphos (0.11 g, 0.19 mmol) were added and stirred at 100 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25 × 2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give methyl 5-((tert-butoxycarbonyl)amino)-2-cyclopropylthiazole-4-carboxylate (0.3 g, 52% yield). LCMS (ES) m / z calcd. for; C13H18N2O4S 298.10; found 243.1. (M- tbu).

[0475] Step 2: Synthesis of tert-butyl (2-cyclopropyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0476] To a solution of methyl 5-{[(tert-butoxy)carbonyl]amino}-2-cyclopropyl-1,3-thiazole-4-carboxylate (0.2 g, 0.670 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.141 g, 0.804 mmol) in toluene (4 mL) was added 2 M trimethylaluminum in toluene (2 mL, 2 mmol) at 0° C. The reaction mixture was heated at 100° C. for 1 h. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (15 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give a crude brown solid, which was triturated with diethyl ether (10 mL) to give tert-butyl (2-cyclopropyl-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.120 g, 40% yield). LCMS (ES) m / z calcd. for C20H22F3N3O3S 441.13; found 342.1 (M-Boc).

[0477] Step 3: Synthesis of 5-amino-2-cyclopropyl-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0478] A stirred solution of tert-butyl N-[2-cyclopropyl-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]carbamate (0.120 g, 0.272 mmol) in dichloromethane (2 mL) was cooled to 0 °C, and then 4 M HCl in 1,4 dioxane (2 mL) was added. The resulting reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with diethyl ether (10 mL) to give 5-amino-2-cyclopropyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.090 g, 97% yield). LCMS (ES) m / z calcd. for; CHFNOS 341.08; found, 342.1 (M+H).

[0479] Step 4: Synthesis of 2-cyclopropyl-5-(4,6-dichloro-5-hydroxypicolinamido)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide)

[0480] To a solution of 5-amino-2-cyclopropyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.080 g, 0.234 mmol) and 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.048 g, 0.234 mmol) in chlorobenzene (1 mL) was added phosphorus trichloride (0.032 g, 0.234 mmol). The resulting reaction mixture was heated at 120° C. for 1 hour. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), and washed with water (10 mL×2) and brine solution (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography to give 4,6-dichloro-N-[2-cyclopropyl-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]-5-hydroxypyridine-2-carboxamide (0.032 g, 25% yield) as an off-white solid. LCMS (ES): m / z C21H15Cl2F3N4O3S calcd. for 530.0; found 531.1 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 12.60(s,1H),8.95(t,J=6Hz,1H),8.10(s,1H),7.75(d,J=7.6 1H),7.66(t,J=7.2Hz,1H) 7.50-7.46(m,2H),4.71(d,J=6Hz,2H),2.38-2.33(m,1H),1.20-1.14(m,4H).

[0481] Example 60: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0482] [ka]

[0483] Step 1: Preparation of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate

[0484] To a stirred solution of methyl 5-amino-2-bromothiazole-4-carboxylate (1 g, 4.22 mmol) in tetrahydrofuran (20 mL, 246 mmol), di-tert-butyl dicarbonate (1.45 mL, 6.33 mmol), DIPEA (2.2 mL, 12.7 mmol), and DMAP (0.520 g, 4.22 mmol) were added at ambient temperature, followed by stirring at the same temperature for another 2 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography to give methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.9 g, 63%) as a white solid. LCMS(ES): m / z calcd. for C10H13BrN2O4S, 335.98; found,337.0.

[0485] Step 2: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate

[0486] To a stirred solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.460 g, 1.36 mmol) and (2-fluorophenyl)boronic acid (0.382 g, 2.73 mmol) in 1,4-dioxane:water (8:2) (6 mL), potassium carbonate (0.566 g, 4.09 mmol) was added and degassed with nitrogen for 10 minutes, after which bis(tri-tert-butylphosphane)palladium (0.0697 g, 0.136 mmol) was added and stirred for 16 hours at 100° C. The progress of the reaction was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25×2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate (0.350 g, 73%) as a brown solid. LCMS (ES): m / z calcd. for C16H17FN2O4S, 352.09; found, 353.1.

[0487] Step 3: Preparation of tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0488] To a stirred solution of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate (0.3 g, 0.851 mmol) in toluene (5 mL) was added 1-[2-(trifluoromethyl)phenyl]methanamine (0.119 mL, 0.851 mmol) and 2 M trimethylaluminum in toluene (0.245 mL, 2.55 mmol) at 0° C. The resulting reaction mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (25 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography to give tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.3 g, 71%) as an off-white solid. LCMS (ES): m / z calcd. C23H21F4N3O3S, 495.1; found, 496.1.

[0489] Step 4: Preparation of 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0490] To a suspension of tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.250 g, 0.505 mmol) in methanol (1 mL) was added 4 M HCl in dioxane (5 mL, 144 mmol) at 0° C., followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with water (10 ml), brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide) (0.170 mg, 85%) as a white solid. LCMS(ES): m / z calcd. for C18H13F4N3OS, 395.07; found,396.1.

[0491] Step 5: Preparation of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0492] To a suspension of 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.175 g, 0.443 mmol) in chlorobenzene (5 mL) was added 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.101 g, 0.487 mmol) and phosphorus trichloride (0.0387 mL, 0.443 mmol). The resulting reaction mixture was heated at 120° C. for 3 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), and washed with water (10 mL×2) and brine solution (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography over Na2SO4 to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.015 g, 6%) as a white solid. LCMS (ES): m / z C24H14Cl2F4N4O3S calcd. for 584.0; found 585.1 (MH); 1 H NMR(400MHz,DMSO-d6):δ 12.74(s,1H),9.37(t,J=6Hz,1H),8.51-8.47(m,1H),8.15(s,1H),7.78(d, J=7.6Hz,1H),7.68(t,J=7.6Hz,1H),7.58-7.39(m,5H),4.81(d,J=6Hz,2H).

[0493] The following compounds were synthesized using the above procedure:

[0494] [Table 5-1]

[0495] [Table 5-2]

[0496] Example 78: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1,1-dioxidethiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0497] [ka]

[0498] Step 1: Synthesis of methyl-5-amino-2-bromothiazole-4-carboxylate

[0499] To a stirred solution of methyl 5-aminothiazole-4-carboxylate (0.7 g, 4.43 mmol) in tetrahydrofuran (7 mL, 86 mmol) was added N-bromosuccinimide (0.86 g, 4.87 mmol) at 0 °C, and the reaction mixture was then stirred at ambient temperature for 1 h. The reaction mixture was quenched with ice-water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography to give methyl 5-amino-2-bromothiazole-4-carboxylate as a brown solid (0.960 g, 92%). LCMS (ES) m / z calcd. for C5H5BrNO2S, 235.93; found, 237.0 (M+H).

