Amide heteroaromatic compounds useful in the treatment of liver diseases

Abstract

To provide a compound which can be used for the treatment of diseases such as liver diseases, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them.SOLUTION: Provided is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein A represents a specific ring, one of X1, X2 and X3 is selected from NH, O and S, and the other two of X1, X2 and X3 are independently selected from N and CRY, and R1 and R2 represent specific groups.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 364,976, filed May 19, 2022, 63 / 367,843, filed July 7, 2022, and 63 / 383,982, filed November 16, 2022, the entire texts of which are incorporated herein by reference.

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

[0003] Nonalcoholic fatty liver disease (NAFLD) refers to a variety of liver diseases, ranging from simple fatty liver (nonalcoholic fatty liver) to nonalcoholic steatohepatitis (NASH) with or without fibrosis and cirrhosis. Fatty liver is defined as excess fat accumulation in the liver of greater than 5% due to causes other than alcohol consumption. NASH is defined as fatty liver accompanied by inflammation and hepatocellular injury, with or without fibrosis. It is estimated that approximately 25% of the world's population has NAFLD, and mortality from NAFLD-related diseases is expected to increase significantly by 2030.

[0004] To date, there are no approved treatments for NAFLD (including NASH), and therapeutic interventions focus on addressing comorbidities that also contribute to the development of NAFLD, such as treating insulin resistance, obesity, type 2 diabetes, and dyslipidemia.

[0005] Recently, mutations in the 17βHSD13 gene have been associated with decreased serum aminotransferase levels and reduced risk of liver diseases, such as alcoholic and non-alcoholic liver disease, cirrhosis, and hepatocellular carcinoma (HCC), in an allele-dose-dependent manner (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 therefore characterized as a 17βHSD13 loss-of-function (LoF) variant (Non-Patent Document 3). The association between LoF 17βHSD13 (rs72613567:TA) and reduced disease severity has been replicated in a further cohort with histologically proven NAFLD, and in a study of 111,612 individuals from the general Danish population, it was also associated with reduced plasma transaminases, cirrhosis, HCC, and liver-related mortality (Non-Patent Document 4). Interestingly, the protective effect of the LoF 17βHSD13 (rs72613567:TA) variant on plasma transaminase levels appears to be amplified by several important risk factors for liver disease, such as obesity and alcohol consumption, as well as 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 progression to fibrosis and advanced liver disease, but not with fatty liver.

[0006] Based on the genetic validation of 17βHSD13LoF variants that protect against liver disease risk and progression, inhibiting 17βHSD13 activity with small molecule inhibitors may be an effective therapeutic approach for treating liver diseases such as NAFLD (e.g., NASH, liver fibrosis, cirrhosis, and isolated fatty liver), hepatitis, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV), and hepatocellular carcinoma (HCC) in individuals with several important risk factors for liver disease, such as obesity, alcohol consumption, and established genetic risk factors, such as the (rs738409C>G) variant in PNPLA3.

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

[0008] Fifteen 17βHSD (HSD17B) members have been identified in humans. Although the sequence homology between different members is quite low, the overall structure appears to be conserved. 17β-hydroxysteroid dehydrogenases are primarily 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 over 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 estrogen inactivation in numerous peripheral tissues. Mutations in 17βHSD4 are known to cause DBP deficiency, an autosomal recessive disorder of peroxisomal fatty acid β-oxidation that is generally fatal within the first two years of life. Homozygous missense variants in 17βHSD4 have been identified in Perot syndrome, a recessive disorder characterized by ovarian agenesis in women, sensorineural hearing loss in both men and women, and neurological symptoms in some patients (Non-Patent Documents 8 and 9).

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

[0011] The compounds herein may also exhibit advantageous physical properties (e.g., lower lipophilicity, higher aqueous 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. Thus, such compounds may be particularly suitable as therapeutic agents, such as for the treatment of liver disease. [Prior art documents] [Non-patent literature]

[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): [ka] [In the formula, A is, [ka] Selected from; Each R A are independently H, halo, and R X , -OR x and -CN, where each R X is independently C optionally substituted with 1 to 3 F 1~3 alkyl); R B is halo, -CHF2, -CF3, -OCHF2 or -OCF3; X 1 , X 2 and X 3 is selected from NH, O and S, and X 1 , X 2 and X 3 The other two are independently N and CR Y (where each R Y are independently H, -CN, -C(=O)N(R 7 )2 or R XA and 、 R XA is independently C optionally substituted with 1 to 3 F 1~3 alkyl); R 1 and R 2 teeth, (i)R 1 and R 2 together with the N atom to which they are attached form a ring system, where the ring system optionally contains one or more R C Each R is replaced by C are independent, F, R 3 , R 4 , -O(R 4 ), -O(R 5 ), R5 , R 6 , -OH, -CN, oxo and -C(=O)N(R 7A )2 is selected); (ii)R 1 is R 8 and R 4A Selected from R 2 is R 8A and H; or (iii)R 1 is R 5A and R 2 is R 8B is It is something; Each R 3 independently, C 1~4 Alkyl or C 3~6 cycloalkyl, each of which is optionally R 4X , R 5x , -O(R 4X ), -O(R 5X ) and F; Each R 3X independently, C 1~4 Alkyl or C 3~6 cycloalkyl, each of which is optionally substituted with one or more F; Each R 4 and R 4B are independently monocyclic or bicyclic 5- to 9-membered heteroaryl, each of which optionally is 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 substituted with one or more groups independently selected from halo; R 4A is optionally R 4X , -O(R 4X ), R 5X , -O(R 5X ), -OH, -CN, C 1~4Alkoxy, -C(=O)OH, -C(=O)O(C 1~4 alkyl), -C(=O)N(R 7B )2, R 3 and 5-membered monocyclic heteroaryl substituted with one or more groups independently selected from halo; Each R 5 , R 5A and R 5B are independently phenyl, 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 substituted with one or more groups independently selected from halo; Each R 4X are independently monocyclic or bicyclic 5- to 9-membered heteroaryl, each of which optionally is selected from -OH, -CN, C 1~4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B )2, R 3X and substituted with one or more groups independently selected from halo; Each R 5X are independently phenyl, each of which optionally is —OH, —CN, C 1~4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B )2, R 3x and substituted with one or more groups independently selected from halo; R 6 is optionally R 4X , R 5x and C substituted with one or more groups independently selected from F 1~4 is alkoxy; Each R 7 , R 7A , R 7B and R 7C are independently H, C 1~4 Alkyl or C 3~6 is cycloalkyl; R 8 , R 8A , R 8B independently, C 1~4 Alkyl or C 3~6 cycloalkyl, each of which is optionally R 4B , R 5B , F, -OH, -CN, C 1~4 Alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) substituted with one or more groups independently selected from The ring system is a saturated or partially saturated monocyclic, bicyclic or tricyclic 4-13 membered ring containing one N atom and optionally containing one or two additional heteroatoms independently selected from N, O and S; 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.

