Amide heteroaromatic compounds useful for the treatment of liver diseases

Abstract

This specification relates to a compound of formula (I): JPEG2025516080000211.jpg3244 and its pharmaceutically acceptable salts, methods and intermediates used in their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases such as liver diseases.

Description

Technical Field

[0001] Cross - reference to related applications This specification claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 364,976 (filed May 19, 2022), 63 / 367,843 (filed Jul. 7, 2022), and 63 / 383,982 (filed Nov. 16, 2022). The entire text of the above - mentioned patent applications is incorporated herein by reference.

[0002] This specification relates to certain amido heteroaromatic compounds that inhibit 17β - hydroxysteroid dehydrogenase 13 (17βHSD13 or HSD17B13), and pharmaceutically acceptable salts thereof, and their use in the treatment of diseases such as liver diseases. This specification also relates to processes and intermediate compounds involved in the preparation of the heteroaromatic compounds, and to pharmaceutical compositions containing them.

Background Art

[0003] Non - alcoholic fatty liver disease (NAFLD) refers to a variety of liver diseases ranging from simple fatty liver (non - alcoholic fatty liver) to non - alcoholic steatohepatitis (NASH) with or without fibrosis, and cirrhosis. Fatty liver is defined as an excessive fat accumulation in the liver exceeding 5% caused by causes other than alcohol intake. NASH is defined as fatty liver with or without fibrosis, accompanied by inflammation and hepatocyte injury. It is estimated that about 25% of the world's population has NAFLD, and the mortality rate due to NAFLD - related diseases is expected to increase significantly by 2030.

[0004] To date, there are no approved treatments for NAFLD (such as NASH), and treatment interventions have focused on addressing comorbidities that also contribute to the development of NAFLD, such as the treatment of insulin resistance, obesity, type II diabetes, and dyslipidemia.

[0005] In recent years, mutations in the 17βHSD13 gene have been associated, in an allele dose-dependent manner, with a decrease in serum aminotransferase levels and also with a reduced risk of liver diseases such as alcoholic and non-alcoholic liver diseases, cirrhosis, and hepatocellular carcinoma (HCC) (Non-Patent Document 1, Non-Patent Document 2). The 17βHSD13 splice variant (rs72613567:TA) results in a truncated, unstable, and enzymatically inactive protein and is thus characterized as a 17βHSD13 loss-of-function (LoF) variant (Non-Patent Document 3). The association between LoF 17βHSD13 (rs72613567:TA) and a reduced disease severity has been replicated in an additional cohort with histologically proven NAFLD and was also associated with a decrease in plasma transaminases, cirrhosis, HCC, and liver-related mortality in a study of 111,612 individuals from the general population of Denmark (Non-Patent Document 4). Interestingly, the protective effect of the LoF 17βHSD13 (rs72613567:TA) variant on plasma aminotransferase levels appears to be amplified by several important risk factors for liver disease such as obesity, alcohol intake, and established genetic risk factors such as the (rs738409C>G) variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Furthermore, two additional 17βHSD13 LoF variants (rs62305723) and (rs143404524) have also been reported to protect against the progression of chronic liver disease (Non-Patent Document 5). In general, LoF 17βHSD13 protective variants are strongly associated with fibrosis and progression to advanced liver disease but not with fatty liver

[0006] Based on the genetic verification of the 17βHSD13 LoF variant that protects against the risk and progression of liver diseases, inhibiting 17βHSD13 activity with small molecule inhibitors can treat liver diseases such as non-alcoholic fatty liver disease (NAFLD) (e.g., NASH, liver fibrosis, cirrhosis, and isolated fatty liver), hepatitis, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV), and hepatocellular carcinoma (HCC), for example, several important risk factors for liver diseases such as obesity and alcohol intake, and individuals with established genetic risk factors such as the (rs738409C>G) variant in PNPLA3. It can be an effective treatment method.

[0007] The compounds of the present specification provide an anti-liver disease effect by acting as at least 17βHSD13 inhibitors. Furthermore, the compounds of the present disclosure can selectively inhibit 17βHSD13 over 17βHSD4 and / or 17βHSD9.

[0008] Fifteen 17βHSD (HSD17B) members have been identified in humans. The sequence homology between different members is quite low, but the overall structure seems to be conserved. 17β-Hydroxysteroid dehydrogenases are mainly involved in sex hormone metabolism. Some 17βHSD enzymes also play important roles in cholesterol and fatty acid metabolism (Non-Patent Document 6, Non-Patent Document 7). A clean off-target profile is an advantage of 17βHSD13 inhibitors to avoid potential toxicity caused by off-target activity. This includes selectivity for other 17βHSD members.

[0009] 17βHSD4 / D-bifunctional protein (DBP) is involved in fatty acid β-oxidation and steroid metabolism. 17βHSD4 is ubiquitously expressed and plays an important role in the inactivation of estrogen in many peripheral tissues. Mutations in 17βHSD4 are known to cause DBP deficiency, an autosomal recessive disorder of peroxisomal fatty acid β-oxidation that is generally lethal within 2 years of birth. Homozygous missense variants in 17βHSD4 have been identified in Pelizaeus-Merzbacher disease, a recessive disorder characterized by ovarian dysgenesis in females, sensorineural hearing loss in both males and females, and neurological signs in some patients (Non-Patent Documents 8 and 9).

[0010] 17βHSD9 / RDH5 (retinol dehydrogenase 5) is involved in retinoid metabolism. This enzyme is mainly expressed in the retinal pigment epithelium. The RDH5 gene encodes an enzyme that is part of the visual cycle and catalyzes the reduction of 11-cis-retinol to 11-cis-retinal, the 11-cis-retinol dehydrogenase enzyme. Mutations in the RDH5 gene cause progressive cone dystrophy or macular dystrophy and night blindness. Fundus albipunctatus is a rare congenital night blindness associated with rod system disorders and is characterized by the presence of numerous small white to yellow retinal lesions. This disorder is mainly caused by mutations in the RDH5 gene (Non-Patent Documents 10 and 11).

[0011] The compounds of the present specification can also exhibit advantageous physical properties (e.g., lower lipophilicity, higher water solubility, higher permeability, lower plasma protein binding, and / or greater chemical stability), and / or favorable toxicity profiles (e.g., reduced activity at hERG), and / or favorable metabolic or pharmacokinetic profiles compared to other known 17βHSD13 inhibitors. Therefore, such compounds can be particularly suitable as therapeutic agents, such as for the treatment of liver diseases.

Prior Art Documents

Non-Patent Documents

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Summary of the Invention

Means for Solving the Problems

[0013] According to one aspect of the present specification, a compound of formula (I):

Chemical formula

Chemical formula

[0014] In a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided.

[0015] In a further aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is provided.

[0016] In a further aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of liver disease is provided.

[0017] In a further aspect, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament is provided.

[0018] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of liver disease.

[0019] In a further aspect, there is provided a method of treating cancer in a patient, the method comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] In a further aspect, there is provided an intermediate useful in the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] Definitions For the present specification to be more readily understood, certain terms are defined explicitly below. Further, the definitions are set forth as necessary throughout the detailed description.

[0022] As used herein, the term "alkyl" refers to both straight-chain and branched-chain saturated hydrocarbon groups having a specified number of carbon atoms.

[0023] As used herein, the prefix C x~y in terms such as "C x~y (where x and y are integers) indicates the range of the number of carbon atoms present in the group. Examples of suitable C 1~3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl. Examples of suitable C 1~4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0024] As used herein, the prefix X~Y in terms such as "X~Y-membered ring" (where X and Y are integers) indicates the range of the number of atoms (i.e., carbon atoms and heteroatoms) present in the group.

[0025] As used herein, the term "alkoxy" refers to a saturated group containing the specified number of carbon atoms and one oxygen atom. To avoid ambiguity, the alkoxy group may be straight-chain or branched-chain. Suitable C 1~3 Examples of alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr), and i-propoxy (O i Pr). Suitable C 1~4 Examples of alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr), i-propoxy (O i Pr), n-butoxy (O n Bu), i-butoxy (O i Bu), s-butoxy (O s Bu) and t-butoxy (O t Bu).

[0026] As used herein, the term "cycloalkane" refers to a saturated carbocyclic ring. C 3~6 Examples of cycloalkane groups are cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0027] As used herein, the term "cycloalkylidine" refers to a 1,1-diradical of a cycloalkane C 3~6 Examples of cycloalkylidine are cyclopropylidene (i.e.,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0028] Unless otherwise specified, "halo" is selected from Cl, F, Br, and I. In an embodiment, it is selected from Cl and F.

[0029] The term "heteroatom" refers to N, O, or S.

[0030] Unless otherwise specified, the term "heteroaryl" is an aromatic monocyclic or bicyclic 5- to 9-membered ring containing one or more heteroatoms independently selected from N, O, and S. When the compounds of the present disclosure contain two or more heteroaryl groups, the heteroaryl groups may be the same or different. Heteroaryl can be a 5- or 6-membered monocyclic heteroaryl. Suitable 5-membered heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, furazanyl, 1,3,4-thiadiazolyl, and tetrazolyl. Suitable 6-membered heteroaryl groups include pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and 1,3,4-triazinyl. Heteroaryl can be a 9-membered bicyclic heteroaryl. When heteroaryl is bicyclic, one or both rings can be aromatic. Suitable 9-membered heteroaryl groups include indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, indolinyl, isoindolinyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, [1,2,4]triazolo[4,3-b]pyridazinyl (such as 6-[1,2,4]triazolo[4,3-b]pyridazinyl), and benz[d]oxazolyl (such as 2-benz[d]oxazolyl).

[0031] Unless otherwise indicated, the term "heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring containing one N atom and one additional heteroatom selected from one of N, O, and S atoms. To avoid ambiguity, the other atoms of the ring are carbon. Examples of suitable heterocycloalkyls include 4- to 8-membered monocyclic heterocycloalkyls, 8- to 11-membered spirocyclic bicyclic heterocycloalkyls, 7- to 10-membered fused bicyclic heterocycloalkyls, and 8- to 10-membered bridged bicyclic heterocycloalkyls.

[0032] The term "4- to 8-membered monocyclic heterocycloalkyl" refers to a saturated 4- to 8-membered monocyclic ring containing one nitrogen atom and one additional heteroatom selected from nitrogen, oxygen, and sulfur, optionally. To avoid ambiguity, the other atoms of the ring are carbon. A suitable 4-membered heterocycloalkyl group is azetidin-1-yl. A suitable 5-membered heterocycloalkyl group is pyrrolidin-1-yl. Examples of suitable 6-membered heterocycloalkyl groups include piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, and thiomorpholin-4-yl. Examples of suitable 7-membered heterocycloalkyl groups include azepan-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, and 1,4-thiazepan-4-yl. Examples of suitable 8-membered heterocycloalkyl groups include azocan-1-yl, 1,4-diazocan-1-yl, 1,5-diazocan-1-yl, 1,4-oxazocan-4-yl, 1,5-oxazocan-5-yl, 1,4-thiazocanyl, and 1,5-thiazocanyl.

[0033] The term "8- to 11-membered spirocyclic bicyclic heterocycloalkyl" refers to a saturated 8- to 11-membered monocyclic ring containing one nitrogen atom and one additional heteroatom selected from the group consisting of N, O, and S, optionally. To avoid ambiguity, the other atoms of the ring are carbon. Examples of suitable 8-membered spirocyclic heterocycloalkyl groups include 5-azaspiro[2.5]octan-5-yl, 4,7-diazaspiro[2.5]octan-7-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, and 4-thia-7-azaspiro[2.5]octan-7-yl. Examples of suitable 9-membered spirocyclic heterocycloalkyl groups include 6-azaspiro[3.5]nonan-6-yl, 5,8-diazaspiro[3.5]nonan-8-yl, 5-oxa-8-azaspiro[3.5]nonan-8-yl, and 5-thia-8-azaspiro[3.5]nonan-8-yl. Examples of suitable 10-membered spirocyclic heterocycloalkyl groups include 7-azaspiro[4.5]decane-7-yl, 6,9-diazaspiro[4.5]decane-9-yl, 6-oxa-9-azaspiro[4.5]decane-9-yl, and 6-thia-9-azaspiro[4.5]decane-9-yl. Examples of suitable 11-membered spirocyclic heterocycloalkyl groups include 2-azaspiro[5.5]undecan-2-yl, 1,4-diazaspiro[5.5]undecan-4-yl, 1-oxa-4-azaspiro[5.5]undecan-4-yl, and 1-thia-4-azaspiro[5.5]undecan-4-yl.

[0034] The term "7- to 10-membered fused bicyclic heterocycloalkyl" refers to a saturated 7- to 10-membered bicyclic fused ring containing one nitrogen atom and one additional heteroatom selected from optional N, O, and S. To avoid ambiguity, the remaining atoms of the ring are carbon. Examples of suitable 7-membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.1.0]heptan-2-yl, 2,5-diazabicyclo[4.1.0]heptan-2-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, and 2-thia-5-azabicyclo[4.1.0]heptan-5-yl. Examples of suitable 8-membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.2.0]octan-2-yl, 2,5-diazabicyclo[4.2.0]octan-2-yl, 2-oxa-5-azabicyclo[4.2.0]octan-5-yl, and 2-thia-5-azabicyclo[4.2.0]octan-5-yl. Examples of suitable 9-membered fused bicyclic heterocycloalkyl groups include octahydro-1H-cyclopenta[b]pyridin-1-yl, octahydro-1H-cyclopenta[b]pyrazin-1-yl, octahydrocyclopenta[b][1,4]oxazin-4-yl, and octahydrocyclopenta[b][1,4]thiazin-4-yl. Examples of suitable 10-membered fused bicyclic heterocycloalkyl groups include decahydroquinolin-1-yl, decahydroquinoxalin-1-yl, octahydro-2H-benzo[b][1,4]oxazin-4-yl, and octahydro-2H-benzo[b][1,4]thiazin-4-yl.

[0035] The term "8- to 10-membered bridged bicyclic heterocycloalkyl" refers to a saturated 8- to 10-membered bicyclic bridge containing one N atom and one additional heteroatom selected from optional nitrogen, oxygen, and sulfur, and the remaining atoms of the 8- to 10-membered fused bicyclic heterocycloalkyl are carbon. Examples of suitable 8- to 10-membered bridged bicyclic heterocycloalkyl groups include 3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.2.2]nonane, and 3-azabicyclo[3.3.2]decane-3-yl.

[0036] The term "oxo" refers to an oxygen atom that forms a double bond (i.e., =O) with a suitable atom, such as carbon.

[0037] Unless otherwise indicated, the term "ring system" refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic 4- to 13-membered ring containing one N atom and one or two additional heteroatoms independently selected from N, O and S at will. To avoid ambiguity, the other atoms of the ring are carbon. When the ring system is bicyclic, it can be spirocyclic, fused or bridged. Examples of suitable monocyclic ring systems include 4- to 6-membered heterocycloalkyl. Examples of suitable bicyclic ring systems include 8- to 11-membered spirocyclic bicyclic heterocycloalkyl, 7- to 10-membered fused bicyclic heterocycloalkyl and 8- to 10-membered bridged bicyclic heterocycloalkyl.