[0500] Step 2: Synthesis of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate

[0501] To a stirred solution of methyl 5-amino-2-bromothiazole-4-carboxylate (0.96 g, 4.05 mmol) in tetrahydrofuran (15 mL, 184 mmol), di-tert-butyl dicarbonate (1.4 mL, 6.07 mmol), N,N-diisopropylethylamine (2.12 mL, 12.1 mmol), and 4-(dimethylamino)pyridine (0.5 g, 4.05 mmol) were added at ambient temperature. The resulting reaction mixture was stirred at room temperature for an additional 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography to give methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate as a white solid (1.1 g, 81%). LCMS (ES) m / z calcd. C10H13BrN2O4S, 335.98; found, 337.0 (M+H).

[0502] Step 3: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-(1,1-dioxidethiomorpholino)thiazole-4-carboxylate

[0503] To a stirred solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.7 g, 2.08 mmol) and thiomorpholine 1,1-dioxide (421 mg, 3.11 mmol) in 1,4-dioxane (8 mL) was added cesium carbonate (2.03 g, 6.23 mmol), degassed with nitrogen for 10 minutes, followed by the addition of Pd(dba) (0.095 g, 0.155 mmol) and Xantphos (0.18 g, 0.311 mmol) and stirring at 100 °C for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25 × 2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give methyl 5-((tert-butoxycarbonyl)amino)-2-(1,1-dioxidethiomorpholino)thiazole-4-carboxylate as an off-white solid (0.70 g, 87%). LCMS (ES) m / z calcd. C14H21N3O6S2, 391.09; found, 392.0 (M+H).

[0504] Step 4: Synthesis of tert-butyl (2-(1,1-dioxidethiomorpholino)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0505] To a suspension of methyl 5-((tert-butoxycarbonyl)amino)-2-(1,1-dioxidethiomorpholino)thiazole-4-carboxylate (0.7 g, 1.79 mmol) and (2-(trifluoromethyl)phenyl)methanamine (345 mg, 1.97 mmol) in toluene (7 mL) was added 2 M trimethylaluminum in toluene (1.32 mL, 2.68 mmol) at 0° C. The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (15 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography to give tert-butyl (2-(1,1-dioxidothiomorpholino)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate as a yellow solid (0.680 g, 71%). LCMS (ES) m / z calcd. C21H25F3N4O5S2, 534.1; found, 535.1 (M+H).

[0506] Step 5: Synthesis of 5-amino-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0507] To a stirred solution of tert-butyl (2-(1,1-dioxidothiomorpholino)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (680 mg, 1.27 mmol) in methanol (2 mL) was added 4 M HCl in dioxane (15 mL, 60 mmol) at 0° C. and stirred for 2 hours at room temperature. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and the resulting residue was triturated with diethyl ether to give 5-amino-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a brown solid (0.68 g, 58%). LCMS(ES)m / z calcd.C16H17F3N4O3S2, 434.07; found,435.0(M+H).

[0508] Step 6: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1,1-dioxidethiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0509] To a suspension of 5-amino-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (630 mg, 1.45 mmol) and 4,6-dichloro-5-hydroxypicolinic acid (332 mg, 1.6 mmol) in chlorobenzene (5 mL) was added phosphorus trichloride (0.063 mL, 0.725 mmol) dropwise under a nitrogen atmosphere. The resulting reaction mixture was heated to 130° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water (20 ml), and the precipitated solid was filtered and purified by flash column chromatography to give a brown solid, which was further purified by preparative HPLC to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a yellow solid (0.153 g, 17%). LCMS (ES) m / z calcd. C22H18Cl2F3N5O5S2, 623.01; found, 622.1 (M-1); 1 H NMR(400MHz,DMSO-d6) δ 12.45(s,1H),8.93(t,J=6.0Hz,1H),8.09(s,1H),7.80(d,J=4.0Hz,1H),7.67(t,J=4.0Hz,1H),7.51-7.42(m,2H),4.7(d,J=8.0Hz,2H),4.02(br s,4H),3.31(br s,4H).

[0510] Example 79: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-2-(1,1-dioxidethiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0511] [ka]

[0512] To a suspension of 5-amino-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.5 g, 1.15 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (262 mg, 1.27 mmol) in chlorobenzene (5 mL) was added phosphorus trichloride (0.050 mL, 0.575 mmol) dropwise under a nitrogen atmosphere. The reaction mass was heated to 130° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography. The column purified compound was further purified by preparative HPLC to give 5-(3,5-dichloro-4-hydroxybenzamido)-2-(1,1-dioxidothiomorpholino)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a yellow solid (0.057 g, 8%). LCMS (ES) m / z calcd. C23H19Cl2F3N4O5S2, 622.0; found, 621.1 (MH); 1 H NMR(400MHz,DMSO-d6) δ 12.0(s,1H),11.28(br s,1H),9.01(t,J=8.0Hz,1H),7.79(s,2H),7.75(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.48(t,J=8.0Hz,2H),4.70(d,J=4.0Hz,2H),4.02(br s,4H),3.28(br s,4H).

[0513] Example 80: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0514] [ka]

[0515] Step 1: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-morpholinothiazole-4-carboxylate

[0516] To a stirred solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (1.65 g, 4.89 mmol) and morpholine (0.633 mL, 7.34 mmol) in 1,4-dioxane (8 mL) was added cesium carbonate (4.78 g, 14.7 mmol) and degassed with nitrogen for 10 minutes. Pd(dba) (0.14 g, 0.244 mmol), Xantphos (0.27 g, 0.48 mmol) were then added and stirred at 100 °C for 12 hours. The reaction progress was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25 × 2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give methyl 5-((tert-butoxycarbonyl)amino)-2-morpholinothiazole-4-carboxylate as a yellow solid (740 mg, 44%). LCMS (ES) m / z calcd. C14H21N3O5S, 343.12; found, 344.2 (M+H).

[0517] Step 2: Synthesis of tert-butyl (2-morpholino-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0518] To a suspension of methyl 5-((tert-butoxycarbonyl)amino)-2-morpholinothiazole-4-carboxylate (0.7 g, 2.04 mmol) and (2-(trifluoromethyl)phenyl)methanamine (428 mg, 2.45 mmol) in toluene (7 mL) was added 2 M trimethylaluminum in toluene (1.53 mL, 3.06 mmol) at 0° C. The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (15 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography using 50% ethyl acetate in n-hexane to give tert-butyl (2-morpholino-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate as a yellow solid (430 mg, 43%). LCMS (ES) m / z calcd. C21H25F3N4O4S, 486.1; found, 487.1 (M+1).

[0519] Step 3: Synthesis of 5-amino-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0520] To a stirred solution of tert-butyl (2-morpholino-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (430 mg, 0.884 mmol) in methanol (2 mL) was added HCl in dioxane (15 mL, 60 mmol) at 0 °C and stirred at room temperature for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and washed with diethyl ether to give 5-amino-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a brown solid (300 mg, 26%). LCMS (ES) m / z calcd. C16H17F3N4O2S, 386.10; found, 387.0 (M+1).