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

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

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

[0017] 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.

[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, 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 are provided intermediates useful in the synthesis of compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0021] definition In order that this specification may be more readily understood, certain terms are specifically defined below. Further definitions are set forth throughout the detailed description, where appropriate.

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

[0023] In this specification, "C x~y The prefix C used in terms such as "alkyl" x~y (where x and y are integers) indicates the range of the number of carbon atoms present in the group. 1~3 Examples of alkyl groups include methyl, ethyl, n-propyl, and i-propyl. 1~4 Examples of 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 (where X and Y are integers) used in terms such as "X- to Y-membered ring" indicates the range of numbers 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. For the avoidance of doubt, an alkoxy group may be straight or branched chain. Suitable C 1~3 Examples of alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O nPr), and i-propoxy (O i Pr). 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 carbon ring. 3~6 Examples of cycloalkane groups are cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0027] As used herein, the term "cycloalkylidyne" refers to a 1,1-diradical of a cycloalkane. 3~6 An example of a cycloalkylidine is cyclopropylidene (i.e., [ka] ), cyclobutylidene (i.e., [ka] ), cyclopentylidene (i.e., [ka] ) and cyclohexylidene (i.e., [ka] )

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

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

[0030] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic or bicyclic 5- to 9-membered ring containing one or more heteroatoms independently selected from N, O, and S. When a compound of the present disclosure contains two or more heteroaryl groups, the heteroaryl groups can be the same or different. A 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 (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and 1,3,4-triazinyl. The heteroaryl can be a 9-membered bicyclic heteroaryl. When the 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, benzthiazolyl, purinyl, [1,2,4]triazolo[4,3-b]pyridazinyl (e.g., 6-[1,2,4]triazolo[4,3-b]pyridazinyl), and benzo[d]oxazolyl (e.g., 2-benzo[d]oxazolyl).

[0031] Unless otherwise stated, the term "heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring containing one N atom and one further heteroatom selected from N, O, and S atoms. For the avoidance of doubt, the other atoms in the ring are carbon. Examples of suitable heterocycloalkyls include 4-8 membered monocyclic heterocycloalkyls, 8-11 membered spirocyclic bicyclic heterocycloalkyls, 7-10 membered fused bicyclic heterocycloalkyls, and 8-10 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, optionally, one additional heteroatom selected from nitrogen, oxygen, and sulfur. For the avoidance of doubt, the other atoms in the ring are carbon. A preferred 4-membered heterocycloalkyl group is azetidin-1-yl. A preferred 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-oxazocane-4-yl, 1,5-oxazocane-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 optionally one further heteroatom selected from N, O, and S. For the avoidance of doubt, the other atoms in 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]decan-7-yl, 6,9-diazaspiro[4.5]decan-9-yl, 6-oxa-9-azaspiro[4.5]decan-9-yl, and 6-thia-9-azaspiro[4.5]decan-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 "7-10 membered fused bicyclic heterocycloalkyl" refers to a saturated 7-10 membered fused bicyclic ring containing one nitrogen atom and optionally one further heteroatom selected from N, O, and S. For the avoidance of doubt, the other atoms in 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, octahydro-1H-cyclopenta[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 optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, with the remaining atoms of the fused 8- to 10-membered bicyclic heterocycloalkyl being 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]decan-3-yl.

[0036] The term "oxo" refers to an oxygen atom that forms a double bond (ie, =0) with a suitable atom, such as carbon.

[0037] Unless otherwise specified, the term "ring system" refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic 4-13 membered ring containing one N atom and, optionally, one or two additional heteroatoms independently selected from N, O, and S. For the avoidance of doubt, the other atoms in the ring are carbon. If the ring system is bicyclic, it may be spirocyclic, fused, or bridged. Examples of suitable monocyclic ring systems include 4-6 membered heterocycloalkyls. Examples of suitable bicyclic ring systems include 8-11 membered spirocyclic bicyclic heterocycloalkyls, 7-10 membered fused bicyclic heterocycloalkyls, and 8-10 membered bridged bicyclic heterocycloalkyls.

[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 atom or bond of a group may be at any suitable atom of that group, for example, propyl includes prop-1-yl and prop-2-yl.

[0040] For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents within the given group.

[0041] For the avoidance of doubt, the use of a circle within a five-membered ring indicates that the five-membered ring is aromatic. [ka] teeth, [ka] represents an aromatic ring selected from:

[0042] For the avoidance of doubt, the term " [ka] " indicates the point of attachment between different groups. [ka] denotes a 3-hydroxyphenyl group bonded to a different group via the carbon atom meta to the OH substituent.

[0043] For the avoidance of doubt, the use of a bond between a substituent and the center of the ring indicates that the substituent may replace any hydrogen atom directly attached to the ring, regardless of whether that hydrogen atom is attached to a C atom or a N atom. [ka] teeth, [ka] represents a group selected from:

[0044] When any embodiment herein includes a group that is said to be "optionally substituted," a further embodiment includes that embodiment in which said group is unsubstituted.

[0045] For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents within the given group.

[0046] Units, prefixes, and symbols are expressed in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers delimiting 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 those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0048] Reference will now be made to the accompanying drawings to describe embodiments and experiments illustrating the principles of the present disclosure. [Brief explanation of the drawings]

[0049] [Figure 1] FIG. 1 shows a flow diagram for the synthesis of intermediate 1. DETAILED DESCRIPTION OF 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 embodiments, 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 4-13 membered ring containing one N atom and optionally one or two additional heteroatoms independently selected from N, O, and S.

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

[0053] In embodiments, the ring system is an aliphatic monocyclic or bicyclic 5-11 membered ring containing one N atom and optionally one additional heteroatom selected from N, O, and S, wherein the ring system optionally contains one or more R C substituted with ), or a pharmaceutically acceptable salt thereof.