[0038] The term "saturated or partially saturated" ring system refers to an aliphatic ring system, or a ring system containing at least one aliphatic ring and one or two aromatic rings.

[0039] Unless otherwise specified, the bond of an atom or group can be any suitable atom of that group. For example, for propyl, prop-1-yl and prop-2-yl are included.

[0040] To avoid ambiguity, when multiple substituents are independently selected from a given group, the selected substituents may include the same substituents or different substituents within the scope of the given group.

[0041] To avoid ambiguity, when a circle is used within a 5-membered ring, it indicates that the 5-membered ring is an aromatic ring. Just as an example,

Chem.

Chem.

[0042] To avoid ambiguity, in the formulas of this specification, " [Chem.] The use of " " indicates the point of attachment between different groups. By way of example only, [Chem.] represents a 3-hydroxyphenyl group bonded to different groups via the carbon atom at the meta position of the OH substituent.

[0043] To avoid ambiguity, the use of a bond between a substituent and the center of a ring indicates that any hydrogen atom to which the substituent is directly bonded to the ring can be replaced regardless of whether the hydrogen atom is bonded to a C atom or an N atom. By way of example only, [Chem.] represents [Chem.] a group selected from

[0044] If any embodiment herein includes a group that is said to be "optionally substituted", further embodiments include those embodiments in which the group is unsubstituted.

[0045] To avoid ambiguity, if multiple substituents are selected independently from a given group, the substituents selected may include the same substituents or different substituents within the scope of the given group.

[0046] Units, prefixes and symbols are expressed in the form recognized in these International System of Units (SI). A numerical range includes the numbers defining the range.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide many common dictionaries of terms used in this disclosure to those skilled in the art.

[0048] Here, with reference to the accompanying drawings, embodiments and experiments illustrating the principles of the present disclosure will be described.

Brief Description of the Drawings

[0049]

Figure 1

Modes for Carrying Out the Invention

[0050] In one aspect, there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0051] In an embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic monocyclic, bicyclic or tricyclic 4- to 13-membered ring containing one N atom and one or two further heteroatoms independently selected from optional N, O and S.

[0052] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 4- to 11-membered ring containing one N atom and one or two additional heteroatoms independently selected from optional N, O, and S (wherein the ring system is optionally substituted with one or more R C ), a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided.

[0053] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 5- to 11-membered ring containing one N atom and one additional heteroatom selected from optional N, O, and S (wherein the ring system is optionally substituted with one or more R C ), a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided.

[0054] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 5- to 8-membered ring containing one N atom and one additional heteroatom selected from optional N, O, and S (wherein the ring system is optionally substituted with one or more R C ), a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided.

[0055] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 5- to 11-membered ring containing one N atom and one additional heteroatom selected from N, O, and S (wherein the ring system is optionally substituted with one or more R C ), a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided.

[0056] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 5- to 8-membered ring containing one N atom and one additional heteroatom selected from N, O, and S (wherein the ring system is optionally substituted with one or more R C ), a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided.

[0057] In an embodiment, the ring system is an aliphatic monocyclic or bicyclic 5- to 8-membered ring containing one N atom and one O atom (wherein the ring system is optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0058] In an embodiment, the ring system is an aliphatic monocyclic 5- to 8-membered ring containing one N atom and one O atom (wherein the ring system is optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0059] In an embodiment, the ring system is a 4- to 8-membered monocyclic heterocycloalkyl optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0060] In an embodiment, the ring system is a 5- to 7-membered monocyclic heterocycloalkyl optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0061] In an embodiment, the ring system is an 8- to 11-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0062] In an embodiment, the ring system is a 7- to 10-membered fused bicyclic heterocycloalkyl optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0063] In an embodiment, the ring system is an 8- to 10-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more R C ), and a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0064] In an embodiment, the ring system is optionally substituted with one or more R C to provide a compound of formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the ring system is optionally substituted with 1 to 3 R C . In a further embodiment, the ring system is optionally substituted with 1 or 2 R C . In a further embodiment, the ring system is unsubstituted.

[0065] In an embodiment, each R C is independently selected from F, R 3 , R 4 , -O(R 4 ), -O(R 5 ), R 5 , R 6 , -OH, -CN and -C(=O)N(R 7A ) 2 to provide a compound of formula (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, each R C is independently selected from R 3 , R 4 , -O(R 4 ), -O(R 5 ), R 5 and R 6 . In a further embodiment, each R C is independently selected from R 3 , R 4 and R 5 . In a further embodiment, each R C is independently R 3 . In a further embodiment, each R C is independently C 1~4 alkyl optionally substituted with one or more (e.g., 1 to 3) F. In a further embodiment, each R C is independently selected from C 1~4 alkyl, phenyl and -O(phenyl). In a further embodiment, each R C is independently C 1~4 alkyl. In a further embodiment, each R C is CH 3 .

[0066] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, where NR 1 R 2 is

Chemical formula

[0067] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, where NR 1 R 2 is

Chemical formula

[0068] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, where NR 1 R 2 is

Chemical formula

[0069] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, where NR 1 R 2 is

Chemical formula

[0070] In an embodiment, the compound of formula (I) is of formula (II): [Chemical formula] [wherein J is selected from O, S, CH 2 , NH and a covalent bond, G is absent or, together with the carbon atom to which it is attached, forms a C 3~6 cycloalkane ring; Z is (i) when G is absent and J is selected from O, S, CH 2 and a covalent bond, Z is CH 2 , CH 2 CH 2 and C 3~6 selected from cycloalkylidine, (ii) when G is absent and J is NH, Z is CH 2 , CH 2 CH 2 , C 3~6 selected from cycloalkylidine and C(=O), and (iii) when G, together with the carbon atom to which it is attached, forms a C 3~6 cycloalkane ring, Z is CH 2 ) is such that; x is selected from 0 to 3; and each R 9 is independently R 3 , R 4 and R 5 selected from) is a compound of or a pharmaceutically acceptable salt thereof.

[0071] In an embodiment, the compound of formula (II) is of formula (IIA) or formula (IIB):

Chemical formula

[0072] In an embodiment, the compound of formula (II) is of formula (IIC):

Chemical formula

[0073] In an embodiment, the compound of formula (II) is of formula (IID):

Chemical formula

[0074] In an embodiment, the compound of formula (II) is of formula (IIE):

Chemical formula

[0075] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0076] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0077] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0078] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0079] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0080] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein the ring system is

Chemical formula

[0081] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein the ring system is

Chemical formula

[0082] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein the ring system is

Chemical formula

[0083] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 1 is selected from R 8 and R 4A , and R 2 is selected from R 8A and H.

[0084] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 1 is R 8 , and R 2 is selected from R 8A and H.

[0085] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 8 is C 1~4 alkyl or C 3~6 cycloalkyl (e.g., C 1~4 alkyl), each of which is optionally R 4B (e.g., R 4x ), R 5B (e.g., R5x ), F, -OH, -CN, C 1~4 alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) 2 is substituted with one or more groups (e.g., 1 to 3 groups) independently selected from. In a further embodiment, R 8 is optionally R 4B (e.g., R 4x ), R 5B (e.g., R 5x ), F, -OH, -CN, C 1~4 alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) 2 is substituted with 1 or 2 groups (e.g., 1 group) independently selected from C 1~4 alkyl (e.g., CH 3 ). In a further embodiment, R 8 is optionally R 4B (e.g., R 4x ) and R 5B (e.g., R 5x ) is substituted with 1 or 2 groups (e.g., 1 group) independently selected from C 1~4 alkyl (e.g., CH 3 ). In a further embodiment, R 8 is optionally substituted with 1 or 2 groups (e.g., 1 group) independently selected from monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., monocyclic 5- or 6-membered heteroaryl) and phenyl C 1~4 alkyl (e.g., CH 3 ), wherein the heteroaryl and phenyl are optionally C 1~4 alkyl (e.g., CH 3 ), C 3~6 cycloalkyl (e.g., cyclohexyl) and phenyl are substituted with one or more groups (e.g., 1 or 2 groups) selected from.

[0086] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided, wherein R 8 is C1~4 alkyl or C 3~6 cycloalkyl (e.g., C 1~4 alkyl), each of which is substituted with one or more groups (e.g., 1 to 3 groups) independently selected from R 4B (e.g., R 4x ), R 5B (e.g., R 5x ), F, -OH, -CN, C 1~4 alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) 2 In a further embodiment, R 8 is C 4B alkyl (e.g., R 4x ) substituted with 1 or 2 groups (e.g., 1 group) independently selected from R 5B (e.g., R 5x ), R 1~4 (e.g., R 1~4 ), F, -OH, -CN, C 7C alkoxy, -C(=O)O(C 2 alkyl) and -C(=O)N(R 1~4 alkyl (e.g., CH 3 ). In a further embodiment, R 8 is C 4B alkyl (e.g., CH 4x ) substituted with 1 or 2 groups (e.g., 1 group) independently selected from R 5B (e.g., R 5x ) and R 1~4 alkyl (e.g., CH 3 ). In a further embodiment, R 8 is C 1~4 alkyl (e.g., CH 3 ) substituted with phenyl or monocyclic or bicyclic 5- to 9-membered heteroaryl, wherein the phenyl or monocyclic or bicyclic 5- to 9-membered heteroaryl is optionally substituted with 1 or 2 groups independently selected from C 1~4 alkyl, C 3~6 cycloalkyl and C 1~4 alkoxy

[0087] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 4A is optionally R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)O(C 1~4 alkyl), -C(=O)N(R 7B ) 2 , R 3 and halo, and is a 5-membered monocyclic heteroaryl substituted with one or more groups (e.g., 1 to 3 groups) independently selected therefrom. In a further embodiment, R 4A is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 groups independently selected from R 4X , R 5X and R 3X . In a further embodiment, R 4A is a 5-membered monocyclic heteroaryl substituted with 1 or 2 groups independently selected from C 1~4 alkyl, C 3~6 cycloalkyl and phenyl. In a further embodiment, R 4A is 1H-pyrazolyl (e.g., 3-1H-pyrazolyl), tetrazolyl (e.g., 5-tetrazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), or 1H-benzo[d]imidazolyl (e.g., 2-1H-benzo[d]imidazole), each of which is optionally substituted with one or more groups (e.g., 1 or 2 groups) selected from C 1~4 alkyl (e.g., CH 3 ), C 3~6 cycloalkyl (e.g., cyclohexyl) and phenyl.

[0088] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 4A is

Chemical formula

[0089] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein each R 4B is independently, optionally R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)O(C 1~4 alkyl), -C(=O)N(R 7B ) 2 , R 3 and halo, and is a monocyclic or bicyclic 5- to 9-membered heteroaryl substituted with one or more (e.g., 1 to 3) groups independently selected therefrom. In a further embodiment, each R 4B is independently, optionally, a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., monocyclic 5- or 6-membered heteroaryl) substituted with one or more (e.g., 1 to 3) groups independently selected from halo, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy and CN. In a further embodiment, R 4B is 1H-pyrazolyl (e.g., 3-1H-pyrazolyl), tetrazolyl (e.g., 5-tetrazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), or 1H-benzo[d]imidazolyl (e.g., 2-1H-benzo[d]imidazole), each of which is optionally substituted with one or two groups selected from C 1~4 alkyl, C 3~6 cycloalkyl and phenyl.

[0090] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R8A is C 1~4 alkyl. In a further embodiment, R 8A is CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 .

[0091] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 1 is R 5A , and R 2 is R 8B .

[0092] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 5A is phenyl, optionally substituted with one or more groups (e.g., 1 to 3 groups) independently selected from -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)N(R 7B ), 2 , R 3x and halo. In a further embodiment, R 5A is phenyl substituted with 1 or 2 groups independently selected from -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)N(R 7B ), 2 , R 3x and halo. In a further embodiment, R 5A is phenyl substituted with 1 or 2 groups independently selected from -CN, C 1~4 alkoxy, R 3x and halo. In a further embodiment, R 5A is phenyl optionally substituted with -CN.

[0093] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 5B is phenyl, optionally substituted with -OH, -CN, C 1~4Alkoxy, -C(=O)OH, -C(=O)N(R 7B ) 2 , R 3x and one or more groups (e.g., 1 to 3 groups) independently selected from halo, and is phenyl substituted therewith. In a further embodiment, R 5B is optionally -CN, C 1~4 alkoxy, R 3x and one or two groups independently selected from halo, and is phenyl substituted therewith. In a further embodiment, R 5B is optionally phenyl substituted with C 1~4 alkoxy.

[0094] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein R 8B is C 1~4 alkyl. In a further embodiment, R 8B is CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 .

[0095] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein NR 1 R 2 is

Chemical formula

[0096] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof, is provided, wherein R A is independently selected from H, halo, R X , -OR x and -CN, and each R X is independently C 1~3 alkyl optionally substituted with 1 to 3 F. In a further embodiment, each R A is independently H, halo, C 1~3Alkyl, C 1~3 Alkoxy, CF 3 , OCF 3 , CHF 2 , OCHF 2 and -CN. In a further embodiment, each R A is independently selected from H, F and Cl. In a further embodiment, each R A is independently selected from H and F.

[0097] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof is provided, wherein A is,

Chemical formula

[0098] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof is provided, wherein A is,

Chemical formula

[0099] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof is provided, wherein A is,

Chemical formula

[0100] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof is provided, wherein A is,

Chemical formula

[0101] In an embodiment, formula (III):

Chemical formula

[0102] In an embodiment, the compound of formula (III) is of formula (IIIA), (IIIB) or (IIIC)

Chemical formula

[0103] In an embodiment, the compound of formula (III) is of formula (IIID)

Chemical formula

[0104] In an embodiment, there is provided a compound of formula (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R E is H, F or Cl. In a further aspect, R E is H or F.

[0105] In an embodiment, X 1 , X 2 and X 3 one of which is O, and X 1 , X 2 and X 3 the other two of which are N and CR Y selected from, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, R Y is H.

[0106] In an embodiment, X 1 , X 2 and X 3 one of which is S, and X 1 , X 2 and X 3 the other two of which are N and CR Y selected from, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, R a is H.

[0107] In an embodiment, X 1 , X 2 and X 3 one of which is O, and X 1 , X 2 and X 3 the other two of which are both N, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided.

[0108] In an embodiment, X 1 , X 2 and X 3 one of which is O, and X 1 , X 2 and X 3One of them is N, and X 1 , X 2 and X 3 One of them is CR Y , a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, R Y is H or -CN.

[0109] In an embodiment, X 1 , X 2 and X 3 One of them is S, and the other two of X 1 , X 2 and X 3 are both N, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided.

[0110] In an embodiment, X 1 , X 2 and X 3 One of them is S, one of X 1 , X 2 and X 3 is N, and one of X 1 , X 2 and X 3 One of them is CR Y , a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, R Y is H.