[0521] Step 4: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0522] To a suspension of 5-amino-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.3 g, 0.776 mmol) and 4,6-dichloro-5-hydroxypicolinic acid (178 mg, 0.854 mmol) in chlorobenzene (4 mL) was added phosphorus trichloride (0.034 mL, 0.388 mmol) dropwise under a nitrogen atmosphere. The reaction mass was heated to 130° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-morpholino-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a yellow solid (14 mg, 3%). LCMS (ES) m / z calcd. C22H18Cl2F3N5O4S, 575.04; found, 576.1 (M+1); 1 H NMR(400MHz,DMSO-d6) δ 12.25(s,1H),8.69(t,J=8.0Hz,1H),7.94(s,1H),7.75(d,J=8.0Hz,1H),7.67(t,J=8.0Hz, 1H),7.49-7.48(m,2H),4.7(d,J=8.0Hz,2H),3.73(t,J=4.0Hz,4H),3.45(t,J=4.0Hz,4H).

[0523] Example 81: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0524] [ka]

[0525] Step 1: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)thiazole-4-carboxylate

[0526] To a stirred solution of methyl 2-bromo-5-{[(tert-butoxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (1 g, 2.97 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.93 g, 4.45 mmol) in 1,4-dioxane:water (10 mL:1 mL), potassium carbonate (1.23 g, 8.9 mmol) was added and the mixture was degassed with nitrogen for 10 minutes, after which 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) was added. DCM complex (110 mg, 0.18 mmol) was added and stirred for 2 hours at 100 °C. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25 × 2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography to give methyl 5-{[(tert-butoxy)carbonyl]amino}-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-4-carboxylate (0.9 g, 89%) as a white solid. LCMS (ES) m / z calcd. C15H20N2O5S 340.11; found 341.2 (M+1).

[0527] Step 2: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate

[0528] To a stirred solution of methyl 5-{[(tert-butoxy)carbonyl]amino}-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-4-carboxylate (0.9 g, 2.64 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 10% w / w palladium on carbon (0.1 g). The resulting reaction mixture was stirred at ambient temperature for 16 hours under a hydrogen atmosphere. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give methyl 5-{[(tert-butoxy)carbonyl]amino}-2-(oxan-4-yl)-1,3-thiazole-4-carboxylate (0.9 g, 99% yield) as a white solid, which was used in the next step without any column purification. LCMS(ES)m / z calcd. C15H22N2O5S 342.12; found,343.0 (M+1).

[0529] Step 3: Synthesis of tert-butyl (2-(tetrahydro-2H-pyran-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0530] To a suspension of methyl 5-{[(tert-butoxy)carbonyl]amino}-2-(oxan-4-yl)-1,3-thiazole-4-carboxylate (0.9 g, 2.63 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (5) (0.691 g, 3.94 mmol) in toluene (10 mL) was added 2 M trimethylaluminum in toluene (1.97 mL, 3.94 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting reaction mixture was heated to 100 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a crude product which was purified by flash column chromatography to give tert-butyl (2-(tetrahydro-2H-pyran-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.65 g, 51%) as a white solid. LCMS (ES) m / z calcd. C22H26F3N3O4S 485.16.; found, 486.0 (M+1).

[0531] Step 4: Synthesis of 5-amino-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0532] To a suspension of tert-butyl N-[-(oxan-4-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]carbamate (0.650 g, 1.34 mmol) in dichloromethane (5 mL) was added 4 M HCl in dioxane (5 mL) at 0 °C, followed by stirring at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 5-amino-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.4 g, 77%) as an off-white solid. LCMS (ES) m / z calcd. C17H18F3N3O2S 385.1; found 386.0 (M+1).

[0533] Step 5: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0534] To a suspension of 5-amino-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.2 g, 0.519 mmol) and 4,6-dichloro-5-hydroxypicolinic acid (0.108 g, 0.519 mmol) in chlorobenzene (4 mL) was added phosphorus trichloride (0.071 g, 0.519 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was heated to 120° C. for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a crude residue that was triturated with diethyl ether (10 mL), filtered, and the solid dried under vacuum to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.101 g, 33%) as a light brown solid. LCMS (ES) m / z calcd. C23H19Cl2F3N4O4S 574.05; found, 575.2 (M+1); 1 H NMR(400MHz,DMSO-d6) δ 12.23(s,1H),8.81(t,J=6.4Hz,1H),7.81-7.74(m,2H),7.71-7.65(m,1H),7.51-7.46(m,2H) 4.72(d,J=5.6Hz,2H),4.00-3.93(m,2H),3.49-3.44(m,2H),3.25-3.17(m,1H),2.09-1.99(m,2H),1.85-1.75(m,2H).

[0535] Example 82: Synthesis of 5-(3,5-dichloro-4-hydroxybenzamido)-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0536] [ka]

[0537] To a suspension of 5-amino-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.2 g, 0.519 mmol) and 3,5-dichloro-4-hydroxybenzoic acid (0.107 g, 0.519 mmol) in chlorobenzene (4 mL) was added phosphorus trichloride (71.3 mg, 0.519 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was heated to 120° C. for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 5-(3,5-dichloro-4-hydroxybenzamido)-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide as a white solid (0.104 g, 34% yield). LCMS (ES) m / z calcd. C24H20Cl2F3N3O4S 573.05; found 572.2 (M-1). 1 H NMR(400MHz,DMSO-d6) δ 12.24(s,1H),11.32(br s,1H),9.12(t,J=6.4Hz,1H),7.82(s,2H),7.77-7.74(m,1H),7.67(t,J=7.6Hz,1H),7.52-7.47(m,2H),4.72( d,J=6Hz,2H),3.97-3.94(m,2H),3.50-3.41(m,2H),3.28-3.23(m,1H),2.03-1.99(m,2H),1.86-1.76(m,2H).

[0538] The following compounds were synthesized according to the procedure described above:

[0539] [Table 6]

[0540] Example 85: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0541] [ka]

[0542] Step 1: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiazole-4-carboxylate

[0543] To a stirred solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.730 g, 2.16 mmol) in 1,4-dioxane (10 ml) and water (1.5 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.483 g, 2.16 mmol) and potassium carbonate (0.898 g, 6.49 mmol). The reaction mixture was purged with nitrogen for 15 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.177 g, 0.216 mmol) was added and stirred at 100°C for 16 hours. The reaction mixture was monitored by TLC. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (10 ml), brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiazole-4-carboxylate (0.7 g, 91%) as a brown solid. LCMS (ES): m / z calcd. for C16H23N3O4S 353.14; found 354.1.

[0544] Step 2: Preparation of tert-butyl (2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0545] To a stirred solution of methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiazole-4-carboxylate (0.3 g, 0.849 mmol) in toluene (5 mL) was added 1-[2-(trifluoromethyl)phenyl]methanamine (0.149 g, 0.849 mmol) and 2 M trimethylaluminum in toluene (0.229 mL, 2.55 mmol) dropwise at 0° C. under a nitrogen atmosphere. The resulting reaction mixture was heated to 100° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a crude product which was purified by flash column chromatography to give tert-butyl (2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.3 g, 71%) as an off-white solid. LCMS (ES): m / z calcd. C23H27F3N4O3S 496.18; found, 497.2.