[0054] In embodiments, the ring system is an aliphatic monocyclic or bicyclic 5-8 membered ring containing one N atom and optionally one additional heteroatom selected from N, O, and S, wherein the ring system optionally contains one or more R C substituted with ), or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0059] In embodiments, the ring system may optionally include one or more R C or a pharmaceutically acceptable salt thereof.

[0060] In embodiments, the ring system may optionally include one or more R C or a pharmaceutically acceptable salt thereof.

[0061] In embodiments, the ring system may optionally include one or more R C or a pharmaceutically acceptable salt thereof.

[0062] In embodiments, the ring system may optionally include one or more R C or a pharmaceutically acceptable salt thereof.

[0063] In embodiments, the ring system may optionally include one or more R C or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, the ring system may optionally include one or more R C 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 one or two R C In a further embodiment, the ring system is unsubstituted.

[0065] In embodiments, each R C are independent, F, R 3 , R 4 , -O(R 4 ), -O(R 5 ), R 5 , R 6 , -OH, -CN and -C(=O)N(R 7A In a further embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R is selected from: C are independent, R 3 , R 4 , -O(R 4 ), -O(R 5 ), R 5 and R 6 In a further embodiment, each R C is independently R 3 , R 4 and R 5 In a further embodiment, each R C are independent, R 3 In a further embodiment, each R C is independently C optionally substituted with one or more (e.g., 1 to 3) F. 1~4 In a further embodiment, each R C independently, C 1~4 In a further embodiment, each R C independently, C 1~4 In a further embodiment, each R C is CH3.

[0066] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] (wherein x is selected from 0 to 3, and each R 9 are independent, R 3 , R 4 and R 5 (selected from is a group selected from

[0067] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] (wherein x is selected from 0 to 3, and each R 9 are independent, R 3 , R 4 and R 5 (selected from is a group selected from

[0068] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] (wherein x is selected from 0 to 3, and each R 9 are independent, R 3 , R 4 and R 5 (selected from is a group selected from

[0069] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] (wherein x is selected from 0 to 3, and each R 9 are independent, R 3 , R 4 and R 5 (selected from is.

[0070] In embodiments, the compound of formula (I) has formula (II): [ka] [In the formula, J is selected from O, S, CH, NH, and a covalent bond; G is either absent or, together with the carbon atom to which it is attached, forms a C 3~6 Forms a cycloalkane ring; Z is (i) When G is absent and J is selected from O, S, CH2 and a covalent bond, Z is selected from CH2, CH2CH2 and C 3~6 cycloalkylidynes, (ii) When G is absent and J is NH, Z is CH2, CH2CH2, C 3~6 selected from cycloalkylidine and C(=O), and (iii) G, together with the carbon atom to which it is attached, forms C 3~6 When forming a cycloalkane ring, Z is CH2 It is something; x is selected from 0 to 3; and Each R 9 are independent, R 3 , R 4 and R 5 Select from or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the compound of formula (II) has formula (IIA) or formula (IIB): [ka] [where, X 1 , X 2 , X3 , A., J., R. 9 and x is as defined for compounds of formula (II). is.

[0072] In embodiments, the compound of formula (II) has formula (IIC): [ka] [where, X 1 , X 2 , X 3 , A., J., R. 9 and x is as defined for compounds of formula (II). is a compound of

[0073] In embodiments, the compound of formula (II) has the formula (IID): [ka] [where, X 1 , X 2 , X 3 , A., J., R. 9 and x is as defined for compounds of formula (II), and y is an integer from 1 to 4. is a compound of

[0074] In embodiments, the compound of formula (II) has the formula (IIE): [ka] [where, X 1 , X 2 , X 3 , A., J., R. 9 and x is as defined for compounds of formula (II), and z is an integer from 1 to 4. is a compound of

[0075] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is a group selected from

[0076] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is a group selected from

[0077] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is a group selected from

[0078] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is a group selected from

[0079] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is a group selected from

[0080] In embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is: [ka] is selected from.

[0081] In embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is: [ka] is selected from.

[0082] In embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the ring system is: [ka] is selected from.

[0083] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is R 8 and R 4A Selected from R 2 is R 8A and H.

[0084] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is R 8 and R 2 is R 8A and H.

[0085] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 (For example, R 4x ), R 5B (For example, 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, R8 is optionally R 4B (For example, R 4x ), R 5B (For example, R 5x ), F, -OH, -CN, C 1~4 Alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) C substituted with 1 or 2 groups (e.g., 1 group) independently selected from 1~4 In a further embodiment, R 8 is optionally R 4B (For example, R 4x ) and R 5B (For example, R 5x C substituted with 1 or 2 groups (e.g., 1 group) independently selected from 1~4 In a further embodiment, R 8 is optionally substituted with one or two groups (e.g., one group) independently selected from monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., monocyclic 5- or 6-membered heteroaryl) and phenyl; 1~4 alkyl (e.g., CH), where heteroaryl and phenyl are optionally C 1~4 Alkyl (e.g., CH3), C 3~6 It is substituted with one or more groups (eg, 1 or 2 groups) selected from cycloalkyl (eg, cyclohexyl) and phenyl.

[0086] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is C 1~4 Alkyl or C 3~6 Cycloalkyl (e.g., C 1~4 alkyl), each of which is R 4B (For example, R 4x ), R 5B (For example, R 5x ), F, -OH, -CN, C 1~4 Alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R7C )2. In a further embodiment, R 8 is R 4B (For example, R 4x ), R 5B (For example, R 5x ), F, -OH, -CN, C 1~4 Alkoxy, -C(=O)O(C 1~4 alkyl) and -C(=O)N(R 7C ) C substituted with 1 or 2 groups (e.g., 1 group) independently selected from 1~4 In a further embodiment, R 8 is R 4B (For example, R 4x ) and R 5B (For example, R 5x C substituted with 1 or 2 groups (e.g., 1 group) independently selected from 1~4 In a further embodiment, R 8 is a C substituted with phenyl or monocyclic or bicyclic 5- to 9-membered heteroaryl 1~4 alkyl (e.g., CH), where phenyl or monocyclic or bicyclic 5-9 membered heteroaryl is optionally C 1~4 Alkyl, C 3~6 Cycloalkyl and C 1~4 substituted with one or two groups independently selected from alkoxy

[0087] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 3and halo. In a further embodiment, R 4A is optionally R 4X , R 5X and R 3X In a further embodiment, R is a 5-membered monocyclic heteroaryl substituted with 1 or 2 groups independently selected from 4A is C 1~4 Alkyl, C 3~6 In a further embodiment, R is a 5-membered monocyclic heteroaryl substituted with 1 or 2 groups independently selected from cycloalkyl and phenyl. 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 optionally is C 1~4 Alkyl (e.g., CH3), C 3~6 It is substituted with one or more groups (eg, 1 or 2 groups) selected from cycloalkyl (eg, cyclohexyl) and phenyl.