[0111] In an embodiment, X 1 , X 2 and X 3 One of them is S, and the other two of X 1 , X 2 and X 3 are both CRY There is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof. In a further embodiment, each R Y is H.

[0112] In an embodiment, (i) X 1 is N, X 2 is O, X 3 is N; (ii) X 1 is N, X 2 is N, X 3 is O; (iii) X 1 is CR Y and X 2 is CR Y and X 3 is S; (iv) X 1 is O, X 2 is N, X 3 is CR Y ; (v) X 1 is N, X 2 is O, X 3 is CR Y ; (vi) X 1 is CR Y and X 2 is N, X 3 is O; (vii) X 1 is O, X 2 is N, X 3 is N; (viii) X 1 is N, X 2 is N, X 3 is S; or (ix) X 1 is CR Y and X 2 is S, X 3 is CR Y ; Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0113] In embodiments, (i) X 1 is N, X 2 is O, X 3 is N; (ii) X 1 is N, X 2 is N, X 3 is O; (iii) X 1 is CR Y and X 2 is CR Y and X 3 is S; (iv) X 1 is O, X 2 is N, X 3 is CR Y ; (v) X 1 is N, X 2 is O, X 3 is CR Y ; (vi) X 1 is CR Y and X 2 is N, X 3 is O; (vii) X 1 is O, X 2 is N, X 3 is N; (viii) X 1 is N, X 2 is N, X 3 is S; (ix) X 1 is CR Y and X 2 is S and X 3 is CR Y ; or (x) X 1 is CR Yand X 2 is N and X 3 is S, Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof are provided.

[0114] In embodiments, (i) X 1 is N, X 2 is O, X 3 is N; (ii) X 1 is N, X 2 is N, X 3 is O; (iii) X 1 is CH, X 2 is CH, X 3 is S; (iv) X 1 is O, X 2 is N, X 3 is CH; (v) X 1 is N, X 2 is O, X 3 is CH; (vi) X 1 is CH, X 2 is N, X 3 is O; (vii) X 1 is O, X 2 is N, X 3 is N; (viii) X 1 is N, X 2 is N, X 3 is S; or (ix) X 1 is CH, X 2 is S, X 3 is CH, Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0115] In embodiments, (i) X 1 is N, X 2 is O, X 3 is N; (ii) X 1 is N, X 2 is N, X 3 is O; (iii) X 1 is CH, X 2 is CH, X 3 is S; (iv) X 1 is O, X 2 is N, X 3 is CH; (v) X 1 is N, X 2 is O, X 3 is CH; (vi) X 1 is CH, X 2 is N, X 3 is O; (vii) X 1 is O, X 2 is N, X 3 is N; (viii) X 1 is N, X 2 is N, X 3 is S; (ix) X 1 is CH, X 2 is S, X 3 is CH; or (x) X 1 is CH, X 2 is N, X 3 is S, Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0116] In embodiments, X 1 is N, X 2 is O, X 3 is N, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0117] In embodiments, X 1 is N, X 2 is N, X 3 is O, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0118] In embodiments, X 1 is N, X 2 is N, X 3 is S, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided.

[0119] In embodiments, X 1 is N, X 2 is O, X 3 is CR Y and compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or pharmaceutically acceptable salts thereof, are provided. In further embodiments, R Y is H or -CN.

[0120] In an embodiment, X 1 is CR Y and X 2 is N and X 3 is O, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, each R Y is H.

[0121] In an embodiment, X 1 is CR Y and X 2 is S and X 3 is CR Y and a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof is provided. In a further embodiment, each R Y is H.

[0122] In an embodiment, formula (IV):

Chemical formula

[0123] In an embodiment, formula (V):

Chemical formula

[0124] In an embodiment, formula (VI):

Chemical formula

[0125] In an embodiment, formula (VII):

Chemical formula

[0126] In an embodiment, each R 9 is independently C 1~4 alkyl, C 3~6Compounds of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are provided, which are selected from cycloalkyl and phenyl. In a further embodiment, each R 9 is independently C 1~4 alkyl. In a further embodiment, each R 9 is CH 3 .

[0127] In an embodiment, each R 3 is independently C 1~4 alkyl or C 3~6 cycloalkyl, each of which is optionally substituted with one or more (e.g., 1 to 3) groups independently selected from R 4X , R 5x , -O(R 4X ), -O(R 5X ) and F, of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) compounds, or a pharmaceutically acceptable salt thereof are provided. In a further embodiment, each R 3 is independently C 4X substituted with 1 to 3 (e.g., 1 or 2) groups independently selected from R 5x , R 1~4 and F optionally. In an embodiment, in a further embodiment, each R 3 is independently C 1~4 alkyl, CF 3 , CHF 2 or CH 2 F.

[0128] In an embodiment, each R 3 is R 3XThere is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof.

[0129] In embodiments, each R 3X is independently C 1~4 alkyl or C 3~6 cycloalkyl, each of which is optionally substituted with one or more (e.g., 1 - 3) Fs. There is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof. In further embodiments, each R 3X is independently C 1~4 alkyl optionally substituted with 1 - 3 Fs. In further embodiments, each R 3X is independently C 1~4 alkyl, CF 3 , CHF 2 or CH 2 F. In further embodiments, each R 3X is C 1~4 alkyl.

[0130] In embodiments, each R 4 is independently a monocyclic or bicyclic 5 - 9 - membered heteroaryl (e.g., monocyclic 5 - or 6 - membered heteroaryl), each of which is optionally R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)O(C 1~4 alkyl), -C(=O)N(R 7B ) 2 , R 3Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, which are substituted by one or more (e.g., 1 to 3) groups independently selected from the halo. Further embodiments, each R 4 is independently, optionally, halo (e.g., F or Cl), C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy and CN, and is a monocyclic or bicyclic 5- to 9-membered (e.g., monocyclic 5- or 6-membered heteroaryl) substituted by one or more (e.g., 1 to 3) groups independently selected therefrom. Further embodiments, each R 4 is independently selected from [1,2,4]triazolo[4,3-b]pyridazinyl (such as 6-[1,2,4]triazolo[4,3-b]pyridazinyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), benzod]oxazolyl (such as 2-benzod]oxazolyl), each of which is optionally halo (e.g., F or Cl), C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy and CN, and is substituted by one or more (e.g., 1 to 3) groups independently selected therefrom.

[0131] In embodiments, each R 4X is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., monocyclic 5- or 6-membered heteroaryl), each of which is optionally -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)N(R 7B ) 2 , R 3XCompounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided, which are substituted with one or more (e.g., 1 to 3) groups independently selected from halo. Further embodiments, each R 4x is independently, optionally, halo (e.g., F or Cl), C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy and CN, and is a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., monocyclic 5- or 6-membered heteroaryl) substituted with one or more (e.g., 1 to 3) groups independently selected therefrom. Further embodiments, each R 4x is independently, optionally, C 1~4 alkyl (e.g., CH 3 )-substituted tetrazolyl (such as 5-tetrazolyl).

[0132] In embodiments, R 5 is independently, optionally, R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1~4 alkoxy, -C(=O)OH, -C(=O)O(C 1~4 alkyl), -C(=O)N(R 7B ) 2 , R 3 and halo, and is phenyl substituted with one or more (e.g., 1 to 3) groups independently selected therefrom. Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided. Further embodiments, each R 5 is independently, optionally, halo (e.g., F or Cl), C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4In further embodiments, each R is phenyl substituted with one or more (e.g., 1-3) groups independently selected from alkoxy and CN. 5 is phenyl.

[0133] In an embodiment, each R 5X are independently optionally -OH, -CN, C 1~4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B ) 2 , R 3x and halo. 5X are independently optionally halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In further embodiments, each R is phenyl substituted with one or more (e.g., 1-3) groups independently selected from alkoxy and CN. 5X is phenyl.

[0134] In embodiments, R 6 is optionally R 4X , R 5x and C substituted with one or more groups (e.g., 1 to 3 groups) independently selected from F 1~4

[0023] There is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharma- ceutically acceptable salt thereof, wherein R is alkoxy. 6 is optionally substituted with one or more (e.g., 1 to 3) F; 1~4 In a further embodiment, R 6 is C1~4 is an alkoxy group.

[0135] In an embodiment, compounds of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are provided, where x is 0, 1, 2 or 3. In a further embodiment, x is 1, 2 or 3.

[0136] In an embodiment, A is

Chemical formula

[0137] In an embodiment, A is

Chemical formula

[0138] In an embodiment, compounds of formula (I), (II) or (IIA) or a pharmaceutically acceptable salt thereof are provided, provided that the compounds are other than (3-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(3-methylpiperidin-1-yl)methanone and (3-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)(4-methylpiperidin-1-yl)methanone.

[0139] In an embodiment, compounds of formula (I) or a pharmaceutically acceptable salt thereof are provided, where the compounds of formula (I) are selected from the following: (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone; (3-Phenoxyazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone; (3-(2-Methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide; (3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide; (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone; 4-(3-(3-Phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one; 4-(3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one; (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone; N-(1-Cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide; 5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile; 3-(4-(3-(4-Fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile; 3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; N-(tert-Butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide; 3-(3-Cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; (S)-3-(3-(4-Chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-((2R,6S)-2,6-Dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-((5-Methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 3-(3-Cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile; 3-(7-Cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile; 2-(5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile; 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile; (2,2,6,6-Tetramethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone; (S)-6-Ethyl-4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-one; (3-Isopropylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((3R,5S)-3,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; Morpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; Thiomorpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 3-(4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-yl)benzonitrile; (8,8-Difluoro-3-azabicyclo[3.2.1]octan-3-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; Piperidin-1-yl(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (6-Oxa-9-azaspiro[4.5]decan-9-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (S)-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl)morpholino)methanone; (2-Isobutylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (3,3-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(2-(Fluoromethyl)morpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2R,5R)-2,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(7-Methyl-1,4-oxazepan-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (5-Oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (1,9-Dioxa-4-azaspiro[5.5]undecan-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2S,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-(4-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 4-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidin-4-yl)benzonitrile; (4-(3-(4-Fluorophenoxy)propyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-(Pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 4-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile; (3-Phenylazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-(3-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-Phenyl-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-(3-Cyanophenyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide; (3,4-Dihydroisoquinolin-2(1H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (5-Fluoroisoindolin-2-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile; (4-(3-Chloro-5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-((5-Methoxypyridin-2-yl)oxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (4-(Pyridin-3-yloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-((5,6-Dimethyl-1H-benzo[d]imidazol-2-yl)methyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide; (4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-Methyl-N-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide; (3-(4-Fluorophenyl)azetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-Isopropyl-N-((3-methylpyridin-2-yl)methyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide; (3-Propylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (1-Phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-(1-(4-Methoxyphenyl)ethyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide; (3-(4-Fluorophenoxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 4-Phenyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidine-4-carbonitrile; (4-Phenylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 2-(4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile; 4-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile; (4-(2-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; 3-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile; 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile; ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone; (5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone; 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide; 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (3-(Benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide; N-((1-Cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide; (R)-(5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone; (3H-Spiro[isobenzofuran-1,3'-pyrrolidine]-1'-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (S)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone; N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide; 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile; (4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone; 2-(5-(2,4,5-Trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile; ((2R,6S)-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone; and ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone.

[0140] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein the compound of formula (I) is selected from the following: ((4aR,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((4aS,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((4aR,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((4aS,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (5-(3,4-Difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone; (5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone; (4-Oxa-7-azaspiro[2.5]octan-7-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; ((3R,5S)-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; and ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone.

[0141] In an embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided, wherein the compound of formula (I) is selected from: rac-((2R,6S)-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; rac-((2R,6S)-2-Isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; (6-Methyl-5-oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; and (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone.

[0142] A further feature is any of the embodiments described herein, provided that any one of the specific examples is individually disclaimed. A further feature is any of the embodiments described herein, provided that any one or more of the compounds selected from the list of examples of the compounds hereinabove described are individually disclaimed.

[0143] The compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers, as diastereoisomers or as stereoisomer-enriched mixtures. Unless otherwise stated, all such stereoisomers (and enriched) mixtures are included within the scope of the embodiments. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents and the like.

[0144] Unless the chemical structure or chemical name explicitly indicates stereochemistry, the chemical structure or chemical name is intended to include all possible stereoisomers, diastereoisomers, conformational isomers, rotational isomers, and tautomers of the indicated compound. For example, a compound containing a chiral carbon atom is intended to include both the (R) enantiomer and the (S) enantiomer, and mixtures of enantiomers including racemic mixtures, and a compound containing two chiral carbons is intended to include all enantiomers and diastereoisomers including (R,R), (S,S), (R,S), and (S,R).

[0145] In an embodiment, a pharmaceutical composition comprising a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, is present in the composition with an enantiomeric excess (ee%) of ≧90% and a diastereomeric excess (de%) of ≧90% is provided.

[0146] Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), and pharmaceutically acceptable salts thereof, can be prepared, used or supplied in amorphous, crystalline or semi-crystalline form, and any given compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), and pharmaceutically acceptable salts thereof, may also form in two or more crystalline / polymorphic forms, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric hydrates) and / or solvated forms. It will be understood that this specification encompasses all such solid forms of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), and pharmaceutically acceptable salts thereof.

[0147] In further embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided, which are obtained by the methods described in the "Examples" section below.

[0148] This specification is to be taken to include any isotopes of the atoms present in the compounds of the invention. It will be understood that isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C. Isotopes of nitrogen include 15 N. Isotopes of fluorine include 18 F.

[0149] Suitable pharmaceutically acceptable salts of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are, for example, base addition salts. Base addition salts of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) can be formed by contacting the compound with a suitable inorganic base or organic base under conditions known to those skilled in the art. Base addition salts are, for example, alkali metal salts (such as sodium salts, potassium salts, lithium salts, etc.) or alkaline earth metal salts (such as calcium salts), and can be formed using hydroxides or alkoxides of alkali metals or alkaline earth metals (such as ethoxides or methoxides). Base addition salts can also be formed using suitable basic organic amines (such as choline or meglumine salts).

[0150] Suitable pharmaceutically acceptable salts of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are, for example, acid addition salts. Acid addition salts of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) can be formed by contacting the compound with a suitable inorganic acid or organic acid under conditions known to those skilled in the art. Acid addition salts can be formed, for example, using inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Also, acid addition salts can be formed using organic acids selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0151] Further suitable pharmaceutically acceptable salts of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are, for example, salts formed in the body of a patient after administration to the patient of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII).

[0152] Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, can be prepared as co-crystalline solid forms. It will be understood that pharmaceutically acceptable co-crystals of compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, form one aspect of the present specification.

[0153] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0154] The term "pharmaceutical composition" refers to a preparation that is in a form that permits the biological activity of the active ingredient and contains no additional ingredients that exhibit unacceptable toxicity to the patient to whom the composition is administered. Such a composition can be sterile. The pharmaceutical compositions described herein comprise a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. For example, the composition can be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or in a form suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular injection, or as a suppository for rectal administration). Such compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives. An effective amount of the compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is usually present in the composition.