[0546] Step 3: Preparation of 5-amino-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0547] To a suspension of tert-butyl N-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]carbamate (0.280 g, 0.564 mmol) in methanol (5 mL) was added 4 M HCl in dioxane (7 mL) at ambient temperature. Stirring continued for an additional 1 h. The reaction mixture was concentrated under reduced pressure to give 5-amino-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-{(2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.18 g, 80%) as a white solid. LCMS (ES): m / z calcd. for C18H19F3N4OS 396.16; found 397.1.

[0548] Step 4: Preparation of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0549] To a suspension of 5-amino-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide] (0.150 mg, 0.378 mmol) in chlorobenzene (5 mL) was added 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.0866 g, 0.416 mmol) and phosphorus trichloride (0.0331 mL, 0.378 mmol) at ambient temperature, and the resulting reaction mixture was stirred at 130° C. for 3 hours. The reaction was monitored by TLC. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with water (10 mL), brine (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC to give 4,6-dichloro-5-hydroxy-N-[2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]pyridine-2-carboxamide-TFA salt (0.006 g, 3%) as a white solid. LCMS (ES) m / z calcd. For C24H20Cl2F3N5O3S 585.06; found 584.2 (MH); 1 H NMR(400MHz,DMSO-d6):δ 12.63(s,1H),9.80(br s,1H),9.04(t,J=6Hz,1H),8.04(s,1H),7.78(d,J=7.6Hz,1H),7.67(t,J=8Hz,1H),7.50(t,J=7.6Hz,2H),6.63(s,1H),4.75(br s,2H),4.05-3.88(m,1H),3.76-3.64(m,1H),3.36(br s,2H),2.92(s,3H),2.68-2.67-2.87(m,2H).

[0550] Example 86: 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1-methylpiperidin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0551] [ka]

[0552] Step 1: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methylpiperidin-4-yl)thiazole-4-carboxylate

[0553] To a stirred solution of 5-{[(tert-butoxy)carbonyl]amino}-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-4-carboxylate (0.250 g, 0.707 mmol) in MeOH:THF (4:1) (6 mL) was added 10% palladium on carbon (0.150 g) and stirred at room temperature under an H atmosphere for 3 hours. The reaction progress was monitored by LCMS. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methylpiperidin-4-yl)thiazole-4-carboxylate (0.250 g, 99%) as a brown solid. LCMS(ES)m / z calcd. C16H25N3O4S for, 355.16; found,356.2(M+H)

[0554] Step 2: Synthesis of tert-butyl (2-(1-methylpiperidin-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate.

[0555] To a stirred solution of methyl 5-((tert-butoxycarbonyl)amino)-2-(1-methylpiperidin-4-yl)thiazole-4-carboxylate (0.250 g, 0.703 mmol) in toluene (10.0 mL) was added 1-[2-(trifluoromethyl)phenyl]methanamine (0.123 g, 0.703 mmol) and trimethylaluminum (2.0 M in toluene) (0.101 g, 1.41 mmol) dropwise at 0° C. The resulting reaction mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled to ambient temperature, poured into ice-cold water (25 mL), and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified using flash chromatography to give tert-butyl (2-(1-methylpiperidin-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.150 g, 43%) as an off-white solid. LCMS (ES) m / z calcd. for. C23H29F3N4O3S, 498.19; found 499.2 (M+H).

[0556] Step 3: Synthesis of 5-amino-2-(1-methylpiperidin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0557] To a stirred solution of tert-butyl (2-(1-methylpiperidin-4-yl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.150 g, 0.301 mmol) in DCM (3.0 mL) was added hydrogen chloride (4 M in 1,4-dioxane) (0.054 g, 1.5 mmol) and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was triturated with diethyl ether (15 mL) and n-pentane (15 mL) to give 5-amino-2-(1-methylpiperidin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.1 g, 83%) as a brown solid. LCMS(ES)m / z calcd. for. C18H21F3N4OS, 398.14; found 399.2(M+H).

[0558] Step 4: Synthesis of 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1-methylpiperidin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide.

[0559] To a stirred solution of 5-amino-2-(1-methylpiperidin-4-yl)-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.1 g, 0.251 mmol) in acetonitrile (10 mL, 191 mmol) were added 4,6-dichloro-5-hydroxypyridine-2-carboxylic acid (0.052 g, 0.251 mmol) and phosphorus trichloride (0.027 g, 0.201 mmol) at ambient temperature. The resulting reaction mixture was heated to 130° C. for 1 hour. The reaction was cooled to room temperature, after which ice-cold water (15 mL) was added thereto, and the precipitated solid was filtered to obtain a crude solid. The crude compound was purified by preparative HPLC to give 5-(4,6-dichloro-5-hydroxypicolinamido)-2-(1-methylpiperidin-4-yl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide formate (0.0227 g, 15.3%) as an off-white solid. LCMS (ES) m / z calcd. for. C24H22Cl2F3N5O3S, 587.08; found 588.2 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 12.25(s,1H),9.30(s,1H),8.77(s,1H),7.75-7.77(m,1H),7.6-7.70(m,1H),7.47-7.52(m,2H),4.73(d,J=5.6Hz,2H),3.46(br s,4H),3.08(br s,2H),2.8(s,3H),2.3-2.4(br s,1H),1.8-2.1(br s,2H).

[0560] The following compounds were synthesized as described above:

[0561] [Table 7-1]

[0562] [Table 7-2]

[0563] Example 105: Synthesis of 5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0564] [ka]

[0565] Step 1: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-formylphenyl)thiazole-4-carboxylate

[0566] To a solution of methyl 2-bromo-5-{[(tert-butoxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (0.9 g, 2.67 mmol) and (2-fluoro-5-formylphenyl)boronic acid (0.538 g, 3.2 mmol) in 1,4-dioxane (10 mL) was added potassium carbonate (1.11 g, 8.01 mmol) and water (1 mL). The reaction mixture was purged with nitrogen gas for 15 minutes, after which Pd(dppf)Cl.DCM complex (0.218 g, 0.26 mmol) was added at room temperature. The resulting reaction mixture was heated to 100 °C for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a Celite pad, the Celite pad was washed with ethyl acetate (25 mL), and the filtrate was washed with water (2 × 50 mL), brine solution (25 mL), dried over NaSO, concentrated, and dried to give the crude product (0.85 g, 83.7% yield) as a brown solid. LCMS (ES): m / z calcd. for C17H17FN2O5S 380.08; found 381.0 (M+H).