[0088] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4A teeth, [ka] (In the formula, R 10 is R 3 or R 5x and X 4 and X 5 are independently N or CH. In a further embodiment, X 4 is CH. In a further embodiment, X 5 is CH.

[0089] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 4B are independently and optionally R4X , -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. 4B are independently optionally halo, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In a further embodiment, R is a monocyclic or bicyclic 5-9 membered heteroaryl (e.g., a monocyclic 5- or 6-membered heteroaryl) substituted with one or more (e.g., 1-3) groups independently selected from alkoxy and CN. 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 optionally is C 1~4 Alkyl, C 3~6 It is substituted with one or two groups selected from cycloalkyl and phenyl.

[0090] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8A is C 1~4 In a further embodiment, R 8A is CH3, CH(CH3)2 or C(CH3)3.

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

[0092] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5A is phenyl, optionally -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 optionally -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 optionally -CN, C 1~4 Alkoxy, R 3x and halo. In a further embodiment, R 5A is phenyl optionally substituted with —CN.

[0093] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5B is phenyl, optionally -OH, -CN, C 1~4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B )2, R 3x and halo. In a further embodiment, R 5B is optionally -CN, C 1~4 Alkoxy, R 3x and halo. In a further embodiment, R 5B optionally C 1~4 It is phenyl substituted with alkoxy.

[0094] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8B is C1~4 In a further embodiment, R 8B is CH3, CH(CH3)2 or C(CH3)3.

[0095] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein NR 1 R 2 teeth, [ka] is selected from.

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

[0097] In embodiments, there is provided a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof, wherein A is [ka] (In the formula, R A is as defined above).

[0098] In embodiments, there is provided a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof, wherein A is [ka] (In the formula, R A and R B is as defined above. In a further embodiment, R B is F, Cl, or CF. In a further embodiment, one or more R A is F. In a further embodiment, two or more R A is F. In a further embodiment, each R A is F.

[0099] In embodiments, there is provided a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof, wherein A is [ka] (In the formula, R A is as defined above. In a further embodiment, each R A is independently H, F, or Cl. In a further embodiment, each R A is H or F.

[0100] In embodiments, there is provided a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE), or a pharmaceutically acceptable salt thereof, wherein A is [ka] (In the formula, R E is H or halo).

[0101] In embodiments, the compound of formula (III): [ka] (In the formula, J is selected from O, S, CH, NH, and a covalent bond; x is selected from 0 to 3; Each R 9 are independent, R 3 , R 4 and R 5 selected from; and R E is H or halo) or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the compound of formula (III) has the formula (IIIA), (IIIB) or (IIIC): [ka] (In the formula, X 1 , X 2 , X 3 , R E , R 9 and x are as defined for compounds of formula (III), or a pharmaceutically acceptable salt thereof. 9 independently, C 1~4 In a further embodiment, x is selected from 1, 2 and 3.

[0103] In an embodiment, the compound of formula (III) has the formula (IIID) [ka] (In the formula, X 1 , X 2 , X 3 and R E is as defined for compounds of formula (III), and each R 11 are independently H, R 3 , R 4 and R 5 or a pharmaceutically acceptable salt thereof. In a further embodiment, each R 11 are independently H, R 3 , R 4x or R5x In a further embodiment, each R 11 are independently H, R 3x , R 4x or R 5X In a further embodiment, each R 11 are independently H or R 3x In a further embodiment, each R 11 are independently H or C 1~4 In a further embodiment, each R 11 are independently H or CH3.

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

[0105] In embodiments, X 1 , X 2 and X 3 One of them is O and the other is X 1 , X 2 and X 3 The other two are N and CR Y In a further embodiment, 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, wherein R Y is H.

[0106] In embodiments, X 1 , X 2 and X 3 One of them is S and the other is X 1 , X 2 and X 3 The other two are N and CR YIn a further embodiment, 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, wherein R a is H.

[0107] In embodiments, X 1 , X 2 and X 3 One of them is O and the other is X 1 , X 2 and X 3 and the other two are both N.

[0108] In embodiments, X 1 , X 2 and X 3 One of them is O and the other is X 1 , X 2 and X 3 One of them is N and the other is X 1 , X 2 and X 3 One of them is CR Y In a further embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), wherein R Y is H or —CN.

[0109] In embodiments, X 1 , X 2 and X 3 One of them is S and the other is X 1 , X 2 and X 3and the other two are both N.

[0110] In embodiments, X 1 , X 2 and X 3 One of them is S and the other is X 1 , X 2 and X 3 One of them is N and the other is X 1 , X 2 and X 3 One of them is CR Y In a further embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), wherein R Y is H.

[0111] In embodiments, X 1 , X 2 and X 3 One of them is S and the other is X 1 , X 2 and X 3 The other two are both CR Y In a further embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), wherein: Y is H.

[0112] In an embodiment, (i)X 1 is N and X 2 is O and X 3 is N, (ii) X 1 is N and X 2 is N and X 3 is O; (iii)X1 is CR Y and X 2 is CR Y and X 3 is S; (iv) X 1 is O and X 2 is N and X 3 is CR Y is; (v)X 1 is N and X 2 is O and X 3 is CR Y is; (vi)X 1 is CR Y and X 2 is N and X 3 is O; (vii)X 1 is O and X 2 is N and X 3 is N; (viii)X 1 is N and X 2 is N and X 3 is S; or (ix)X 1 is CR Y and X 2 is S and X 3 is CR Y That is, Provided are compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof.

[0113] In an embodiment, (i)X 1 is N and X 2 is O and 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 2is CR Y and X 3 is S; (iv) X 1 is O and X 2 is N and X 3 is CR Y is; (v)X 1 is N and X 2 is O and X 3 is CR Y is; (vi)X 1 is CR Y and X 2 is N and X 3 is O; (vii)X 1 is O and X 2 is N and 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 is; or (x)X 1 is CR Y and X 2 is N and X 3 is S, Provided are compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof.