[0155] A compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is usually in a pharmaceutically acceptable dosage form, in the form of a pharmaceutical preparation containing the active ingredient or a pharmaceutically acceptable salt or solvate thereof or a solvate of such a salt, and can be administered via the oral route, parenterally, intravenously, intramuscularly, subcutaneously or by other injection methods, orally, rectally, vaginally, transdermally and / or intranasally, and / or by inhalation. Depending on the disorder to be treated, the patient, and the route of administration, the composition can be administered in various doses.

[0156] Pharmaceutical preparations of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) above can be prepared, for example, for parenteral, subcutaneous, intramuscular or intravenous administration.

[0157] Pharmaceutical preparations of the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) above can be administered conveniently in unit dosage forms and can be prepared by any method well known in the pharmaceutical art, for example, as described in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA. (1985).

[0158] Oral dosage forms suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules can be prepared using binders, fillers, lubricants, and surfactants. Liquid compositions may contain conventional additives such as suspending agents, emulsifying agents, and preservatives. The liquid composition may be encapsulated, for example, in gelatin to provide a unit dosage form. Examples of solid oral dosage forms include tablets, two-piece hard shell capsules, and soft elastic gelatin (SEG) capsules. Exemplary oral compositions will comprise a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) filled in a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule, and at least one pharmaceutically acceptable excipient.

[0159] As a result of their 17β-HSD13 inhibitory activity, the compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), and pharmaceutically acceptable salts thereof, are expected to be useful in the treatment of diseases or medical conditions mediated, at least in part, by 17β-HSD13, including the treatment of liver diseases such as NASH.

[0160] In one aspect of the present disclosure, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0161] In one aspect of the present specification, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of liver diseases. In embodiments, the liver disease is selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD (NASH, liver fibrosis, cirrhosis and isolated fatty liver), hepatitis, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).

[0162] The term "treatment" is intended to have its standard meaning of addressing a disease by reducing in whole or in part one, some or all of its symptoms, or correcting or compensating for the underlying pathology. The term "treatment" also includes "prevention" unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

[0163] The term "prevention" is intended to have its standard meaning and includes primary prevention to prevent the occurrence of a disease, and secondary prevention to temporarily or continuously protect a patient against the progression or worsening of a disease that has already occurred, or the occurrence of new symptoms associated with the disease.

[0164] The term "treatment" is used synonymously with "therapy". Similarly, the term "treat" can be considered to mean "apply therapy" (where "therapy" is as defined herein).

[0165] In embodiments, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in providing an inhibitory effect against 17βHSD13.

[0166] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of diseases mediated by 17βHSD13, such as liver diseases (e.g., NASH).

[0167] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of fatty liver disease.

[0168] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of non-alcoholic fatty liver disease (NAFLD), such as isolated fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis or cirrhosis. In further embodiments, the liver disease is end-stage liver disease.

[0169] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of liver diseases, such as NASH, where the patient also has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0170] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of liver diseases, such as NASH, where the patient has a body mass index (BMI) of 27 kg / m 2 ~ 40 kg / m 2 . In further embodiments, the subject has a BMI of 30 kg / m 2 ~ 39.9 kg / m 2 . In further embodiments, the patient has a BMI of at least 40 kg / m 2 . In further embodiments, the patient is overweight. In further embodiments, the patient is obese.

[0171] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of liver diseases, such as NASH, where the patient also has or is susceptible to having dyslipidemia.

[0172] In embodiments, compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided for use in the treatment of liver diseases, such as NASH, where the patient also has or is susceptible to having insulin resistance.

[0173] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of liver diseases, such as NASH, is provided, wherein the patient also has or is prone to having type 2 diabetes.

[0174] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of liver diseases, such as NASH, is provided, wherein the patient also has or is prone to having renal insufficiency.

[0175] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of liver diseases, such as NASH, is provided, wherein the patient also has or is prone to having liver fibrosis. In a further embodiment, the patient (i) has or is prone to having liver fibrosis and (ii) has or is prone to having one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0176] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of liver diseases, such as NASH, is provided, wherein the patient also has or is prone to having cirrhosis. In a further embodiment, the patient (i) has or is prone to having cirrhosis and (ii) has or is prone to having one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0177] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of NAFLD is provided. In a further embodiment, the NAFLD is stage 1 NAFLD. In a further embodiment, the NAFLD is stage 2 NAFLD. In a further embodiment, the NAFLD is stage 3 NAFLD. In a further embodiment, the NAFLD is stage 4 NAFLD. See, for example, “The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases,” Hepatology, Vol. 67, No. 1, 2018.

[0178] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of NAFLD, such as NASH. In a further embodiment, the patient is obese. In a further embodiment, the patient has alcoholic liver disease. In a further embodiment, the patient has a genetic risk factor for liver disease, such as the (rs738409C>G) variant in PNPLA3.

[0179] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of NASH. In a further embodiment, the NASH is stage 1 NASH. In a further embodiment, the NASH is stage 2 NASH. In a further embodiment, the NASH is stage 3 NASH. In a further embodiment, the NASH is stage 4 NASH. In a further embodiment, the patient also has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0180] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of liver fibrosis. In a further embodiment, the liver fibrosis is stage 3 liver fibrosis. In a further embodiment, the patient also has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0181] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cirrhosis. In a further embodiment, the cirrhosis is stage F4 cirrhosis. In a further embodiment, the patient also suffers from or is prone to suffering from one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0182] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of hepatitis. In a further embodiment, the inflammation is chronic inflammation. In a further embodiment, the chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease. In a further embodiment, the chronic inflammation is rheumatoid arthritis.

[0183] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of hepatocellular carcinoma (HCC).

[0184] In an embodiment, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of alcoholic steatohepatitis (ASH).

[0185] In an embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, for use in the treatment of hepatitis C virus (HCV).

[0186] In one aspect of the present specification, there is provided the use of a compound of formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA) described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for example a medicament for the treatment of a disease (for example, NASH).

[0187] In one aspect of the present specification, there is provided a method of treating a disease such as NASH in a patient, comprising administering to the patient an effective amount of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof.

[0188] Terms such as "treating" or "treatment" refer to both (1) therapeutic means for curing, delaying, alleviating, and / or halting the progression of the symptoms of a diagnosed condition or disorder, and (2) prophylactic or preventive means for preventing and / or delaying the progression of the target condition or disorder. Thus, those in need of treatment include those who already have a disorder, those who tend to have a disorder, and those in whom the disorder should be prevented.

[0189] The term "effective amount" means an amount of the active ingredient sufficient to significantly and positively modify the symptoms and / or condition to be treated (for example, provide a positive clinical response). The effective amount of the active ingredient used in a pharmaceutical composition will vary depending on the particular symptoms to be treated, the severity of the condition, the duration of treatment, the nature of the combination therapy, the particular active ingredient used, the particular pharmaceutically acceptable excipient / carrier utilized, and similar factors within the knowledge and expertise of the attending physician.

[0190] The term "patient" refers to any animal (e.g., a mammal) that is the recipient of a particular treatment, including but not limited to humans, non-human primates, rodents, etc. Typically, the term "patient" refers to a human subject.

[0191] In embodiments, a method of treating a patient's disease is provided, which includes administering to the patient an effective amount of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, wherein the disease is selected from isolated fatty liver, NASH, liver fibrosis and cirrhosis.

[0192] In embodiments, a method of treating a 17βHSD13-mediated disease such as NASH in a patient is provided, which includes administering to the patient an effective amount of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof.

[0193] The compounds of the present disclosure can be used in the above methods as a single pharmacological agent or in combination with other pharmacological agents or techniques. Such combination therapies can be achieved by administering the individual components of the treatment simultaneously, sequentially or separately. In these combination therapies (and corresponding combination products), the compounds of the present disclosure and other pharmacological agents are used.

[0194] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In a further embodiment, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and remogliflozin.

[0195] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof.

[0196] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a glucagon-like peptide-1 receptor (GLP1) agonist. In a further embodiment, the GLP1 agonist is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.

[0197] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a dipeptidyl peptidase 4 (DPP4) inhibitor. In a further embodiment, the DPP4 inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.

[0198] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a PPAR agonist. In a further embodiment, the PPAR agonist is a PPARα agonist. In a further embodiment, the PPAR agonist is a PPARγ agonist. In a further embodiment, the PPAR agonist is a PPARα / γ agonist. In a further embodiment, the PPAR agonist is selected from clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate. In a further embodiment, the PPAR agonist is a thiazolidinedione. In a further embodiment, the thiazolidinedione is selected from pioglitazone, rosiglitazone, lobeglitazone, and riboglitazone. In a further embodiment, the PPAR agonist stimulates the hepatic expression of FGF21.

[0199] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a Pan-PPAR agonist. In a further embodiment, the Pan-PPAR agonist is lanifibranor.

[0200] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and a ThrB agonist. In a further embodiment, the ThrB agonist is resmetirom.

[0201] In an embodiment, a combination for use in the treatment of liver diseases such as NASH is provided, which comprises a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, and an FXR agonist. In a further embodiment, the FXR agonist is obeticholic acid.

[0202] Compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are mainly valuable as therapeutic agents for use in patients, but are also useful when it is necessary to inhibit 17βHSD13. Thus, they are useful as pharmacological criteria for use in the development of novel biological assays and the search for novel pharmacological agents.

[0203] In one aspect of the present specification, intermediates and methods useful for the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided. Schemes P1 to P10 are for a compound of formula (I) [wherein X 1 X 2 X 3 R 1 R 2 and A are as defined herein for the compound of formula (I), LG is a leaving group (e.g., Cl, Br or I), B 1 is a boronic acid or its derivative (e.g., boronic acid, boronic acid ester or trifluoroborate), and unless otherwise specified, R P is a C 1~4 alkyl group], and intermediates and methods useful for the synthesis of the compound are disclosed.

[0204] Scheme P1

Chemical formula

[0205] The compound of formula (I) can also be of formula (P1.1) (wherein RP is an ester of Me or Et) and an amine of formula (P1.3) in a solvent (such as toluene or DMF), optionally in the presence of AlMe 3 or DABAL-Me 3 can be formed by reacting, optionally at 18 to 70 °C (e.g., 50 to 70 °C).

[0206] Scheme P2

Chemical formula

[0207] Scheme P3

Chemical formula

[0208] Scheme P4

Chemical formula

[0209] Scheme P5

Chemical Structure

[0210] Scheme P6

Chemical Structure

[0211] Scheme P7

Chemical formula

[0212] Alternatively, the compound of formula (P7.3) can be formed by reacting a diketone of formula (P7.5) with hydroxylamine hydrochloride in a solvent (e.g., EtOH, acetic acid or formic acid), optionally at a temperature in the range of 50 - 100 °C. The diketone of formula (P7.5) can be formed by reacting a methyl ketone of formula (P7.4) with a base (e.g., LiHMDS or NaOEt) and diethyl oxalate in a solvent (such as THF), optionally at a temperature in the range of 78 °C - 18 °C.

[0213] Scheme P8

Chemical formula

[0214] Scheme P9

Chemical formula

[0215] Scheme P10

Chemical formula

[0216] It is understood that the organic reactions described herein are carried out according to laboratory procedures known to those skilled in the art. It is understood that some of the reactions described herein may optionally be carried out in an order different from the order shown herein. It is understood that the chiral isomers of the compounds described herein can be resolved at any stage of the synthesis process using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatography methods described in the literature and known to those skilled in the art or further described in this example.

[0217] It is understood that in some of the above-described steps, additional and / or other protecting groups may optionally be required, and thus, the deprotection step can optionally be carried out using methods described in the literature and known to those skilled in the art. The protection and deprotection of functional groups are described in "Protective Groups in Organic Synthesis" 3rd Ed, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1999), which is hereby incorporated by reference into this specification.

Examples

[0218] The following non-limiting examples illustrate this specification. In the examples, generally, (i) The operations are carried out at room temperature (rt), that is, in the range of 17 - 28 °C, under an atmosphere of an inert gas such as N 2 etc., if necessary; (ii) When referring to the reaction being degassed or purged, this can be done, for example, by purging the reaction solvent with a constant nitrogen flow over a suitable time (e.g., 5 - 10 minutes), or by repeatedly evacuating the vessel and refilling it with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)); (iii) When the reaction refers to the use of a microwave reactor, use one of the following microwave reactors: BIOTAGE INITIATOR, PERSONAL CHEMISTRY EMRYS OPTIMIZER, PERSONAL CHEMISTRY SMITH CREATOR or CEM EXPLORER; (iv) Generally, after the reaction process, thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) connected to a mass spectrometer (LCMC) were usually carried out.

[0219] (v) If necessary, the organic solution was dried over anhydrous MgSO 4 or Na 2 SO 4 or passed through an ISOLUTE phase separator using an ISOLUTE phase separator, and the post - treatment procedure was carried out using conventional phase separation techniques. When using a drying agent such as MgSO 4 or Na 2 SO 4 for drying the organic layer, it is understood that after filtering the organic layer, the layer was concentrated.