[0567] Step 2: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)thiazole-4-carboxylate

[0568] To a stirred solution of methyl 5-{[(tert-butoxy)carbonyl]amino}-2-(2-fluoro-5-formylphenyl)-1,3-thiazole-4-carboxylate (0.6 g, 1.58 mmol) in methanol (6 mL, 148 mmol), pyrrolidine (1.12 g, 15.8 mmol) and titanium isopropoxide (4.78 mL, 15.8 mmol) were added at room temperature and stirred for 12 hours under an argon atmosphere. To this, NaBH4 (298 mg, 7.89 mmol) was added at room temperature. The resulting reaction mixture was stirred for an additional 2 hours at room temperature. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with water (20 mL), and the resulting residue was filtered through a Celite pad and washed with DCM (25 mL x 2). The combined organic phases were washed with water (15), dried over sodium sulfate, and evaporated under reduced pressure to give the crude compound. The crude material was triturated with 10% ethyl acetate:hexane (10 mL x 2) and diethyl ether (10 mL x 2) to give methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)thiazole-4-carboxylate (0.205 g, 29.84%) as an off-white solid. LCMS (ES): m / z calcd. for CHFN0S, 435.16; found, 436.1 (M+H).

[0569] Step 3: Preparation of tert-butyl (2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0570] To a stirred solution of methyl 5-{[(tert-butoxy)carbonyl]amino}-2-{2-fluoro-4-[(pyrrolidin-1-yl)methyl]phenyl}-1,3-thiazole-4-carboxylate (0.205 g, 0.471 mmol) in toluene (2 mL, 16.9 mmol), 1-[2-(trifluoromethyl)phenyl]methanamine (0.066 mL, 0.471 mmol) was added and cooled to 0 °C. To this was added 1 M trimethylaluminum in toluene (0.136 mL, 1.41 mmol). The resulting reaction mixture was heated to 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water (25 mL) and extracted into EtOAc (25 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude material was purified by Combiflash chromatography using 3% methanol:dichloromethane as eluent to give tert-butyl (2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.4 g, 77%) as an off-white solid. LCMS (ES): m / z calcd. for C28H30F4N4O3S, 578.20; found, 579.0 (M+H).

[0571] Step 4: Preparation of 5-amino-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0572] To a solution of tert-butyl N-(2-{2-fluoro-4-[(pyrrolidin-1-yl)methyl]phenyl}-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl)carbamate (0.4 g, 0.691 mmol) in methanol (4 mL) was added 4 M HCl in dioxane (0.86 mL) at 0° C. and stirred at room temperature under an argon atmosphere for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was basified with sodium bicarbonate (10 mL) and extracted into ethyl acetate (25 mL×2). The combined organic layers were washed with water (10 mL), brine solution (10 ml), dried over sodium sulfate, and evaporated under reduced pressure to give 5-amino-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (95 mg, 29%) as a pale yellow solid. LCMS (ES): m / z calcd. for C23H22F4N4OS, 478.15; found, 479.0 (M+H).

[0573] Step 5: Preparation of 5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0574] To a suspension of 5-amino-2-{2-fluoro-5-[(pyrrolidin-1-yl)methyl]phenyl}-N-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazole-4-carboxamide (0.095 g, 0.199 mmol) in acetonitrile (1 mL), 3-chloro-5-fluoro-4-hydroxybenzoic acid (41.6 mg, 0.218 mmol) and phosphorus trichloride (0.017 mL, 0.199 mmol) were added at room temperature, followed by stirring at 130° C. for 2 hours. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was poured into ice-cold water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with water (10 mL), brine solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC using a water:acetonitrile gradient with 0.1% TFA. The collected pure fractions were lyophilized to give 5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.012 g, 9.28%). LCMS (ES): m / z calcd. for C30H24ClF5N4O3S, 650.12; found, 651.4 (M+H). 1 H NMR(400MHz,DMSO-d6) δ 12.31(s,1H),10.87(bs,1H),9.27(bs,1H),8.45(d,J=6.8Hz,1H),7.77(d,J=7.6Hz,1H),7.71-7.63(m,4H),7.57(d, LC-MS purity: 99.62% at 240nm

[0575] Example 106: Synthesis of N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluorophenyl)thiazole-4-carboxamide

[0576] [ka]

[0577] Step 1: Preparation of methyl 2-(2-fluorophenyl)thiazole-4-carboxylate

[0578] To a stirred solution of methyl 2-bromo-1,3-thiazole-4-carboxylate (50 g, 225 mmol) in 1,4-dioxane (750 mL) and water (125 mL) was added (2-fluorophenyl)boronic acid (47.25 g, 337.5 mmol) and potassium carbonate (93.5 g, 67.5 mmol). The reaction mixture was purged with nitrogen gas for 15 minutes, after which Pd(dppf)Cl.DCM complex (9.2 g, 0.05 equiv., 2.25 mmol) was added at room temperature. The resulting reaction mixture was heated to 100 °C for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a Celite pad, the Celite pad was washed with EtOAc (2 L), and the filtrate was washed with water (2 × 1000 mL), brine solution (500 mL), dried over NaSO, concentrated, and dried to give the crude product. The crude material was purified by column chromatography using 5% EtOAc:hexane as the eluent to give methyl 2-(2-fluorophenyl)-1,3-thiazole-4-carboxylate (41 g, 77% yield) as a white solid. LCMS (ES): m / z calcd. for C5H5BrN2O2S 237.03; found 237.9 (M+H).

[0579] Step 2: Preparation of methyl 5-bromo-2-(2-fluorophenyl)thiazole-4-carboxylate

[0580] To a stirred solution of methyl 2-(2-fluorophenyl)-1,3-thiazole-4-carboxylate (20 g, 84.3 mmol) in acetonitrile was added NBS (45 g, 253 mmol) at room temperature. The resulting reaction mixture was refluxed for 24 hours, after which another portion of NBS (30 g) was added and stirring continued at reflux for another 24 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water (2 L), and the precipitated solid was filtered, washed with water (1 L), and dried to give methyl 5-bromo-2-(2-fluorophenyl)thiazole-4-carboxylate (20 g, 75% yield) as a white fluffy solid. LCMS (ES): m / z calcd. for C11H7BrFNO2S, 314.94; found, 316.0 (M+H).

[0581] Step 3: Preparation of 5-bromo-2-(2-fluorophenyl)thiazole-4-carboxylate

[0582] To a stirred solution of methyl 5-bromo-2-(2-fluorophenyl)-1,3-thiazole-4-carboxylate (16 g, 50.6 mmol) in tetrahydrofuran (200 mL), methanol (75 mL), and water (30 mL) was added LiOH.HO (3.64 g, 152 mmol) at room temperature. The resulting reaction mixture was stirred at 60 °C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into cold water and acidified to pH ∼2 with dilute HCl solution. The precipitated solid was filtered, washed with water (1 L), and dried to give 5-bromo-2-(2-fluorophenyl)-1,3-thiazole-4-carboxylic acid (14 g, 96%) as a white solid. LCMS (ES): m / z calcd. for CHBrFNOS, 300.92; found, 301.9 (M+H).

[0583] Step 4: Preparation of N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-bromo-2-(2-fluorophenyl)thiazole-4-carboxamide.