[0114] In an embodiment, (i)X 1 is N and X 2 is O and X 3 is N, (ii) X 1 is N and X 2 is N and X 3 is O; (iii)X1 is CH and X 2 is CH and X 3 is S; (iv) X 1 is O and X 2 is N and X 3 is CH; (v)X 1 is N and X 2 is O and X 3 is CH; (vi)X 1 is CH and X 2 is N and X 3 is O; (vii)X 1 is O and X 2 is N and X 3 is N; (viii)X 1 is N and X 2 is N and X 3 is S; or (ix)X 1 is CH and X 2 is S and X 3 is CH, Provided are compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof.

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

[0116] In embodiments, X 1 is N and X 2 is O and X 3 is N; or a pharmaceutically acceptable salt thereof.

[0117] In embodiments, X 1 is N and X 2 is N and X 3is O; or a pharmaceutically acceptable salt thereof.

[0118] In embodiments, X 1 is N and X 2 is N and X 3 is S; or a pharmaceutically acceptable salt thereof.

[0119] In embodiments, X 1 is N and X 2 is O and X 3 is CR Y In a further embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), wherein R Y is H or —CN.

[0120] In embodiments, X 1 is CR Y and X 2 is N and X 3 is O. In a further embodiment, 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, wherein each R Y is H.

[0121] In embodiments, X 1 is CR Y and X 2 is S and X 3 is CR YIn a further embodiment, there is provided a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID), wherein: Y is H.

[0122] In embodiments, the compound of formula (IV): [ka] (x is selected from 0 to 3; (Each R 9 are independent, R 3 , R 4 and R 5 selected from; and R E is H or halo) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0123] In embodiments, the compound of formula (V): [ka] (x is selected from 0 to 3; Each R 9 are independent, R 3 , R 4 and R 5 selected from; and R E is H or halo) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0124] In embodiments, the compound of formula (VI): [ka] (x is selected from 0 to 3; Each R 9 are independent, R 3 , R 4 and R 5selected from; and R E is H or halo) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment, a compound of formula (VII): [ka] (x is selected from 0 to 3; Each R 9 are independent, R 3 , R 4 and R 5 selected from; and R E is H or halo) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0126] In embodiments, each R 9 independently, C 1~4 Alkyl, C 3~6 In a further embodiment, compounds of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) are provided wherein each R is selected from cycloalkyl and phenyl. 9 independently, C 1~4 In a further embodiment, each R 9 is CH3.

[0127] In embodiments, each R 3 independently, C 1~4 Alkyl or C 3~6 cycloalkyl, each of which is optionally R 4X , R 5x , -O(R 4X ), -O(R 5XIn a further 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, wherein each R is substituted with one or more (e.g., 1-3) groups independently selected from 3 are independently and optionally R 4X , R 5x and C substituted with 1 to 3 (e.g., 1 or 2) groups independently selected from 1~4 In a further embodiment, each R 3 independently, C 1~4 alkyl, CF3, CHF2 or CH2F.

[0128] In embodiments, each R 3 But R 3X or a pharmaceutically acceptable salt thereof.

[0129] In embodiments, each R 3X independently, C 1~4 Alkyl or C 3~6

[0023] In a further embodiment, compounds 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, are provided, wherein each R is cycloalkyl, each of which is optionally substituted with one or more (e.g., 1-3) F. In a further embodiment, each R is cycloalkyl, or a pharmaceutically acceptable salt thereof. 3X is independently C optionally substituted with 1 to 3 F 1~4 In a further embodiment, each R 3X independently, C 1~4 alkyl, CF, CHF, or CHF. In further embodiments, each R3X is C 1~4 It is alkyl.

[0130] In embodiments, each R 4 are independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., a 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 3 and halo. 4 are independently optionally halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In a further embodiment, each R is a monocyclic or bicyclic 5-9 membered (e.g., monocyclic 5- or 6-membered heteroaryl) substituted with one or more (e.g., 1-3) groups independently selected from alkoxy and CN. 4 are 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), benzo[d]oxazolyl (such as 2-benzo[d]oxazolyl), each of which optionally includes halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 It is substituted with one or more (eg, 1 to 3) groups independently selected from alkoxy and CN.

[0131] In embodiments, each R 4X are independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., a monocyclic 5- or 6-membered heteroaryl), each of which optionally includes —OH, —CN, C 1~4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B )2, R 3X and halo. 4x are independently optionally halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In a further embodiment, each R is a monocyclic or bicyclic 5- to 9-membered heteroaryl (e.g., a monocyclic 5- or 6-membered heteroaryl) substituted with one or more (e.g., 1-3) groups independently selected from alkoxy and CN. 4x are independently and optionally C 1~4 Tetrazolyl (such as 5-tetrazolyl) substituted with alkyl (eg, CH3).

[0132] In embodiments, R 5 are independently and 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 3and halo. In a further 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, wherein each R is phenyl substituted with one or more (e.g., 1-3) groups independently selected from halo and halo. 5 are independently optionally halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In a further embodiment, each R is phenyl substituted with one or more (e.g., 1 to 3) groups independently selected from alkoxy and CN. 5 is phenyl.

[0133] In embodiments, 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. In a further 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, wherein each R is phenyl substituted with one or more (e.g., 1-3) groups independently selected from halo and halo. 5X are independently optionally halo (e.g., F or Cl), C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 In a further embodiment, each R is phenyl substituted with one or more (e.g., 1 to 3) groups independently selected from alkoxy and CN. 5X is phenyl.

[0134] In embodiments, R 6 is optionally R 4X , R 5xand C substituted with one or more groups (e.g., 1 to 3 groups) independently selected from 1~4 In a further 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, wherein R is alkoxy. 6 is C optionally substituted with one or more (e.g., 1 to 3) F 1~4 In a further embodiment, R 6 is C 1~4 It is an alkoxy.

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

[0136] In an embodiment, A is [ka] and X 3 If N, then X 1 is N, or a pharmaceutically acceptable salt thereof.

[0137] In an embodiment, A is [ka] and X 3 If N, then X 2 is O, or a pharmaceutically acceptable salt thereof.