[0220] (vi) Evaporation was carried out by rotary evaporation under vacuum or in a Genevac HT - 4 / EZ - 2 or Biotage V10; (vii) Unless otherwise specified, flash column chromatography is carried out using normal phase silica with prepacked cartridges such as Merck Silica Gel (Art.9385), or BIOTAGE SNAP cartridge (40 - 63μm silica, 4 - 330g), BIOTAGE Sfaer Silica HC D cartridge (20μm, 10 - 100g), INTERCHIM PURIFLASH cartridge (25μm, 4 - 120g), INTERCHIM PURIFLASH cartridge (50μm, 25 - 330g), GRACE GRACERESOLV Silica Flash cartridge (4 - 120g) or AGELA Flash Colum Silica-CS cartridge (80 - 330g), or using reversed phase silica with automated AGELA TECHNOLOGIES C-18, spherical cartridges (20 - 35μm, 100A, 80 - 330g) using a manual or GRACE REVELERIS X2 Flash system or similar systems; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC are each carried out using standard HPLC and SFC equipment equipped with fraction collection devices operated by MS and / or UV, using the uniform concentration or gradient of the mobile phase as described in the experimental section and carried out using one of the following methods: Preparative method A: The compound was purified by preparative HPLC using a WATERS SUNFIRE C18 ODB column (5μm, 150×19mm ID) with a gradient of MeCN in H 2 O / FA (0.1M); Preparative method B: The compound was purified by preparative HPLC using an XBRIDGE C18 ODB column (5μm, 150×30mm ID) with a gradient of MeCN in H 2 O / NH 4 HCO 3 (10mM); Preparative method C: The compound was purified by preparative HPLC using a KROMASIL C8 column (10μm, 250×20mm ID) with a gradient of MeCN in H 2Purified using a gradient of MeCN in O / MeCN / FA (95 / 5 / 0.2); Preparative method D: The compound was separated by preparative HPLC using a KROMASIL C8 column (10 μm, 250×50 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / MeCN / FA (95 / 5 / 0.2); Preparative method E: The compound was separated by preparative HPLC using a WATERS SUNFIRE C18 ODB column (5 μm, 150×30 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1 M); Preparative method F: The compound was separated by preparative HPLC using a Waters HSS C18 OBD column (5 μm, 100×10 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1 M). Preparative method G: The compound was separated by preparative HPLC using a WATERS SUNFIRE C18 column (5 μm, 100×10 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1 M, pH 3); Preparative method H: The compound was separated by preparative HPLC using a WATERS XBRIDGE C18 column (5 μm, 100×10 mm ID) with H as the mobile phase 2 O / NH 3 Purified using a gradient of MeCN in (0.2%, pH 10). Preparative method I: The compound was separated by preparative HPLC using a WATERS XSELECT CSH Fluoro Phenyl column (5 μm, 100×10 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1 M); Preparative method J: The compound was separated by preparative HPLC using an XBRIDGE C18 column (10 μm, 250×50 mm ID) with H as the mobile phase 2 O in MeCN / MeCN / NH 3 Purified using a gradient of (95 / 5 / 0.2); Preparative method K: The compound was separated by preparative HPLC using an XBRIDGE Prep OBD C18 column (5 μm, 30×150 mm) with H as the mobile phase 2Purified using a gradient of MeCN in O / TFA (0.1%). Preparative method L: The compound was purified by preparative HPLC using a YMC-ACTUS TRIART C18 column (5 μm, 30 × 250 mm) with H as the mobile phase 2 O / NH 3 (0.05%) using a gradient of MeCN; Preparative method M: The compound was purified by preparative HPLC using a WATERS XSELECT CSH Fluoro Phenyl column (5 μm, 100 × 10 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / TFA (0.05%); Preparative method N: The compound was purified by preparative HPLC using a WATERS XSELECT CSH OBD column (5 μm, 150 × 30 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1%); Preparative method O: The compound was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS column (5 μm, 30 × 150 mm ID) with H as the mobile phase 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH using a gradient of MeCN; Preparative method P: The compound was purified by preparative HPLC using an XBRIDGE C18 OBD column (5 μm, 250 × 19 mm ID) with H as the mobile phase 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH using a gradient of MeCN; Preparative method Q: The compound was purified by preparative HPLC using a WATERS SUNFIRE C18 column (5 μm, 150 × 30 mm ID) with H as the mobile phase 2 Purified using a gradient of MeCN in O / FA (0.1 M); Preparative method R: The compound was purified by preparative HPLC using an XBRIDGE SHIELD RP18 OBD column (5 μm, 150 × 30 mm ID) with H as the mobile phase 2 O / NH 4 HCO 3(Purified using a gradient of MeCN in (10 mM); Fractionation method S: The compound was purified by preparative SFC using a Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) with CO as the mobile phase 2 in MeOH / NH 3 (20 mM); Fractionation method T: The compound was purified by preparative HPLC using a WATERS XSELECT CSH OBD column (5 μm, 150×30 mm ID) with HH as the mobile phase 2 A gradient of MeCN in O / FA (0.1 M) was used for purification; Fractionation method U: The compound was purified by preparative SFC using a PHENOMENEX Luna Hilic column (5 μm, 250×30 mm ID) with CO as the mobile phase 2 Purified using EtOH / FA (20 mM) in; Fractionation method V: The compound was purified by preparative HPLC using a Waters Xselect CSH OBD column (5 μm, 250×19 mm ID) with H as the mobile phase 2 A gradient of MeCN in O / FA (0.1 M) was used for purification; Fractionation method X: The compound was purified by preparative HPLC using an XBridge (trademark) C18 OBD column (5 μm, 250×30 mm ID) with H as the mobile phase 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH; A gradient of MeCN in was used for purification; Fractionation method Y: The compound was purified by preparative HPLC using an XBridge (trademark) C18 OBD column (5 μm, 150×30 mm ID) with H as the mobile phase 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH; A gradient of MeCN in was used for purification; Fractionation method Z: The compound was purified by preparative HPLC using an XBridge (trademark) C18 ODB column (5 μm, 150×30 mm ID) with H as the mobile phase 2Purified using a gradient of MeCN in O / AcOH (0.1%). SFC preparative method: Preparative method SFC-A: The compound was purified by preparative SFC using Waters™ BEH (5 μm, 250×30 mm ID) with CO as the mobile phase 2 in MeOH / H 2 O(NH 3 50 mM) (97 / 3).

[0221] In some examples, the compound can be dissolved in a solvent, such as DMSO, and filtered through a syringe filter before purification by preparative HPLC.

[0222] The relevant fractions were collected, combined, and lyophilized or evaporated to obtain the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na 2 SO 4 or using a phase separator, and then concentrated under reduced pressure to obtain the purified compound.

[0223] (ix) Chiral preparative chromatography was performed using HPLC or SFC with standard HPLC or SFC equipment respectively, and using a uniform concentration or gradient run with the mobile phase as described below; (x) The yields are not necessarily the maximum achievable values where present, and the reaction can be repeated if more reaction product is required as necessary; (xi) When a particular compound is obtained as an acid addition salt, such as a monohydrochloride or dihydrochloride, the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the exact stoichiometry of the salt is generally not determined, for example, by elemental analysis data; (xii) Generally, the structure of the final product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; the proton NMR chemical shift values are at 300, 400, 500, and 600 MHz respectively 1Measurements on the delta scale were made using BRUKER AVANCE III 300, 400, 500 and 600 spectrometers operating at H frequency. Experiments were usually recorded at 25 °C. Chemical shifts are given in ppm units by the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected by NMR, so there may be no description. In certain examples, the protons may be hidden or partially hidden by the solvent peak, so there is no description, not reported or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives, e.g., dd, doublet of doublets, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. In some examples, the structure of the final product of formula (I) may appear as a rotamer in the NMR spectrum, in which case only the peaks of the major rotamer are reported. In certain examples, the structure of the intermediate and / or final product of formula (I) may appear as a rotamer in the NMR spectrum, in which case the peaks of all rotamers are reported and only the total number of protons is reported. The ratio of the major rotamer to the minor rotamer is reported if known. Electrospray mass spectrometry data were obtained using a WATERS ACQUITY UPLC connected to a WATERS single quadrupole mass spectrometer or similar device that acquires both positive and negative ion data, and generally only ions related to the parent structure are reported; high-resolution electrospray mass spectrometry data were obtained using a WATERS XEVO qToF mass spectrometer or similar device connected to a WATERS ACQUITY UPLC that acquires either positive or negative ion data, and generally only ions related to the parent structure are reported; (xiii) The intermediates were not necessarily fully purified, but their structures and purities were evaluated by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Compounds containing asymmetric carbon and / or sulfur atoms were not resolved unless otherwise specified; (xv) Generally, examples and intermediate compounds are named using CHEMDRAW PROFESSIONAL version 20.1.1.125 manufactured by PerkinElmer. CHEMDRAW PROFESSIONAL version 20.1.1.125 generates the name of the chemical structure using the Cahn-Ingold-Prelog (CIP) ranking rules for stereochemistry and follows the IUPAC rules as faithfully as possible when generating chemical names. Stereoisomers have different stereochemical designations cited in the name and are assigned according to the CIP rules. The prefix "rac-" indicates that the compound is a racemate.

[0224] (xvi) In addition to those described above, the following abbreviations and units were used: AcOH Acetic acid Aq Aqueous Boc tert-Butyloxycarbonyl tBuOH tert-Butanol Brine Aqueous saturated sodium chloride solution Calcd Calculated CBz Benzyloxycarbonyl COMU (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (CAS registration number 1075198-30-9) 18-Crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane DABAL-Me 3 CAS registration number 137203-34-0 DCM Dichloromethane DEAD Diethyl azodicarboxylate DIC Diisopropylmethanediamine DIPEA N-Ethyl-N-isopropyl-propan-2-amine DMAP N,N-Dimethylpyridin-4-amine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphorazidate EDC 3-(((Ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine ESI Electrospray ionization Et 2 O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol eq Equivalent FA Formic acid (g) Gas GC Gas chromatography HPLC High performance liquid chromatography HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxohexafluorophosphate) HOBt 1-Hydroxybenzotriazole; hydrate HRMS High resolution mass spectrometry ID Inner diameter Lawesson's reagent 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide LiHMDS Lithium bis(trimethylsilyl)amide LC Liquid chromatography Me 3 Al Trimethylaluminum MeCN Acetonitrile MeI Iodomethane MeMgBr Methylmagnesium bromide MeOH Methanol MS Mass spectrometry MTBE Methyl tert-butyl ether m / z Mass spectrometry peak NBS N-Bromosuccinimide NIS 1-Iodopyrrolidine-2,5-dione NMR Nuclear magnetic resonance PE Petroleum ether Pd-118 [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd-C Palladium on carbon PPh 3 Triphenylphosphane sat saturated SFC Supercritical fluid chromatography TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography UPLC Ultra performance liquid chromatography UV Ultraviolet Xphos Pd G3 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate

[0225] Intermediate 1: Ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate [Chem.] EDC (43.5 g, 227.07 mmol) and HOBt (15.34 g, 113.53 mmol) were added to ethyl (Z)-2-amino-2-(hydroxyimino)acetate (15 g, 113.53 mmol), 2,4,5-trifluoro-3-hydroxybenzoic acid (21.81 g, 113.53 mmol) and NaHCO 3 (28.6 g, 340.60 mmol) in DMF (150 mL) under an N 2 (g) atmosphere. The resulting solution was stirred at 100 °C for 1 hour. The reaction mixture was filtered through CELITE, the filtrate was concentrated, diluted with DCM (300 mL), and washed with water (300 mL). The organic layer was dried over Na 2 SO 4It was dried, filtered, and evaporated. The crude product was purified by flash chromatography on a C18 column (gradient 50 - 60% MeCN / H2O (FA)) to give the title compound (7.0 g, 21%) as a white solid; MS (ESI) m / z [M+H] + 289; 1 1H NMR (300 MHz, DMSO-d 6 ) δ 1.36 (t, 3H), 4.45 (m, 2H), 7.28 - 7.81 (m, 1H), 11.70 (s, 1H).

[0226] Alternative synthesis of Intermediate 1: SOCl 2(1.7 mol eq, 0.96 L) was added to a mixture of 2,4,5-trifluoro-3-hydroxybenzoic acid (1.45 kg, 7.55 mol) and toluene (14.5 L) at 75 - 85 °C over 4 hours. The temperature was adjusted to 85 - 95 °C and the mixture was stirred for 20 hours. The mixture was concentrated to about 4 L at below 50 °C, and then toluene (14.5 L) was added. This concentration and toluene addition process was repeated twice. Then, toluene (14.5 L) was added to the resulting mixture, and it was concentrated to about 3 L at below 50 °C to obtain 2,4,5-trifluoro-3-hydroxybenzoyl chloride. This was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (966.4 g, 7.31 mol, 1.05 eq), pyridine (2629.9 g, 33.25 mol, 5 eq) and MeCN (5.6 L) at 20 - 30 °C. The resulting mixture was stirred at 20 - 30 °C for 0.5 - 1.5 hours and then heated to 55 - 65 °C. Then, the mixture was heated at 140 °C for a residence time of 45 minutes under flow (see Figure 1). After heating, the reaction mixture was quenched under flow with a pre-heated mixture of EtOH (1.4 L) and water (1.4 L) at 20 - 30 °C. At the end of the flow reaction, the resulting mixture was adjusted to pH 2 - 3 with 2 M HCl (13.72 L) at 5 - 15 °C over 6 hours. EtOAc (14 L) was added and the mixture was stirred at 20 - 30 °C for 2 hours. Then, the organic layer was separated and the aqueous layer was extracted with EtOAc (14 L). Next, the organic layers were combined and concentrated under vacuum at 35 - 45 °C, and then EtOH (14 L) was added. After repeating this concentration and EtOH addition process, the mixture was concentrated under vacuum at 35 - 45 °C. Then, the mixture was treated with water (12.6 L) at 20 - 30 °C over 2 hours and then stirred at 20 - 30 °C for 16 hours. The resulting mixture was filtered, washed with water (2.8 L) and n-heptane (4.2 L), and the obtained filter cake was stirred at 30 - 40 °C for 16 hours to obtain the title compound as a solid (1.52 kg @ 95.28% w / w, 1.45 Kg @ 100% w / w, 5.03 mol, 66.6% yield in two steps).

[0227] Intermediate 2: 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid

Chem.

[0228] Intermediate 3: (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

Chem.

[0229] Intermediate 4: Ethyl (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycinate

Chem.

[0230] Intermediate 5: Ethyl (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycinate

Chem.

[0231] Intermediate 6: (S)-4-Benzyl-6-ethylpiperazin-2-one

Chemical formula

[0232] Intermediate 7: (S)-6-Ethylpiperazin-2-one

Chemical formula

[0233] Intermediate 8: 4-(((2-Hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-ol

Chemical Structure

[0234] Intermediate 9: Benzyl (2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)carbamate

Chemical Structure

[0235] Intermediate 10: Benzyl 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylate

Chemical Structure

[0236] Intermediate 11: 1,9-Dioxo-4-azaspiro[5.5]undecane

Chemical formula

[0237] Intermediate 12: tert-Butyl 4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate

Chemical formula

[0238] Intermediate 13: 1-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazine

Chemical formula

[0239] Intermediate 14: 2,4,5-Trifluoro-N,3-dimethoxy-N-methylbenzamide

Chemical formula

[0240] Intermediate 15: 1-(2,4,5-Trifluoro-3-methoxyphenyl)ethan-1-one

Chemical formula

[0241] Intermediate 16: Ethyl 2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoate

Chemical formula

[0242] Intermediate 17: Ethyl 5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate

Chemical formula

[0243] Intermediate 18: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone

Chem.

[0244] Intermediate 19: Methyl 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazinyl)-2-oxoacetate

Chem.

[0245] Intermediate 20: Methyl 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate [Chemical formula] POCl 3 A mixture of methyl 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazinyl)-2-oxoacetate Intermediate 19 (10 g, 39.03 mmol) in POCl + 239.