[0584] To a stirred solution of 5-bromo-2-(2-fluorophenyl)-1,3-thiazole-4-carboxylic acid (0.2 g, 0.66 mmol) in N,N-dimethylformamide (5 mL) was added bicyclo[1.1.1]pentan-1-ylmethanamine (0.064 g, 0.66 mmol), HATU (0.3 g, 0.794 mmol), and triethylamine (0.37 mL, 2.65 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water, brine solution, dried over NaSO, concentrated, and dried to give the crude product. The crude material was purified by flash column chromatography using 5% ethyl acetate in hexane as eluent to give N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-bromo-2-(2-fluorophenyl)thiazole-4-carboxamide (0.075 g, 30%) as a white solid. LCMS (ES): m / z calcd. for C16H14BrFN2OS, 380.00; found, 380.9 (M+H).

[0585] Step 5: Preparation of N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluorophenyl)thiazole-4-carboxamide

[0586] To a stirred solution of N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-bromo-2-(2-fluorophenyl)thiazole-4-carboxamide (0.07 g, 0.184 mmol) and 3-chloro-5-fluoro-4-hydroxybenzamide (0.052 g, 0.275 mmol) in t-butanol (2 mL) was added cesium carbonate (0.18 g, 0.55 mmol). The reaction mixture was then degassed under nitrogen gas for 10 minutes. Xantphos (11 mg, 0.018 mmol) and Pd2(dba)3 (15 mg, 0.018 mmol) were then added at room temperature, and the reaction mixture was heated to 100 °C for 16 hours. The reaction progress was monitored by LCMS and TLC. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water, brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude solid was stirred with diethyl ether (10 ml) for 30 minutes, after which the solid was filtered. The solid was further triturated with methanol, filtered, and dried to give N-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(3-chloro-5-fluoro-4-hydroxybenzamido)-2-(2-fluorophenyl)thiazole-4-carboxamide (0.012 g, 12%). LCMS (ES): m / z calcd. for C23H18ClF2N3O3S, 489.07; found, 490.2 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 12.53(s,1H),11.65(bs,1H),8.79(t,J=6.0Hz,1H),7.73(s,1H),7.69-7.66(m, 1H),7.58-7.39(m,3H),3.43(d,J=6.4Hz,2H),1.69(s,6H);LC-purity: 99.84% at 240nm

[0587] Example 107: Synthesis of 5-(4-chloro-6-fluoro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0588] [ka]

[0589] Step 1: Preparation of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate

[0590] To a stirred solution of methyl 5-amino-2-bromothiazole-4-carboxylate (1 g, 4.22 mmol) in tetrahydrofuran (20 mL, 246 mmol), di-tert-butyl dicarbonate (1.45 mL, 6.33 mmol), DIPEA (2.2 mL, 12.7 mmol), and DMAP (0.520 g, 4.22 mmol) were added at ambient temperature, followed by stirring at the same temperature for another 2 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography using 30% ethyl acetate in hexane as eluent to give methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.9 g, 63%) as a white solid. LCMS (ES): m / z calcd. for C10H13BrN2O4S, 335.98; found, 337.0

[0591] Step 2: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate

[0592] To a stirred solution of methyl 2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.460 g, 1.36 mmol) and (2-fluorophenyl)boronic acid (0.382 g, 2.73 mmol) in 1,4-dioxane:water (8:2) (6 mL), potassium carbonate (0.566 g, 4.09 mmol) was added and degassed with nitrogen for 10 minutes, after which bis(tri-tert-butylphosphane)palladium (0.0697 g, 0.136 mmol) was added and stirred for 16 hours at 100° C. The progress of the reaction was monitored by TLC / LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (25×2 mL), brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography using 20% ​​ethyl acetate in hexane as eluent to give methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate (0.350 g, 73%) as a brown solid. LCMS (ES): m / z calcd. for C16H17FN2O4S, 352.09; found, 353.1

[0593] Step 3: Preparation of tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate

[0594] To a stirred solution of methyl 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylate (0.3 g, 0.851 mmol) in toluene (5 mL) was added 1-[2-(trifluoromethyl)phenyl]methanamine (0.119 mL, 0.851 mmol) and 2 M trimethylaluminum in toluene (0.245 mL, 2.55 mmol) at 0° C. The resulting reaction mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (25 mL), and extracted with ethyl acetate (25×2 mL). The combined organic phases were washed with brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude material was purified by flash column chromatography using 30% EtOAc:hexanes as eluent to give tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.3 g, 71%) as an off-white solid. LCMS (ES): m / z calcd. C23H21F4N3O3S, 495.12; found, 496.1

[0595] Step 4: Preparation of 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0596] To a suspension of tert-butyl (2-(2-fluorophenyl)-4-((2-(trifluoromethyl)benzyl)carbamoyl)thiazol-5-yl)carbamate (0.250 g, 0.505 mmol) in methanol (1 mL) was added 4 M HCl in dioxane (5 mL, 144 mmol) at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with water (10 ml), brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide) (0.170 mg, 85%) as a white solid. LCMS(ES): m / z calcd. for C18H13F4N3OS, 395.07; found,396.1

[0597] Step 5: Preparation of 5-(4-chloro-6-fluoro-5-methoxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0598] To a suspension of 5-amino-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.1 g, 0.25 mmol) in chlorobenzene (0.5 mL) was added 4-chloro-6-fluoro-5-methoxypyridine-2-carboxylic acid (0.065 g, 0.30 mmol) and phosphorus trichloride (0.03 mL, 0.25 mmol). The resulting reaction mixture was heated to 120° C. for 3 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to ambient temperature, the reaction mixture was quenched with ice-cold water (10 mL), and the solid was collected by filtration to give a crude residue which was purified by flash column chromatography using 30% ethyl acetate in hexanes as eluent to give 5-(4-chloro-6-fluoro-5-methoxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (0.08 g, 54%) as an off-white solid. LCMS (ES): m / z C25H16ClF5N4O3S calcd. for 582.06; found 583.1 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 12.78(s,1H),9.37(t,J=5.6Hz,1H),8.48-8.45(m,1H),8.18(s,1H),7.74(d,J=8.0Hz, 1H),7.66-7.63(m,1H),7.54-7.45(m,2H),7.42-7.37(m,3H),4.76(d,J=5.6Hz,2H),19F NMR(400MHz,DMSO-d6): δ-50.05(m,3F),-77.37 (1F),-112.88 (1F).LC purity: 99.1% at 254nm

[0599] Step 6: Preparation of 5-(4-chloro-6-fluoro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide

[0600] To a stirred solution of 4-chloro-6-fluoro-N-[2-(2-fluorophenyl)-4-({[2-(trifluoromethyl)phenyl]methyl}carbamoyl)-1,3-thiazol-5-yl]-5-methoxypyridine-2-carboxamide (80 mg, 0.137 mmol) in NMP (1 mL) was added lithium chloride (17.5 mg, 0.412 mmol) and p-TSA (78.3 mg, 0.412 mmol). The reaction mixture was heated at 100° C. for 3 hours. Upon completion, the reaction mixture was quenched with water (5 mL) and the solid was collected by filtration to give the crude product. This was purified by flash chromatography using 0-10% MeOH / DCM as eluent to give 5-(4-chloro-6-fluoro-5-hydroxypicolinamido)-2-(2-fluorophenyl)-N-(2-(trifluoromethyl)benzyl)thiazole-4-carboxamide (30 mg, 38%). LCMS (ES): m / z C24H14ClF5N4O3S calcd. for 568.04; found 569.2 (M+H); 1 H NMR(400MHz,DMSO-d6):δ 12.68(s,1H),9.39(t,J=6.4Hz,1H),8.50-8.46(m,1H),8.14(S,1H),7.77(d, J=7.6Hz,1H),7.69-7.65(m,1H),7.58-7.38(m,5H),4.78(d,J=6.4Hz,2H).19F NMR(400MHz,DMSO-d6):δ-59.10(3F,-CF3),-81.55(1F,-ArF),-112.92(1F,-ArF).LC purity: 99.5% at 240nm

[0601] Example A: Estrone detection assay for assessing HSD17β13 activity and identifying inhibitors

[0602] The liquid chromatography / mass spectrometry (LC / MS) estrone detection assay monitors the conversion of estradiol to estrone by HSD17B13. The assay was performed in a 96wp format (Eppendorf deep well plate 96 / 500) with 4 μM estradiol (E2; Cayman; #10006315), 6 mM NAD in a reaction containing 1 M potassium phosphate buffer pH 7.4 with 0.5% vehicle (DMSO). + (Sigma; #N0623), and 30 nM HSD17B13 enzyme (in-house; E. coli expressed His-tagged, purified soluble protein) in an 80 μl reaction volume. Reactions were incubated at 26.5°C for 2 hours, and the 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.

[0603] The reaction was terminated by adding two volumes of acetonitrile (MeCN; LCMS grade; CAS#75 / 05 / 8) containing deuterated (D4)-E1, used as an internal standard (Clear Synth; #CS-T-54273; final concentration of 500 ng / mL). The sample was applied to a pre-prepared Bond Elut-C18 extraction cartridge (3 mL; Agilent; #12102028), washed, and eluted with MeCN. The eluent was dried under nitrogen and resuspended in 60% methanol (LCMS grade methanol; CAS#67 / 56 / 1) before being submitted for analysis. Aqueous linearity of E2 and E1 was included for quantification.

[0604] Sample analysis was performed on an XBridge BEH C18 column (Waters; #186003033) using 0.1% diethylamine in MeCN (mobile phase A; DEA CAS #109-89-7) and 0.1% diethylamine in Milli-Q water (mobile phase B) with a 3-minute gradient allowing 25% B. MRM analysis was used to detect the analytes in negative mode; the RT for E2 was 1.85 min and the RT for E1 was 2 min. NAD +The specificity of the conversion was assessed using the activity of the enzyme in the absence of inhibitor. 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 assays were performed in duplicate, pooled during the extraction process, and then injected in duplicate for LC-MS / MS analysis.

[0605] Example B: Estrone detection assay for assessing HSD17B14 activity by detecting estrone products and identifying inhibitors

[0606] The liquid chromatography / mass spectrometry (LC / MS) estrone detection assay monitors the conversion of estradiol to estrone by HSD17B14. The assay was performed in a 96-well plate (Eppendorf deep well) containing 8 μM estradiol (E2; Cayman); 4 mM NAD + (Sigma); 120 nM HSD17B14 enzyme (in-house E. coli expressed His-tagged, purified soluble protein), 1 M potassium phosphate buffer pH 7.4, and 1.2% vehicle (DMSO) were used in an 80 μl reaction volume. Reactions were incubated at 37°C for 2 hours. Conversion of estradiol (E2) to estrone (E1) was quantified by LC-MS / MS-based analyte detection for E1 using LCMS-grade reagents.

[0607] The reaction was terminated by the addition of two volumes of acetonitrile (MeCN; LCMS grade) containing deuterated (D4)-E1, used as an internal standard (Clear Synth; final concentration of 500 ng / mL). The samples were applied to pre-prepared Bond Elut-C18 extraction cartridges (3 mL; Agilent). The cartridges were washed with 1.5 mL of water, followed by 1.5 mL of 5% aqueous methanol, and dried under vacuum for 5 minutes. They were then eluted with 4.5 mL of MeCN. The eluates were dried under nitrogen and resuspended in 200 μL of 60% methanol (LCMS grade) before being submitted for analysis. Standard curves of E2 and E1 in 4% DMSO were included for quantification.

[0608] Sample analysis was performed on an XBridge BEH C18 column (Waters) using 0.1% diethylamine in MeCN (mobile phase A) and 0.1% diethylamine in Milli-Q water (mobile phase B) with a 3 min gradient from 0 to 25% B. MRM analysis was used to detect the analytes in negative mode; the RT for E2 was 1.89 min and the RT for E1 was 2.07 min. NAD + The specificity of the conversion was assessed using the activity of the enzyme in the absence of DMSO. Enzyme activity in the presence of test sample was expressed as a percentage of uninhibited enzyme in the presence of 1.2% DMSO vehicle alone and plotted against inhibitor concentration. Nonlinear regression was performed using a four-parameter logistic model and GraphPad Prism software. All assays were performed in duplicate, which were pooled during the extraction process and then injected as duplicates for LC-MS / MS analysis.

[0609] Example C: Assessment of HSD17B2 activity and identification of inhibitors by detection of reduced nicotinamide adenine dinucleotide (NADH) product

[0610] Fluorescence-based detection assays detect the cofactor NAD +The conversion of estradiol (E2) to NADH was monitored, which occurs simultaneously with the conversion of estradiol to estrone by HSD17B2. These assays were performed in 384-well plates (Greiner V-shape PP-microplates). The reaction volume of 20 μl contained 0.7 μM estradiol (E2); 6 mM NAD + (Sigma), 250 nM HSD17B2 enzyme (Origene; Cat# TP303293), 0.25 M potassium phosphate buffer pH 7.4, 0.75% vehicle (DMSO). Reactions were incubated at 37°C for 2 hours and stopped by freezing the reaction plate at -80°C. Time zero samples were immediately frozen.

[0611] NAD was measured using the NAD-Glo kit (Promega; Cat# G9062) according to the manufacturer's instructions. + The conversion of NADH to NADH was quantified. A volume of 15 μL of enzyme reaction mixture was added to 15 μL of reconstituted Gio Reagent, and the plate was incubated at room temperature for 30 minutes. Luminescence was quantified with a Tecan Spark Reader®. A standard curve of NADH (0.1–50 μL) in potassium phosphate buffer pH 7.4 / 1% DMSO was run on each plate.

[0612] The specificity of the conversion was assessed using the activity of the enzyme in the absence of E2. Enzyme activity in the presence of test sample was expressed as a percentage of uninhibited enzyme in the presence of 1% DMSO vehicle alone and plotted against inhibitor concentration. Nonlinear regression was performed using a four-parameter logistic model and GraphPad Prism software. All evaluations were performed in duplicate.