[0138] In embodiments, provided are compounds of Formula (I), (II) or (IIA), or pharmaceutically acceptable salts thereof, with the proviso that the compound is 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 embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from: (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'-pyrrolidin]-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 embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from: ((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 embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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] Further features are any of the embodiments described herein, provided that any of the specific examples are individually disclaimed. Further features are any of the embodiments described herein, provided that any one or more of the compounds selected from the list of exemplary compounds herein above are individually disclaimed.

[0143] The compounds disclosed herein may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers, diastereoisomers, or stereoisomer-enriched mixtures. Unless otherwise specified, 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, etc.

[0144] Unless stereochemistry is explicitly indicated in a chemical structure or name, the chemical structure or name is intended to encompass all possible stereoisomers, diastereoisomers, conformers, rotamers, and tautomers of the depicted compound. For example, a compound containing a chiral carbon atom is intended to encompass both the (R) and (S) enantiomers, and mixtures of enantiomers, including racemic mixtures; a compound containing two chiral carbon atoms is intended to encompass all enantiomers and diastereoisomers, including (R,R), (S,S), (R,S), and (S,R).

[0145] In embodiments, 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, optionally further comprising a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is present in the composition in an enantiomeric excess (ee%) of ≥ 90% and a diastereomeric excess (de%) of ≥ 90%.

[0146] 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, may be prepared, used or supplied in amorphous, crystalline or semi-crystalline form, and may be used in any suitable form. Any given compound of formula (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), as well as pharmaceutically acceptable salts thereof, may be capable of forming more than one crystalline / polymorphic form, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric hydrates) and / or solvated forms. It will be understood that the present specification encompasses any and all such solid forms of 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, 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, which can be obtained by the methods described in the Examples section below.

[0148] The present specification is intended to include all isotopes of atoms present in the compounds of the present 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. The nitrogen isotopes are: 15 N. Isotopes of fluorine include: 18 F is one example.

[0149] Suitable pharmaceutically acceptable salts of 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 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 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 alkali metal or alkaline earth metal hydroxides or alkoxides (e.g., ethoxides or methoxides). Base addition salts can also be formed using suitable basic organic amines (e.g., choline or meglumine salts).

[0150] Suitable pharmaceutically acceptable salts of 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 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 or organic acid under conditions known to those skilled in the art. Acid addition salts can be formed, for example, using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts may also 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 paratoluenesulfonic acid.

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

[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 an 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 allows the biological activity of the active ingredient and does not contain additional components that are unacceptably toxic to the patient to whom the composition is administered. Such compositions may 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 may be in a form suitable for oral use (e.g., as a tablet, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granule, syrup or elixir) or in a form suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular administration, 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 may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives. 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, is usually present in the composition.

[0155] The 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, may be administered via oral route, parenterally, intravenously, intramuscularly, subcutaneously or other injection methods, buccal, rectal, vaginal, transdermal and / or intranasal routes, and / or by inhalation, usually in a pharmaceutically acceptable dosage form, in the form of a pharmaceutical formulation comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof or a solvate of such a salt. Depending on the disorder and patient to be treated and the route of administration, the compositions may be administered in various dosages.

[0156] Pharmaceutical formulations 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, for example, parenteral, subcutaneous, intramuscular or intravenous administration.

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

[0158] Pharmaceutical formulations 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, emulsifiers, and preservatives. Liquid compositions may be encapsulated, for example, in gelatin, to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules, and soft elastic gelatin (SEG) capsules. An exemplary oral composition would contain a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) and at least one pharmaceutically acceptable excipient, filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0159] As a result of their 17BETAHSD13 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 17BETAHSD13, including liver diseases such as NASH.

[0160] In one aspect herein, 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 herein, 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 treating liver disease. 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 dealing with a disease to alleviate, in whole or in part, one, some, or all of its symptoms, or to correct or rectify the underlying pathology. The term "treatment" also includes "prophylaxis," 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 disease, and secondary prevention, where the disease has already occurred and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0164] The term "treatment" is used synonymously with "therapy." Similarly, the term "treat" can be considered as "applying therapy," as "therapy" is 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 on 17βHSD13.

[0166] 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 treating a disease mediated by 17βHSD13, such as a liver disease (e.g., NASH).

[0167] 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 the treatment of fatty liver disease.

[0168] 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 the treatment of non-alcoholic fatty liver disease (NAFLD), such as isolated fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis or cirrhosis. In a further embodiment, the liver disease is end-stage liver disease.

[0169] 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 the treatment of liver disease, for example NASH, wherein the patient also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0170] 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 the treatment of liver disease, for example NASH, wherein a patient has a liver mass of 27 kg / m 2 ~40kg / m 2 In a further embodiment, the subject has a body mass index (BMI) of 30 kg / m 2 ~39.9kg / m 2 In a further embodiment, the patient has a BMI of at least 40 kg / m 2 In a further embodiment, the patient has a BMI of 0.05 to 0.05. In a further embodiment, the patient is overweight. In a further embodiment, the patient is obese.

[0171] 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 the treatment of liver disease, for example NASH, wherein the patient also suffers from or is susceptible to dyslipidemia.

[0172] 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 the treatment of liver disease, for example NASH, wherein the patient also suffers from or is susceptible to insulin resistance.

[0173] 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 the treatment of liver disease, for example NASH, wherein the patient also has or is susceptible to type 2 diabetes.

[0174] 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 the treatment of liver disease, for example NASH, wherein the patient also suffers from or is susceptible to renal failure.

[0175] 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 treating liver disease, such as NASH, wherein the patient also has or is susceptible to liver fibrosis. In further embodiments, the patient (i) has or is susceptible to liver fibrosis, and (ii) has or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0176] 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 treating liver disease, such as NASH, wherein the patient also has or is prone to have cirrhosis of the liver. In further embodiments, the patient (i) has or is prone to have cirrhosis of the liver, and (ii) has or is prone to have one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0177] In embodiments, provided is 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 treating NAFLD. 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, e.g., "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 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 treating NAFLD, e.g., NASH. In a further embodiment, the patient is obese. In a further embodiment, the patient suffers from alcoholic liver disease. In a further embodiment, the patient has a genetic risk factor for liver disease, e.g., the (rs738409C>G) variant in PNPLA3.

[0179] 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 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 suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0180] 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 the treatment of liver fibrosis. In a further embodiment, the liver fibrosis is stage 3 liver fibrosis. In a further embodiment, the patient also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0181] 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 treating cirrhosis of the liver. In a further embodiment, the cirrhosis is stage F4 cirrhosis. In a further embodiment, the patient also suffers from or is susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal failure.