[0246] Intermediate 21: 1,2,4-Trifluoro-5-iodo-3-methoxybenzene [Chemical formula] Into a 20 mL microwave vial dried in an oven, 2,4,5-trifluoro-3-methoxybenzoic acid (0.5 g, 2.43 mmol), K 3 PO 4 (0.515 g, 2.43 mmol) and iodine (2.463 g, 9.70 mmol), as well as a stir bar were placed. The vial was stoppered, evacuated, and refilled with N 2 . Anhydrous MeCN (8 mL) was added, and the reaction mixture was heated at 120 °C for 23 h. The reaction mixture was cooled to room temperature, and 15% Na 2 SO 3 (aq) was added until the dark color disappeared. A second batch was prepared as described above, the reaction mixtures were combined, and extracted with DCM (×3). The organic layers were combined and washed with 8% Na 2 CO 3Washed with (aq), passed through a phase separator, and concentrated. The residue was purified by normal-phase flash chromatography on silica (gradient: 5 - 17% MTBE / pentane) to afford the title compound (0.841 g, 60%) as a nearly colorless oil; MS (ESI) m / z [M+H] + 288.0

[0247] Intermediate 22: 5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid tert-butyl [Chemical Structure] Into a 20 mL microwave vial were placed 1,2,4-trifluoro-5-iodo-3-methoxybenzene Intermediate 21 (407 mg, 1.41 mmol), EtOH (12 ml), (5-(tert-butoxycarbonyl)thiophen-2-yl)boronic acid (322 mg, 1.41 mmol), Pd-118 (138 mg, 0.21 mmol), 2M K 2 CO 3 (aq) (2.12 ml, 4.24 mmol) and a stir bar. The vial was stoppered, evacuated, and refilled with N 2 (g) three times, then heated at 80 °C for 1.5 h. EtOAc and water were added, and the mixture was washed with 8% NaHCO 3 (aq). The aqueous layer was extracted with EtOAc, the organic layers were combined, passed through a phase separator, and concentrated. The residue was purified by normal-phase flash chromatography on silica (gradient: 0 - 30% EtOAc / heptane). The fractions containing the title compound were pooled, concentrated, the residue was dissolved in MTBE (ca. 10 mL), and treated with SILIAMETS thiol (1 g, loading amount: 1.4 mmol / g) at 40 °C for 30 min. The mixture was filtered and the solid was washed with MTBE. The fractions were combined and concentrated, and the residue was purified by preparative HPLC, preparative method J, (gradient: 50 - 100%) to afford the title compound (176 mg, 36%); 1 H NMR (500 MHz, CDCl 3 ) δ 1.59 (9H, s), 4.08 (3H, d), 7.13 (1H, ddd), 7.34 (1H, dd), 7.69 (1H, dd).

[0248] Intermediate 23: 5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid

Chem.

[0249] Intermediate 24: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

Chem.

[0250] Intermediate 25: tert-Butyl (1-cyclohexyl-1H-pyrazol-5-yl)carbamate

Chemical Structure

[0251] Intermediate 26: tert-Butyl (1-cyclohexyl-1H-pyrazol-5-yl)(methyl)carbamate

Chemical Structure

[0252] Intermediate 27: 1-Cyclohexyl-N-methyl-1H-pyrazol-5-amine

Chemical formula

[0253] Intermediate 28: tert-Butyl 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate

Chemical formula

[0254] Intermediate 29: 3-(4-Fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid

Chem.

[0255] Intermediate 30: N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamide

Chem.

[0256] Intermediate 31: (3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

Chemical Structure

[0257] Intermediate 32: Ethyl 4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate

Chem.

[0258] Intermediate 33: Ethyl 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

Chem.

[0259] Intermediate 34: 5-(4-Fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid

Chem.

[0260] Intermediate 35: 3-Ethynyl-2,5,6-trifluorophenol

Chem.

[0261] Intermediate 36: Ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

Chem.

[0262] Intermediate 37: 5-(2,4,5-Trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid

Chem.

[0263] Intermediate 38: Ethyl 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate

Chemical Structure

[0264] Intermediate 39: Ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

Chem.

[0265] Intermediate 40: 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid

Chem.

[0266] Intermediate 41: 2-(4-Fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid [Chemical Structure] Methyl 2-bromooxazole-5-carboxylate (470 mg, 2.28 mmol), (4-fluoro-3-hydroxyphenyl)boronic acid (391 mg, 2.51 mmol), K 3 PO 4 hydrate (1576 mg, 6.84 mmol) and XPhos Pd G3 (97 mg, 0.11 mmol) were placed in a vial and the reaction mixture was flushed with N 2 (g). THF (10 mL) and water (10 mL) were added and the reaction mixture was flushed again with N 2 (g). The reaction mixture was heated at 60 °C overnight in a preheated heating block. The reaction mixture was allowed to reach room temperature. Another batch was prepared as above starting with methyl 2-bromooxazole-5-carboxylate (50 mg, 0.24 mmol). The reaction mixtures were combined and diluted with EtOAc and satNH 4 Cl (aq). The aqueous layer was extracted with EtOAc (×3). The organic layers were combined, dried over MgSO 4 , filtered and concentrated under reduced pressure to give a residue. Then, the aqueous layer was acidified to pH ~1 with 2 M HCl, extracted with EtOAc (×4), the organic layers were combined, dried over MgSO 4 , filtered and concentrated under reduced pressure to give a second residue. The residues were combined and purified by normal-phase flash chromatography on silica (gradient: 0 - 10% MeOH / EtOAc). The fractions containing the product were combined and concentrated, dissolved in EtOAc. The organic layer was extracted with 0.1 M NaOH (aq). The aqueous layer was acidified with 2 M HCl and extracted with EtOAc (×3). The organic layers were combined, dried over MgSO 4 , filtered and the solvent was removed under reduced pressure to give the title compound (370 mg, 73%); MS m / z (ESI) [M+H] + 224.

[0267] Intermediate 42: 3-(4-Fluoro-3-hydroxyphenyl)-3-oxopropanenitrile

Chem.

[0268] Intermediate 43: Ethyl 4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

Chem.

[0269] Intermediate 44: Ethyl 4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

Chem.

[0270] Intermediate 45: N-Methyl-1-phenyl-1H-tetrazol-5-amine

Chem.

[0271] Intermediate 46: tert-Butyl (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prolinate

Chem.

[0272] Intermediate 47: (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline

Chem.

[0273] Intermediate 48: N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

Chem.

[0274] Intermediate 49: (Z)-4-((((1-Amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl [Chemistry] TBTU (524 mg, 1.63 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (309 mg, 1.36 mmol) and DIPEA (0.521 mL, 2.99 mmol) in DCM (6 mL) at room temperature. The mixture was stirred for about 10 minutes, and then a solution of (Z)-N'-hydroxyisobutyramide (176 mg, 1.72 mmol) in DCM (2 mL) / mixture was added. The reaction mixture was stirred at room temperature for 3 hours and then washed with 8% NaHCO 3 (aq, 3 × 5 mL) using a phase separator. The organic layer was concentrated and the residue was purified by flash chromatography on silica (gradient: 0 - 75% EtOAc / heptane) to give the title compound (141 mg, 33%) as a white solid; MS(ESI) m / z [M+H] + = 312.4

[0275] Intermediate 50: tert-Butyl 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [Chemistry] A solution of sodium acetate (0.784 mL, 2.15 mmol) in water (0.784 mL) was added to a mixture of (Z)-4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl intermediate 49 (610 mg, 1.96 mmol) in EtOH (6 mL), and the mixture was stirred at 86 °C for 5.5 hours. The solvent was removed under reduced pressure and the residue was partitioned between DCM and water using a phase separator. The organic layer was concentrated under reduced pressure and the residue was purified by preparative HPLC, preparative method E (gradient: 40 - 80%) to give the title compound (339 mg, 59%); MS(ESI) m / z [M+H] + = 238.2

[0276] Intermediate 51: 3-Isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazole

Chem.

[0277] Intermediate 52: Methyl 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate

Chem.

[0278] Intermediate 53: Ethyl 5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

Chem.

[0279] Intermediate 54: 2,4,5-Trifluoro-3-methoxybenzothioamide

Chem.

[0280] Intermediate 55: Ethyl 2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate

Chemical formula

[0281] Intermediate 56: ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanone

Chemical formula

[0282] Example 1: (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone [Chemical formula] DIPEA (0.440 mL, 2.52 mmol) was added dropwise at 25 °C under an atmosphere to methyl 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate intermediate 20 (100 mg, 0.42 mmol) and (R)-3-phenylpyrrolidine HCl (463 mg, 2.52 mmol) in DMF (4 mL), and the reaction mixture was stirred at 80 °C for 16 hours. The reaction was quenched with water (100 mL), extracted with EtOAc (3×100 mL), and the organic layer was dried over Na 2 (g), filtered, and evaporated. The crude product was purified by preparative HPLC, preparative method B (gradient: 42 - 52%) to give the title compound (61 mg, 41%) as a white solid; HRMS (ESI) m / z [M+H] 2 SO 4 , filtered, and concentrated under reduced pressure. DCM was added to the residue and the resulting mixture was filtered. The filtrate was concentrated to give the title compound (288 mg, 94%); MS m / z (ESI) [M+H] + C 19 H 17 FN 3 O 3Calculated value: 354.1248, measured value: 354.1254; 1 H NMR (300 MHz, DMSO-d 6 ) δ 1.97 - 2.18 (1H, m), 2.22 - 2.45 (overlapping with solvent, m), 3.41 - 3.72 (overlapping with solvent, m), 3.72 - 4.15 (2H, m), 4.17 - 4.56 (1H, m), 7.13 - 7.56 (7H, m), 7.59 - 7.72 (1H, m), 10.64 (1H, s).

[0283] Example 2: (3 - Phenoxyazetidin - 1 - yl)(5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone

Chemical formula

[0284] Example 3: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone

Chemical formula

[0285] Example 4: (3-(2-Methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical formula

[0286] Example 5: N-(1-Cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide [Chemical formula] BBr in DCM 3 (1M, 10 mL, 10.00 mmol) was slowly added to a stirred solution of N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamide intermediate 30 (90 mg, 0.23 mmol) in anhydrous DCM (2 mL) cooled to 0 °C under N 2 (g) atmosphere. The resulting solution was stirred at 15 °C for 2 hours. To the solution cooled to 0 °C, BBr in DCM 3 (1M, 20 mL, 20.00 mmol) was slowly added under N 2 (g) atmosphere. The resulting solution was stirred at 15 °C for 2 hours. The reaction mixture was poured into 2M NaOH (aq, 50 mL) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na 2 SO 4 and filtered and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:2) and then further purified by preparative HPLC, preparative method N (gradient 45 - 55%) to give the title compound as a white solid (0.014 g, 16%); HRMS (ESI) m / z [M+H] + C 20 H 22 FN 4 O 3 calculated value: 385.1670, found value: 385.1674; 1 1H NMR (300 MHz, DMSO-d 6 ) δ 1.06 - 1.92 (10H, m), 3.31 (3H, s), 3.92 - 4.1 (1H, m), 6.30 (1H, d), 6.69 (1H, s), 7.12 - 7.36 (3H, m), 7.51 (1H, d), 10.38 (1H, s).

[0287] Example 6: (3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

Chemical Structure

[0288] Example 7: N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide

Chemical Structure

[0289] Example 8: (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

Chemical Structure

[0290] Example 9: 4-(3-(3-Phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

Chemical Structure

[0291] Example 10: 4-(3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

Chemical Structure

[0292] Example 11: (R)-(5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

Chemical Structure

[0293] Example 12: N-(1-Cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

Chemical Structure

[0294] Example 13: 5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile

Chem.

[0295] Examples 14 - 29 below were prepared in the same manner as in Example 13 from ethyl 4 - cyano - 5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)isoxazole - 3 - carboxylate intermediate 44 using a commercially available appropriate amine. The HCl salt and AcOH salt of the amine were dissolved in MeOH, passed through a 5g ISOLUTE NH 2 ion - exchange column, concentrated, and then used. The crude product was purified by the specified method.

[0296] Example 14: 3 - (4 - (3 - (4 - fluorophenoxy)propyl)piperazine - 1 - carbonyl)-5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)isoxazole - 4 - carbonitrile [Chemical formula] The crude product was purified by preparative HPLC, preparative method C (gradient: 20 - 80%) to obtain the title compound (24 mg, 37%) as an off - white solid; HRMS (ESI) m / z [M + H] + ; C 24 H 21 F 4 N 4 O 4 calculated value: 505.1494, measured value: 505.1486; 1 H NMR (500 MHz, CD 3 OD) δ 2.04(p, 2H), 2.7 - 2.82(m, 6H), 3.81 - 3.92(m, 4H), 4.04(t, 2H), 6.86 - 6.93(m, 2H), 6.95 - 7.03(m, 2H), 7.31(ddd, 1H).

[0297] Example 15: 3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chem.

[0298] Example 16: 3-(4-(3-Methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chem.

[0299] Example 17: 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile

Chemical Structure

[0300] Example 18: 3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical Structure

[0301] Example 19: N-(tert-Butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide

Chem.

[0302] Example 20: 3-(3-Cyclopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chem.

[0303] Example 21: (S)-3-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical Structure

[0304] Example 22: 3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chem.

[0305] Example 23: 3 - (4 - (Benzo[d]oxazol - 2 - yl)piperazine - 1 - carbonyl)-5-(2,4,5 - trifluoro - 3 - hydroxyphenyl)isoxazole - 4 - carbonitrile

Chem.

[0306] Example 24: 3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical Structure

[0307] Example 25: 3-(4-((5-Methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical Structure

[0308] Example 26: 3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical formula

[0309] Example 27: 3-(3-Cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical formula

[0310] Example 28: 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile

Chemical Structure

[0311] Example 29: 3-(7-Cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

Chemical Structure

[0312] Example 30: 2 - (5 - (2 - Bromo - 3,4,6 - trifluoro - 5 - hydroxyphenyl) - 1,2,4 - oxadiazole - 3 - carbonyl) - 1,2,3,4 - tetrahydroisoquinoline - 5 - carbonitrile

Chemical Structure

[0313] Example 31: 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile [Chemical formula] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (38 mg, 0.15 mmol), HATU (111 mg, 0.29 mmol) and DMF (0.5 mL) were mixed in a vial. 1,2,3,4-Tetrahydroisoquinoline-6-carbonitrile HCl (28 mg, 0.15 mmol) dissolved in DMF (0.5 mL) was added, followed by DIPEA (153 μL, 0.88 mmol). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DMSO and purified by preparative HPLC, preparative method A (gradient: 5 - 95%) to obtain the title compound (15 mg, 26%); HRMS (ESI) m / z [M+H] + C 19 H 12 F 3 N 4 O 3 Calculated value for: 401.0856, Measured value: 401.0834; Mixture of rotamers major:minor ratio: 1:0.6: 1 1H NMR (600 MHz, DMSO-d 6 )δ 2.97 (2H, dt), 3.79 (1.2H, t), 3.92 (0.8H, t), 4.84 (0.8H, s), 4.94 (1.2H, s), 7.52 (0.6H, d), 7.31 (0.4H, d) 7.62 - 7.75 (3H, m), 11.71 (1H, s). Total number of protons in the spectrum: 11.

[0314] Example 32: (2,2,6,6 - Tetramethylmorpholino)(5-(2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone

Chem.

[0315] Example 33: (R)-(3 - Phenylpyrrolidin - 1 - yl)(5-(2,4,5 - trifluoro - 3 - hydroxyphenyl)thiophen - 2 - yl)methanone

Chem.

[0316] General Preparation A The appropriate amine (0.08 mmol, 2 eq) was added to a solution of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (0.08 - 0.2 M, 0.04 mmol, 1 eq) and HATU (0.15 - 0.4 M, 0.08 mmol, 2 eq) in DMF. DIPEA (0.23 mmol, 6 eq) was added and the reaction mixture was shaken at room temperature for 20 h. The solvent was removed under reduced pressure and the crude product was dissolved in DMSO (0.3 mL), filtered and generated by preparative HPLC using the following methods, namely preparative methods F, G, H or I (gradient 2 - 94%).