[0613] Data from Examples A, B, and C are shown in Tables 2 and 3 below.

[0614] [Table 8]

[0615] Table 9-1

[0616] Table 9-2

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is thiazolyl; R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, or C １ -C ６ is an aminoalkyl; R ２ is hydrogen or C １ -C ６ is alkyl, R ３ is C １ -C １０ Alkyl, C １ -C １０ Haloalkyl, C １ -C １０ Deuterated alkyl, C １ -C １０ Hydroxyalkyl, C １ -C １０ Aminoalkyl, C １ -C １０ Heteroalkyl, C ２ -C １０ Alkenyl, C ２ -C １０ Alkynyl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ is replaced by R ３ａ 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; Alternatively, two R on the same atom ３ａ come together to form oxo, R ４ Deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R ４ａ is replaced by R ４ａ 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, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom ４ａ come together to form oxo, Alternatively, two R on the same carbon ４ａ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Alternatively, two R on different atoms ４ａ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; X is N or CR Ｘ and R Ｘ is hydrogen, 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 is a deuterated alkyl; R ５ is hydrogen, 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 is a deuterated alkyl; R ６ are each independently a halogen; 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 Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; 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 Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and 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 Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is independently a halogen, —CN, —OH, or —OC １ -C ３ Alkyl, -OC １ -C ３ Haloalkyl, -SC １ -C ３ Alkyl, -S(=O)C １ -C ３ Alkyl, -S(=O) ２ C １ -C ３ Alkyl, -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C. １ -C ３ Alkyl, -S(=O) ２ N (C １ -C ３ Alkyl) ２ , -NH ２ , -NHC １ -C ３ Alkyl, -N(C １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Deuterated alkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, or C ３ -C ６ is cycloalkyl, Alternatively, two R on the same atom form an oxo, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound has the formula (Ia) 【Chemistry 2】 2. The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is:

3. The compound has the formula (Ib) 【Chemistry 3】 2. The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is:

4. R １ The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

5. R ２ The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

6. R ３ is C １ -C １０ Alkyl, C １ -C １０ Haloalkyl, C １ -C １０ Deuterated alkyl, C １ -C １０ Hydroxyalkyl, C １ -C １０ Aminoalkyl, C １ -C １０ Heteroalkyl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

7. R ３ is C ４ -C １０ Alkyl, C １ -C １０ Haloalkyl, C １ -C １０ Deuterated alkyl, C １ -C １０ Hydroxyalkyl, C １ -C １０ Aminoalkyl, C １ -C １０ Heteroalkyl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

8. R ３ is C １ -C １０ Alkyl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

9. R ３ is C ４ -C １０ Alkyl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

10. R ３ is C １ -C １０ Alkyl, or C １ -C ６ alkylene(aryl), where the alkyl, alkylene, and aryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

11. R ３ is C ４ -C １０ Alkyl, or C ２ -C ６ alkylene(aryl), where the alkyl, alkylene, and aryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

12. R ３ optionally independently represents one or more R ３ａ C substituted with １ -C １０ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

13. R ３ optionally independently represents one or more R ３ａ C substituted with ４ -C １０ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

14. R ３ is C ４ -C １０ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

15. R ３ is C １ -C ６ alkylene(aryl), where the alkylene and aryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

16. R ３ is C ２ -C ６ alkylene(aryl), where the alkylene and aryl are optionally independently selected from one or more R ３ａ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

17. R ３ａ each independently represents deuterium, halogen, -CN, -OH, or -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ heteroalkyl; or two R ３ａ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

18. R ３ａ each independently represents deuterium, halogen, —OH, or —OR ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ deuterated alkyl; or two R ３ａ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

19. R ３ａ Each independently represents a halogen, -OR ａ , or C １ -C ６ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

20. R ３ａ are each independently １ -C ６ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

21. 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N.

22. X is CR Ｘ 21. The compound of any one of claims 1 to 20, wherein:

23. R Ｘ is hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ 23. The compound of any one of claims 1 to 20 or 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

24. R Ｘ is hydrogen or C １ -C ６ 24. The compound of any one of claims 1 to 20 or 22 or 23, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

25. R Ｘ 25. The compound of any one of claims 1-20 or 22-24, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is hydrogen.

26. R ５ is hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

27. R ５ is hydrogen or C １ -C ６ 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

28. R ５ 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

29. R ６ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein each is chloro.

30. R ６ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein each is fluoro.

31. R ４ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

32. R ４ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

33. R ４ is one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is 0 or 1;

34. R ４ is one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is a heterocycloalkyl optionally substituted with R.

35. R ４ is aryl or heteroaryl, and the aryl and heteroaryl are optionally joined by one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

36. R ４ is one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is aryl optionally substituted with R.

37. R ４ is one or more R ４ａ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an optionally substituted heteroaryl group.

38. R ４ａ each independently represents deuterium, halogen, -CN, -OH, or -OR ａ , -S(=O)R ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, where the alkyl is optionally independently substituted with one or more R, or two R on the same atom. ４ａ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

39. R ４ａ each independently represents deuterium, halogen, -CN, -OH, or -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R ４ａ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

40. R ４ａ each independently represents deuterium, halogen, -CN, -OH, or -OR ａ , -S(=O)R ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ deuterated alkyl, cycloalkyl, or heterocycloalkyl; or two R ４ａ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

41. R ４ａ each independently represents a halogen, —CN, —OH, or —OR ａ , -S(=O)R ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; or two R ４ａ come together to form oxo.

38. A compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

42. R ４ａ each independently represents a halogen, -S(=O)R ａ , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; or two R ４ａ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form oxo.

43. A compound selected from the compounds found in Table 1a or Table 1b, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

44. 44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

45. 46. ​​A method of treating a disease in a subject in need thereof, comprising administering a pharma- ceutical effective amount of a compound according to any one of claims 1 to 43, or a pharma- ceutical acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 44.

46. 46. ​​The method of claim 45, wherein the disease is a liver disease, a metabolic disease, or a cardiovascular disease.

47. 47. The method of claim 45 or 46, wherein the disease is NAFLD.

48. 47. The method of claim 45 or 46, wherein the disease is NASH.

49. 47. The method of claim 45 or 46, wherein the disease is drug-induced liver injury (DILI).

50. 47. The method of claim 45 or 46, wherein the disease is associated with HSD17B13.

51. 47. The method of claim 45 or 46, wherein the disease is alcoholic liver disease.

52. 47. The method of claim 45 or 46, wherein the disease is cirrhosis of the liver.

53. 47. The method of claim 45 or 46, wherein the disease is decompensated portal hypertension.

54. 47. The method of claim 45 or 46, wherein the disease is a cholestatic liver disease.

55. 44. A method for selectively inhibiting HSD17B13, comprising administering a pharma- ceutical effective amount of a compound according to any one of claims 1 to 43, or a pharma- ceutical acceptable salt, solvate, or stereoisomer thereof.

56. 56. The method of claim 55, wherein the compound selectively inhibits HSD17B13 over HSD17B2, HSD17B14, or any combination thereof.

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