[0182] 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 treating 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 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 the treatment of hepatocellular carcinoma (HCC).

[0184] 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 the treatment of alcoholic steatohepatitis (ASH).

[0185] 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 the treatment of Hepatitis C Virus (HCV).

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

[0187] In one aspect herein, 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 like "treating" or "treatment" refer to both (1) therapeutic measures that cure, delay, alleviate the symptoms of, and / or halt the progression of, a diagnosed condition or disorder, and (2) prophylactic or preventative measures that prevent and / or slow the progression of the targeted condition or disorder. Thus, those in need of treatment include those already with the disorder, those prone to have the disorder, and those in whom the disorder is to be prevented.

[0189] The term "effective amount" means that amount of active ingredient sufficient to significantly and positively alter the symptoms and / or condition being treated (e.g., provide a positive clinical response). The effective amount of active ingredient to be used in a pharmaceutical composition will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the particular active ingredient used, the particular pharmaceutically acceptable excipients / carriers utilized, and similar factors within the knowledge and expertise of the attending physician.

[0190] The term "patient" refers to any animal (e.g., mammal) that will be 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, there is provided a method of treating a disease 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, wherein the disease is selected from isolated fatty liver, NASH, liver fibrosis and cirrhosis.

[0192] In embodiments, there is provided a method of treating a 17βHSD13 mediated 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.

[0193] The compounds of the present disclosure can be used in the above-described methods as the sole pharmacological agent or in combination with other pharmacological agents or procedures. Such combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. These combination therapies (and corresponding combination products) utilize the compounds of the present disclosure and other pharmacological agents.

[0194] In embodiments, there is provided a combination for use in treating liver disease such as NASH, 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 sodium-glucose transport protein 2 (SGLT2) inhibitor. In a further embodiment, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and remogliflozin.

[0195] In embodiments, there is provided a combination for use in treating a liver disease such as NASH, 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 metformin, or a pharmaceutically acceptable salt thereof.

[0196] In embodiments, there is provided a combination for use in treating liver disease such as NASH, 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 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 embodiments, there is provided a combination for use in treating a liver disease such as NASH, 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 dipeptidyl peptidase 4 (DPP4) inhibitor. In further embodiments, the DPP4 inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.

[0198] In embodiments, there is provided a combination for use in treating liver disease, such as NASH, 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 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 rivoglitazone.In a further embodiment, the PPAR agonist stimulates hepatic expression of FGF21.

[0199] In embodiments, there is provided a combination for use in treating liver disease, such as NASH, comprising a compound of Formula (I), (II), (IIA), (IIB), (IIIC), (IIID), (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 embodiments, there is provided a combination for use in treating liver disease such as NASH, 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 ThrB agonist. In a further embodiment, the ThrB agonist is resmetirom.

[0201] In embodiments, there is provided a combination for use in treating liver disease such as NASH, 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 an FXR agonist. In a further embodiment, the FXR agonist is obeticholic acid.

[0202] The compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) are primarily valuable as therapeutic agents for use in patients, but are also useful in situations where inhibition of 17βHSD13 is required. As such, they are useful as pharmacological benchmarks for use in the development of novel biological tests and in the search for novel pharmacological agents.

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

[0204] Scheme P1 [ka] Compounds of formula (I) may be formed by reacting a carboxylic acid of formula (P1.2) with an amine of formula (P1.3) or a salt thereof (e.g., HCl salt) in a solvent (e.g., DMF, MeCN, EtOAc, or mixtures thereof) in the presence of a coupling reagent (DIC, EDC, COMU, TBTU, or HATU), in the presence of a base (e.g., DIPEA or 2,6-lutidine), optionally at a temperature ranging from 18 to 60°C. Optionally, the reaction may be carried out in the presence of HOBt. Compounds of formula (P1.2) may be formed by hydrolyzing an ester of formula (P1.1) by standard methods. In the case of esters such as Me or Et, hydrolysis may be carried out using a base (e.g., LiOH or NaOH) in a solvent (e.g., HO, MeOH, THF, or mixtures thereof), optionally at a temperature ranging from 18 to 60°C. Acid-labile esters (e.g., t In the case of Bu), this can be done neat or in a solvent (such as DCM or H2O) with an acid (e.g., TFA), optionally at 18°C.

[0205] Compounds of formula (I) may also be represented by formula (P1.1) where R Pis Me or Et) with an amine of formula (P1.3) in a solvent (such as toluene or DMF), optionally in the presence of AlMe3 or DABAL-Me3, optionally at a temperature of 18-70°C (e.g., 50-70°C).

[0206] Scheme P2 [ka] The compound of formula (P2.4) can be prepared by reacting a compound of formula (P2.2) with a compound of formula (P2.3) (wherein R P is Me or Et), optionally in pyridine, optionally at 18-50° C. Compounds of formula (P2.2) may be formed by reacting a nitrile of formula (P2.1) with hydroxylamine (or a salt thereof, such as HCl) in a solvent (e.g., HO, MeOH, or EtOH, or a mixture thereof), optionally at 50-80° C. When a hydroxylammonium salt (e.g., HCl) is used, additional base (e.g., NaHCO) may be added.

[0207] Scheme P3 [ka] Compounds of formula (P3.3) may be formed by reacting compounds of formula (P3.1) and (P3.2) with EDC and a base (e.g., NaHCO), optionally in DMF, optionally at 100° C. Optionally, R P is Me or Et.

[0208] Scheme P4 [ka] Formula (P4.4) (where R PCompounds of formula (P4.3) (wherein NH is Me or Et) may be formed by reacting a compound of formula (P4.3) with a dehydrating reagent (e.g., POCl3, SOCl2 or EDC), either neat or in a solvent (e.g., toluene or DCM), optionally at a temperature in the range of 18-90° C., and optionally in the presence of a base (such as pyridine). Compounds of formula (P4.3) may be formed by reacting a hydrazide of formula (P4.1) with a compound of formula (P4.2) in a solvent (dioxane, THF, DCM, or mixtures thereof), optionally at a temperature in the range of 0-18° C., and optionally in the presence of a base (such as TEA or DIPEA).