[0317]

Table 1

[0318]

Table 2

[0319]

Table 3

[0320]

Table 4

[0321]

Table 5

[0322]

Table 6

[0323]

Table 7

[0324]

Table 8

[0325] General Modulation B 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2i (0.4 M, 0.06 mmol, 1 eq) in DMF, followed by DIPEA (0.35 mmol, 6 eq) and HATU (0.47 M, 0.12 mmol, 2 eq) in DMF, were added to a vial containing the appropriate amine (0.12 mmol, 2 eq). The reaction mixture was shaken at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (0.3 mL) and purified by preparative HPLC using the following methods, namely preparative methods F, G, H or I (gradient 2 - 94%).

[0326]

Table 9

[0327]

Table 10

[0328] Example 85: 3-(1-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile

Chem.

[0329] Example 86: 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

Chemical Structure

[0330] Example 87: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical formula

[0331] Example 88: ((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0332] Example 89: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

Chemical Structure

[0333] The following compounds, Examples 90 to 111, were also produced in the same manner as the aforementioned method.

[0334] Example 90: (5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone

Chemical formula

[0335] Example 91: 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide

Chem.

[0336] Example 92: 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide

Chem.

[0337] Example 93: (S)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0338] Example 94: (3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0339] Example 95: (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0340] Example 96: (3 - Phenylpyrrolidin - 1 - yl)(5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone

Chemical Structure

[0341] Example 97: (3 - (Benzyloxy)pyrrolidin - 1 - yl)(5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone

Chemical formula

[0342] Example 98: (R)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0343] Example 99: N-(1-Cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluorophenol-3-yl) isoxazole-3-carboxamide

Chemical Structure

[0344] Example 100: N-((1-Cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

Chemical Structure

[0345] Example 101: (R)-(5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

Chemical Structure

[0346] Example 102: (3H - Spiro[isobenzofuran - 1,3'-pyrrolidine]-1'-yl)(5-(2,4,5-trifluoro - 3-hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone [Chemical Structure] DIC (89 μL, 0.57 mmol) was added to a mixture of 3H - Spiro[isobenzofuran - 1,3'-pyrrolidine] (50 mg, 0.29 mmol) and 5-(2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazole - 3 - carboxylic acid intermediate 2 (74.2 mg, 0.29 mmol) in DMF (1 mL) at N 2 (g) atmosphere at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with sat NaHCO 3 (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na 2 SO 4 and filtered and evaporated. The crude product was purified by flash chromatography on a C18 column (gradient: 60 - 70% MeCN / water) to give the title compound (9 mg, 7%) as a white solid; HRMS (ESI) m / z [M + H] + C 20 H 15 F 3 N 3 O 4 calculated: 418.1008, found: 418.1014; 1 1H NMR (400 MHz, DMSO - d 6 ) δ ppm 2.13 - 2.26 (1H, m) 2.37 - 2.48 (1H, m) 3.66 - 4.01 (3H, m) 4.06 (1H, t) 4.97 - 5.18 (2H, m) 7.27 - 7.42 (3H, m) 7.44 - 7.62 (2H, m).

[0347] Example 103: (S)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0348] Example 104: (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

Chemical Structure

[0349] Example 105: N,N-Dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

Chemical Structure

[0350] Example 106: 2-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile

Chemical Structure

[0351] Example 107: (4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical formula

[0352] Example 108: ((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0353] Example 109: 2-(5-(2,4,5-Trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile

Chemical Structure

[0354] Example 110: ((2R,6S)-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

Chemical Structure

[0355] Example 111: ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone [Chemical formula] The title compound was prepared in the same manner as in the preparation of Example 110 from methyl 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate intermediate 52 (80 mg, 0.29 mmol) and (3S,5R)-3,5-dimethylpiperidine (44 mg, 0.39 mmol). The crude product was purified by preparative HPLC, preparative method D (gradient: 35 - 75%) to obtain the title compound (67 mg, 65%) as a white solid; HRMS (ESI) m / z [M + H] + C 16 H 17 F 3 N 3 O 3 Calculated value for: 356.1216, measured value: 356.1224; 1 H NMR (500 MHz, DMSO-d 6 ) δ 0.83 (3H, d), 0.84 - 0.91 (1H, m), 0.93 (3H, d), 1.57 - 1.72 (2H, m), 1.77 - 1.84 (1H, m), 2.42 (1H, t), 2.74 (1H, dd), 3.89 - 3.96 (1H, m), 4.37 - 4.45 (1H, m), 7.45 (1H, ddd), 11.47 (1H, s).

[0356] Example 112: ((4aR,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [Chem.] (4aR,7aS)-Octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol) was dissolved in MeOH and passed through an Isolute NH 2 column (1 g). The compound was eluted with MeOH. The MeOH was evaporated and the residue was dissolved in dry toluene (0.5 mL). Me 3 Al (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N 2 (g) atmosphere. The solution was stirred at room temperature for 45 minutes and then added dropwise at room temperature under nitrogen to a stirred solution of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 mL). The solution was heated at 60 °C for 20 hours. Tartaric acid (30%, aq, 5 mL) was added dropwise. The mixture was extracted with EtOAc. The phases were separated and the aqueous phase was extracted again with EtOAc. The organic layers were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, preparative method D (gradient: 30 - 100%) to give the title compound (0.032 g, 36%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 15 F 3 N 3 O 4 calculated value: 370.1014, found value: 370.0996; mixture of rotational isomers: 1 H NMR (500 MHz, DMSO-d 6 ) δ 1.42 - 2.13 (6H, m), 3.1 - 3.19 (0.6H, m), 3.37 - 3.51 (1.4H, m), 3.58 (0.4H, d), 3.71 - 3.79 (1H, m), 3.83 - 3.97 (1.6H, m), 4.16 (0.6H, dd), 4.48 - 4.57 (0.4H, m), 7.51 - 7.8 (1H, m), 11.71 (1H, s). Total number of protons in the spectrum: 14.

[0357] Example 113: ((4aS,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chem.

[0358] Example 114: ((4aR,7aR)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0359] Example 115: ((4aS,7aS)-Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chem.

[0360] Example 116: ((5-(3,4-Difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl))((2R,6S)-2,6-dimethylmorpholino)methanone

Chemical Structure

[0361] Example 117: (5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone [Chemical formula] 2,2,6-Trimethylmorpholine (0.041 g, 0.32 mmol) was dissolved in toluene (0.5 mL). Me 3 Al (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N 2 (g) atmosphere. The resulting solution was stirred at room temperature for 45 minutes, and then a stirred solution of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 mL) was added dropwise at room temperature under N 2 (g) atmosphere. The solution was heated at 60 °C for 20 hours. Tartaric acid (30%, aq, 5 mL) was added dropwise. The mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, preparative method D (gradient: 35 - 85%) to obtain the title compound (0.034 g, 38%) as a white solid; HRMS (ESI) m / z [M + H] + C 16 H 17 F 3 N 3 O 4 Calculated value for: 372.1166, Measured value: 372.1158; Mixture of rotamers: 1 H NMR (500 MHz, DMSO-d 6)δ 0.99(1H,d),1.05 - 1.13(3H,m),1.13 - 1.24(5H,m),2.56(0.7H,dd),2.76(0.4H,d),2.83(0.4H,dd),3.02(0.5H,d),3.56(0.5H,dd),3.73 - 3.9(1.5H,m),4.23(0.4H,dd),4.36(0.5H,dt),7.51 - 7.84(1H,m). Total number of protons in the spectrum: 15.

[0362] Example 118: (4 - Oxo - 7 - azaspiro[2.5]octan - 7 - yl)(5 - (2,4,5 - trifluoro - 3 - hydroxyphenyl)-1,2,4 - oxadiazol - 3 - yl)methanone

Chemical formula

[0363] Example 119: ((3R,5S)-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chem.

[0364] Example 120: ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone

Chem.

[0365] Example 121: rac-((2R,6S)-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0366] Example 122 rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

Chemical Structure

[0367] Example 123 (6-Methyl-5-oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [Chemical formula] (racemic) 2M AlMe 3 (1.09 ml, 2.17 mmol) was added dropwise to a solution of rac-(R)-6-methyl-5-oxa-8-azaspiro[3.5]nonane (172 mg, 1.21 mmol) in anhydrous toluene at room temperature under N 2 . The resulting solution was stirred at room temperature for 1 hour, and then added dropwise to a stirred mixture of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 1 (0.25 g, 0.87 mmol) in anhydrous toluene (1.75 mL) at room temperature under N 2 . The resulting solution was heated at 60 °C for 4 hours. Heating was stopped, and the reaction mixture was cooled to room temperature overnight and then further cooled to 0 °C. 30% tartaric acid (aq, 13 mL) was added dropwise, and the mixture was extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, preparative method J (gradient: 35 - 75%). The fraction containing the product was acidified to pH 5 with HOAc, and MeCN was removed under reduced pressure. The resulting aqueous oil / water mixture was extracted with DCM (×3). The combined organic layers were concentrated, and the residue was purified by preparative HPLC, preparative method D (gradient: 35 - 75%) to give the title compound (208 mg, 63%) as a white solid; HRMS (ESI) m / z [M + H] + Calculated for C17H17F3N3O4: 384.1171, Found: 384.1185; 11H NMR (500 MHz, DMSO, 25 °C, mixture of 3:2 rotamers) δ 1.02 (1.3H, d), 1.13 (1.7H, d), 1.47 - 2.08 (5.4H, m), 2.13 - 2.22 (0.5H, m), 2.62 (0.6H, dd), 2.82 (0.4H, dd), 2.89 (0.4H, dd), 3.05 (0.6H, dd), 3.48 - 3.63 (1.1H, m), 3.74 (0.4H, dt), 3.84 (0.6H, dd), 4.31 (0.6H, dt), 4.53 (0.4H, dd), 7.6 - 7.69 (1H, m), 11.72 (1H, s).

[0368] Example 124 (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone

Chemical Structure

[0369] A small amount of the title compound (200 mg) was further purified by preparative HPLC, preparative method D, gradient (30 - 70%) to obtain the title compound (133 mg) as a white solid; HRMS (ESI) m / z [M + H] + Calculated for C15H14BrF3N3O4 436.0120, found: 436.0116; 11H NMR (500 MHz, DMSO, 25 °C) δ 1.06 (3H, d), 1.17 (3H, d), 2.63 (1H, dd), 2.94 (1H, dd), 3.54 - 3.65 (2H, m), 3.70 (1H, dt), 4.37 (1H, dt), 12.05 (1H, s).

[0370] In vitro 17β-HSD13 enzyme assay A 10 μM solution of the compound (0.2 μl) in DMSO was added to a GREINER PP 384-well plate (781280) using an ECHO dispenser (BECKMAN COULTER), followed by the addition of 20 μl of recombinant 17β-HSD13 (N2-K300). The enzyme reaction was initiated by adding 20 μl of a substrate solution containing NAD (SIGMA, N1511) and estradiol (SIGMA, E8875) using a CERTUS-FLEX dispenser (GYGER). After each addition, the plate was centrifuged at 150 × g for 1 minute (EPPENDORF, 5810R, A-4-81). The final assay conditions were 80 nM 17β-HSD13, 0.5 mM NAD, 20 μM estradiol, and various concentrations of the compound in buffer (5 mM EDTA (TEKNOVA E0306) in 50 mM Tris-Cl (pH 7.4), 0.01% DDM (AFFYMETRIX D310)). After 2.5 hours, the reaction was stopped by adding 20 μl of 0.6% formic acid (MERCK 5.33002), and the samples were analyzed using LC-MS / MS.

[0371] SCIEX LC-MS / MS System: Samples were injected using a CTC Analytical Injector and a SHIMATZU LC Pump LC20 and analyzed on a SCIEX API 5000 LCMSMS System with the following settings. Samples were chromatographed on a WATERS, SYMMETRY, C8, 3.5 μm, 2.1×50 mm column at a constant flow rate of 0.5 mL / min. The mobile phase consisted of A (water containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.5 minutes, linearly increasing to 100% B from 0.5 to 1 minute, held at 100% B from 1 to 1.6 minutes, and then returned to 50% B from 1.6 to 2 minutes. The run time was 2 minutes, and the retention times of estradiol and estrone were approximately 0.8 and 1.07 minutes, respectively. Detection was performed on an API 5000 LC / MS / MS System using a triple quadrupole mass spectrometer and a TURBO V ion source in positive polarity multiple reaction monitoring (MRM) mode with an APCI probe. The MRM pairs for estradiol and estrone were m / z273.1~m / z107.0 and m / z271.3~107.0, respectively. The dwell time was 100 ms for each transition, and the declustering and collision energies were 100 and 40, respectively. Data from the MS signal was obtained using the area under the curve (AUC). Ratio = estrone / (estrone + estradiol)

[0372] In Vitro 17bHSD13 Cell Assay Inhibition of 17bHSD13 was measured in a cell-based assay using HSD17β13 overexpressed in HEK293S cells, and the conversion of estradiol to estrone was measured by LCMS / MS.

[0373] Cells were plated at 10 K c / w in 30 μl of culture medium (DMEM containing GLUTAMAX + 10% FBS) in a 384-well plate (GREINER CELL culture plate 384w black / transparent poly-D-lysine). After allowing the cells to adhere for 6 hours, 0.15 μl of the compound at 10 concentrations and 0.03 μl of 10 mM estradiol (SIGMA, E8875) in DMSO were added using ECHO dispensing (BECKMAN COULTIER). After culturing the cells in 20 μl of medium for 18 hours, they were transferred to a GREINER PP 384-well plate (781280) using a BRAVO dispensing robot (AGILENT), and 40 μl of 50% acetonitrile was added. The samples were analyzed using LC-MS / MS.

[0374] SCIEX LC-MS / MS System: Samples were injected using a CTC analytical injector and a SHIMATZU LC pump LC20, and analyzed with an SCIEX API 5000 LCMSMS system under the following settings. The samples were chromatographed at a constant flow rate of 0.5 mL / min on a WATERS, symmetry, C8, 3.5 μm, 2.1×50 mm column. The mobile phase consisted of A (water containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: linearly increasing from 50% B to 100% B between 0 and 0.5 minutes, held at 100% B between 0.5 and 1 minute, then held at 100% B between 1 and 1.6 minutes, and then returned to 50% B between 1.6 and 2 minutes. The run time was 2 minutes, and the retention times of estradiol and estrone were approximately 0.8 and 1.07 minutes, respectively. Detection was performed with a triple quadrupole mass spectrometer, TURBO V ion source, in positive polarity multiple reaction monitoring (MRM) mode using an APCI probe in an API 5000 LC / MS / MS system. The MRM pairs for estradiol and estrone were m / z273.1~m / z107.0 and m / z271.3~107.0, respectively. The dwell time was 100 ms for each transition, and the declustering and collision energies were 100 and 40, respectively. Data from the MS signals were obtained using the area under the curve (AUC). Ratio = estrone / (estrone + estradiol)

[0375] In Vitro 17bHSD4 Enzyme Assay A 10 μM solution of the compound (0.2 μl) in DMSO was added to a GREINER FLUOTRAC 200 384-well plate (781076) using ECHO dispensing (BECKMAN COULTER). 80 nl of 10 mM estradiol (SIGMA, E8875) was added using echo dispensing. The enzyme reaction was initiated by adding 40 μl of a mixture containing recombinant 17βHSD4 (M1-N311) and NAD using MULTIDROP COMBI dispensing (THERMO FISHER). The final assay conditions were 40 nM 17βHSD4, 0.125 mM NAD, 15 μM estradiol, and various concentrations of the compound in buffer (5 mM EDTA (TEKNOVA E0306) in 50 mM Tris-Cl (pH 7.4), 0.01% DDM (AFFYMETRIX D310)). After each addition, the plate was centrifuged at 150 × g for 1 minute (EPPENDORF, 5810R, A-4-81). NADH formation was measured by the fluorescence intensity (FI) (Ex360 / Em460) at 0 hours (t 0 ) and 1.5 hours (t 1 ). The FI of each sample was calculated as the difference between the FI at t 1 and the FI at t 0 .

[0376] In Vitro 17βHSD9 Cell Assay Inhibition of 17βHSD9 was measured in a cell-based assay using HSD17β9 overexpressed in HEK293S cells, and the conversion from retinol to retinal was measured by LCMS / MS.

[0377] Cells were plated at 10 K c / w in 30 μl of culture medium (DMEM containing GLUTAMAX + 10% FBS) in a 384-well plate (GREINER CELL culture plate 384w black / transparent poly-D-lysine). After allowing the cells to adhere for 6 hours, 0.15 μl of a 10 concentration of the compound and 0.015 μl of 10 mM all-trans-retinol (CAYMAN CHEMICAL, 20241) in DMSO were added using ECHO dispensing (BECKMAN COULTIER). After culturing the cells in 20 μl of medium for 18 hours, they were transferred to a GREINER PP 384-well plate (781280) using a BRAVO dispensing robot (AGILENT), and 40 μl of 50% acetonitrile was added. The samples were analyzed using LC-MS / MS.

[0378] SCIEX LC-MS / MS System: Samples were injected using a CTC Analytical Injector and a SHIMATZU LC Pump LC20, and analyzed on a SCIEX API 5000 LCMSMS System with the following settings. Samples were chromatographed at a constant flow rate of 0.5 mL / min using a WATERS, symmetry, C8, 3.5 μm, 2.1×50 mm column. The mobile phase consisted of A (water containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.1 min, linearly increasing to 100% B from 0.1 to 0.8 min, held at 100% B from 0.8 to 1.5 min, then returned to 50% B from 1.5 to 1.6 min and held for the duration of the run time. The run time was 2 minutes, and the retention times of retinol and retinal were approximately 1.54 and 1.62 minutes, respectively. Detection was performed on an API 5000 LC / MS / MS System using a triple quadrupole mass spectrometer and a TURBO V ion source in positive polarity multiple reaction monitoring (MRM) mode with an ESI probe. The MRM pairs for retinol and retinal were m / z269.3~m / z93.0 and m / z285.2~161.0, respectively. The dwell time was 100 ms for each transition, and the declustering and collision energies were 50 and 25, respectively. Data from the MS signal was obtained using the area under the curve (AUC). Ratio = retinal / (retinal + retinol)

[0379] Data Analysis Curve Fitting and IC 50 GENEDATA SCREENER was used for value calculation. The effect of the compound was calculated using the following formula: Compound effect % = -100×[(X - minimum) / (maximum - minimum)] (where X represents the effect in the presence of the test compound, minimum is DMSO, and maximum is the maximum inhibition of the enzyme using a known inhibitor as a control).

[0380]

Table 11

[0381]

Table 12

[0382]

Table 13

[0383]

Table 14

[0384]

Table 15

[0385] The data shown in Table 3 may be the result from one experiment or the average of two or more experiments.

[0386] Assay A: Metabolic Stability in Human Hepatocytes Hepatocyte metabolic stability was determined according to the method described in Jacobson et al., An optimized automated assay for determination of metabolic stability using hepatocytes: assay validation, variance component analysis, and in vivo relevance. Assay Drug Dev Technol 2007, 5(3), 403-415. DOI:10.1089 / adt.2007.059 (this reference is incorporated herein by reference). 10 6Cryopreserved hepatocytes at [number of viable cells] / mL were used. After thawing, the hepatocytes were incubated for 10 minutes to warm to 37 °C, and the test compound dissolved in acetonitrile was added to a final concentration of 1 μM. At time points of 0.5, 5, 15, 30, 45, 60, 80, 100, and 120 minutes, the incubation system was mixed, and at each time point, a 20 μL aliquot was transferred to the wells of a separate plate filled with 80 μL of MeCN to stop the reaction. The quenching plate was then vortexed and subsequently centrifuged, and the supernatant was analyzed by LC-MS / MS. The peak area was determined from the extracted ion chromatogram, and the in vitro intrinsic clearance of the parent compound (in vitro CLint (μL / min / 10 6 cells)) was calculated from the slope in the regression analysis of the natural logarithm of the parent concentration vs. time curve

[0387] Assay B: Cytochrome P450 Inhibition 2C9 Using a 96-well format fluorescence-based method, inhibition of 2C9 was determined (Crespi, C.L. et al., Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal Biochem 1997, 248(1), 188-190. DOI: 10.1006 / abio.1997.2145 (this reference is incorporated herein by reference)). The recombinant human enzymes used were prepared in-house, except for CYP2D6 (CYPEX LTD, Dundee, UK). Various coumarin substrates biotransformed in vivo to fluorescent metabolites were used as probes for each individual CYP. A fluorescence plate reader (SPECTRAMAX GEMINIXS, MOLECULAR DEVICES, Sunnyvale, California, USA) was used to measure the levels of metabolites formed. A dilution series of the test substrate was prepared at eight different concentrations. For each CYP, a mixture of enzyme, the corresponding coumarin substrate, potassium phosphate buffer pH 7.4 and water (concentration and volume depending on the CYP) was added to each well of a black 96-well plate. Test substrates at various concentrations were added. After a 10-minute preincubation, the cofactor NADPH was added to initiate the reaction. After 20 - 50 minutes (depending on the CYP and substrate), Tris base / MeCN (20:80) was added to terminate the reaction. The plate was transferred to a fluorescence plate reader with wavelengths set individually for the different coumarin substrates and their respective fluorescent metabolites. The responses were exported to Excel and the IC 50 curve was plotted (percent inhibition vs. concentration), and the IC 50 was calculated for each test substrate and enzyme using XLfit.

[0388] Assay C: CB1 Agonism Assay Evaluation of the agonist activity of compounds at the human CB1 receptor expressed in transfected CHO cells, determined by measuring the effect on cAMP regulation using the HTRF detection method.

[0389] Experimental protocol: Cells are suspended in HBSS buffer (INVITROGEN) supplemented with 20 mM HEPES (pH 7.4) and then distributed into microplates at a density of 5.103 cells / well in the presence of any of the following: HBSS (basal control), 30 nM (stimulus control) or various concentrations of reference agonist (EC 50 determination), or test compound. Then, the adenylyl cyclase activator NKH 477 is added at a final concentration of 3 μM. After incubation at 37 °C for 20 minutes, the cells are lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (anti-cAMP antibody labeled with europium cryptate) are added. After holding at room temperature for 60 minutes, fluorescence transfer is measured at gex = 337 nm and gem = 620 and 665 nm using a microplate reader (RUBYSTAR, BMG). The cAMP concentration is determined by dividing (ratio) the signal measured at 665 nm by the signal measured at 620 nm. The results are expressed as a percentage of the control response to 30 nM CP55940. The standard reference agonist is CP 55940, which is tested at several concentrations in each test to generate a concentration-response curve from which its EC 50 is calculated.

[0390] Bibliographic reference Felder, C.C. et al., (1995), Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors, Mol. Pharmacol., 48:443 (this document is incorporated herein by reference).

[0391]

Table 16

[0392]

Table 17

[0393]

Table 18

[0394] The data shown in Table 4 can be the results from one experiment or the average of two or more experiments.

[0395] Metabolism study In vitro studies to identify the metabolites of Example 87 gave metabolite 1 and metabolite 2 as defined below. Subsequently, metabolites 1 and 2 were synthesized and characterized.

[0396] Metabolite 1: 3-(3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenyl hydrogen sulfate

Chem.

[0397] Metabolite 2: (2S,3S,4S,5R,6S)-6-(3-(3-((2R,6S)-2,6-Dimethylmorpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

Chem.

[0398] The foregoing description of the exemplary embodiments is intended solely to notify other persons skilled in the art of the applicant's specification, its principles, and its practical application, so that they can easily adapt and apply the specification to a very large number of forms, which may be optimal for the requirements of a particular application. This description and its specific examples are illustrative only while explaining the embodiments of the specification. Therefore, the specification is not limited to the exemplary embodiments described herein and can be variously modified. Furthermore, it will be understood that various features of the specification, which are described in the context of separate embodiments for clarity, can be combined to form a single embodiment. Conversely, various features of the specification, which are described in the context of a single embodiment for brevity, can also be combined to form partial combinations thereof.

Claims

Claim 1 A compound of formula (III): 【Chemical 1】 [wherein X １ , X ２ and X ３ one of which is selected from NH, O and S, and X １ , X ２ and X ３ the other two of which are independently selected from N and CR Ｙ (where each R Ｙ is independently H, -CN, -C(=O)N(R ７ ) ２ or R ＸＡ and R ＸＡ is independently C １～３ alkyl optionally substituted with 1 to 3 F); J is selected from O, S, CH₂, NH and a covalent bond; x is selected from 0 to 3; each R₉ is independently selected from R₃, R₄ and R₅; and Rₑ is H or halo; Each R ３ is independently C １～４ alkyl or C ３～６ cycloalkyl, each of which is optionally substituted with one or more groups independently selected from R ４Ｘ , R ５ｘ , -O(R ４Ｘ ), -O(R ５Ｘ ) and F; Each R ３Ｘ is independently C １～４ alkyl or C ３～６ cycloalkyl, each of which is optionally substituted with one or more F; Each R4 is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl, each of which is optionally R ４Ｘ , -O(R ４Ｘ ), R ５Ｘ , -O(R ５Ｘ ), -OH, -CN, C １～４ alkoxy, -C(=O)OH, -C(=O)O(C １～４ alkyl), -C(=O)N(R ７Ｂ ), ２ R ３ and is substituted with one or more groups independently selected from halo; Each R ５Ｘ is independently phenyl, each of which is optionally substituted with one or more groups independently selected from -OH, -CN, C １～４ alkoxy, -C(=O)OH, -C(=O)N(R ７Ｂ ) ２ , R ３ｘ and halo; Each R ７ and R7B are independently H, C １～４ alkyl or C ３～６ cycloalkyl; and each heteroaryl is independently an aromatic ring containing one or more heteroatoms independently selected from N, O and S]] or a pharmaceutically acceptable salt thereof. Claim 2 (i) X １ is N, X ２ is O, X ３ is N; (ii) X １ is N, and X ２ is N, and X ３ is O; (iii) X １ is CR Ｙ and X ２ is CR Ｙ and X ３ is S; (iv) X １ is O, X ２ is N, X ３ is CR Ｙ ; (v) X １ is N, and X ２ is O, and X ３ is CR Ｙ ; (vi) X １ is CR Ｙ and X ２ is N, and X ３ is O; (vii) X １ is O, X ２ is N, X ３ is N; (viii) X １ is N, and X ２ is N, and X ３ is S; (ix) X １ is CR Ｙ and X ２ is S, and X ３ is CR Ｙ ; or (x) X １ is CR Ｙ and X ２ is N and X ３ is S The compound of formula (III) according to Claim 1 or a pharmaceutically acceptable salt thereof. Claim 3 X １ is N, and X ２ is O, and X ３ is N, the compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof. Claim 4 The compound of formula (III) according to Claim 1 or a pharmaceutically acceptable salt thereof, wherein J is O. Claim 5 Each R ３ is independently C optionally substituted by 1 to 3 F １～４ alkyl, a compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof. Claim 6 Each R4 is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl, each of which is optionally substituted with one or more groups independently selected from OH, -CN, C １～４ alkoxy, -C(=O)OH, -C(=O)O(C １～４ alkyl)-C(=O)N(R ７Ｂ ) ２ , R ３Ｘ and halo, a compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof. Claim 7 Each R5 is independently phenyl, each of which is optionally OH, -CN, C １～４ alkoxy, -C(=O)OH, -C(=O)O(C １～４ alkyl), -C(=O)N(R ７Ｂ ) ２ , R ３Ｘ and one or more groups independently selected from halo, a compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof. Claim 8 The compound of formula (III) according to Claim 1 or a pharmaceutically acceptable salt thereof, wherein Rₑ is H. Claim 9 The compound of formula (III) according to Claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone, (3-(2-methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, 3-(4-(3-(4-fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 5-(2,4,5-trifluoro-3-hydroxyphenyl)-3-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carbonyl)isoxazole-4-carbonitrile, (S)-3-(3-(4-Chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-((2R,6S)-2,6-Dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, 3-(4-(4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile, (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone, (3-Isopropylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((3R,5S)-3,5-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Morpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Thiomorpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, 3-(4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-yl)benzonitrile, Piperidin-1-yl(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (S)-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl)morpholino)methanone, (2-isobutylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3,3-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (R)-(2-(fluoromethyl)morpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,5R)-2,5-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2S,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(4-methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, 4-(1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidin-4-yl)benzonitrile, (4-(3-(4-fluorophenoxy)propyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(3-methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(3-Chloro-5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(2-((5-Bromopyridin-2-yl)oxy)ethyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3-Propylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-Phenylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile, (4-(5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile, (4-(2-Methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, (R)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (S)-(3-(4-Chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, (R)-(3-Phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone, ((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,6S)-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone, ((3R,5S)-3,5-Dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone, (5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone, ((3R,5S)-3,5-Dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone, rac-((2R,6S)-2-Ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, rac-((2R,6S)-2-Isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone and (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone. ​ ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [Chemical Formula 2] The compound of formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

11. ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone 【Chemical Formula 3】 The compound of formula (III) according to claim 10, which is

12. A pharmaceutical composition comprising the compound of formula (III) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12 for use in the treatment of liver diseases.

14. The pharmaceutical composition according to claim 13, wherein the liver disease is selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD, NASH, liver fibrosis, cirrhosis, isolated fatty liver, hepatitis, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).

15. The pharmaceutical composition according to claim 14, wherein the liver disease is liver fibrosis.

16. The pharmaceutical composition according to claim 14, wherein the liver disease is cirrhosis.

17. The compound of formula (III) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and (i) a glucagon-like peptide-1 receptor (GLP1) agonist, (ii) a sodium-glucose cotransporter 2 (SGLT2) inhibitor or (iii) a ThrB agonist A combination agent for use in the treatment of liver diseases.

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