[0209] Scheme P5 [ka] A compound of formula (5.1) can be reacted with a compound of formula (P5.2) using a Pd reagent (e.g., XPhos Pd G3) in the presence of HO and a base (e.g., K3PO4) in a solvent such as dioxane, THF, or a mixture thereof, optionally at 60 °C.

[0210] Scheme P6 [ka] Compounds of formula (P6.3) may be formed by reacting a compound of formula (P6.2) with a compound of formula (P6.1). The reaction may be catalyzed by a Pd reagent (e.g., Pd-118) in a solvent (dioxane, THF, EtOH, DMF, or a mixture thereof) in the presence of a base (e.g., CsCO, KCO, or NaCO) and HO, optionally at 60°C. Alternatively, compounds of formula (P6.3) may be formed by reacting a compound of formula (P6.4) with a compound of formula (P6.5) (where LG is optionally Br). The reaction may be catalyzed by a Pd reagent (e.g., Pd-118) in a solvent (such as 1,4-dioxane) in the presence of a base (e.g., KCO) and HO, optionally at a temperature in the range of 50-80°C.

[0211] Scheme P7 [ka] Compounds of formula (P7.3) may be formed by reacting an alkyne of formula (P7.2) with ethyl (Z)-2-chloro-2-(hydroxyimino)acetate in a solvent such as DCM in the presence of a base such as TEA, optionally at a temperature ranging from 18 to 45° C. Compounds of formula (P7.2) may be formed by reacting an aldehyde of formula (P7.1) with dimethyl (1-diazo-2-oxopropyl)phosphonate in a solvent such as MeOH in the presence of a base such as KCO, optionally at room temperature.

[0212] Alternatively, compounds of formula (P7.3) may be formed by reacting a diketone of formula (P7.5) with hydroxylammonium chloride in a solvent such as EtOH, acetic acid, or formic acid, optionally at a temperature in the range of 50-100° C. Diketones of formula (P7.5) may be formed by reacting a methyl ketone of formula (P7.4) with a base such as LiHMDS or NaOEt and diethyl oxalate in a solvent such as THF, optionally at a temperature in the range of 78° C. to 18° C.

[0213] Scheme P8 [ka] Formula (P8.4) (where R P =Et) can be formed by reacting a compound of formula (P8.2) with a compound of formula (P8.3) in a solvent (such as EtOH) in the presence of a base (e.g., TEA), optionally at room temperature. Compounds of formula (P8.2) can be formed by reacting a compound of formula (P8.1) with MeCN and a strong base (e.g., NaH) in a solvent (e.g., THF), optionally at a temperature in the range of 18-50°C.

[0214] Scheme P9 [ka] Formula (P9.4) (where R P is Me or t Compounds of formula (P9.2) can be formed by reacting a compound of formula (P9.3) with OXONE (potassium peroxymonosulfate) in a solvent (e.g., HO or aqueous MeCN) in the presence of KCl, optionally at 0-18°C. Compounds of formula (P9.2) can be formed by reacting an aldehyde of formula (P9.1) with hydroxylamine or a salt thereof (e.g., HCl) in a solvent (e.g., HO, MeOH, or EtOH, or mixtures thereof), optionally at 0-18°C. When a hydroxylammonium salt (e.g., HCl) is used, a further base (e.g., NaOH, NaOAc, or NaCO) may be added.

[0215] Scheme P10 [ka] Formula (P10.4) (where R P Compounds of formula (P10.2) may be formed by reacting a compound of formula (P10.3) with a compound of formula (P10.3) in a solvent such as toluene, optionally at 105-110° C. Compounds of formula (P10.2) may be formed by reacting a primary amide of formula (P10.1) with Lawesson's reagent in a solvent such as THF, optionally at a temperature in the range of 18-65° C.

[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 a different order than that shown herein. It is understood that chiral isomers of the compounds described herein can be resolved at any stage of the synthetic process using chiral resolving agents described in the literature and known to those skilled in the art, or chiral chromatographic methods described in the literature and known to those skilled in the art, or as further described in the Examples.

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

[0218] The present invention is illustrated by the following non-limiting examples, which generally show: (i) Operations are carried out at room temperature (rt), i.e., in the range of 17-28°C, unless otherwise indicated, and, if necessary, under an atmosphere of an inert gas such as N2; (ii) when reference is made to a reaction being degassed or purged, this can be done, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period of 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) If 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) In general, reaction steps were usually followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) coupled to a mass spectrometer (LCMC).

[0219] (v) Where necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4 or passed through a phase separator using an ISOLUTE Phase Separator, and work-up procedures were carried out using conventional phase separation techniques. It is understood that when a drying agent such as MgSO4 or Na2SO4 is used to dry the organic layer, the layer is filtered prior to concentrating the layer.

[0220] (vi) evaporation was performed by rotary evaporation under vacuum or in a Genevac HT-4 / EZ-2 or Biotage V10; (vii) Unless otherwise specified, flash column chromatography was performed on normal-phase silica using Merck Silica Gel (Art. 9385) or prepacked cartridges such as BIOTAGE SNAP cartridges (40-63 μm silica, 4-330 g), BIOTAGE Sfaer Silica HC D cartridges (20 μm, 10-100 g), INTERCHIM PURIFLASH cartridges (25 μm, 4-120 g), INTERCHIM PURIFLASH cartridges (50 μm, 25-330 g), GRACE GRACERESOLV Silica Flash cartridges (4-120 g) or AGELA Flash Column Silica-CS cartridges (80-330 g), or on reverse-phase silica using AGELA TECHNOLOGIES C-18, spherical cartridges (20-35 μm, 100 A, 80-330 g) either manually or automated using a GRACE REVELERIS X2 Flash system or a similar system; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with MS and / or UV-driven fraction collection instruments; Isocratic or gradient mobile phases as described in the experimental section were used and were performed using one of the following methods: Preparative Method A: Compounds were purified by preparative HPLC using a WATERS SUNFIRE C18 ODB column (5 μm, 150 × 19 mm ID) using a gradient of MeCN in HO / FA (0.1 M) as the mobile phase; Preparative Method B: Compounds were purified by preparative HPLC using an XBRIDGE C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / NH4HCO3 (10 mM) as the mobile phase; Preparative Method C: Compounds were purified by preparative HPLC using a KROMASIL C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative Method D: Compounds were purified by preparative HPLC using a KROMASIL C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase. The compounds were purified by preparative HPLC using a C8 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative Method E: The compounds were purified by preparative HPLC using a WATERS SUNFIRE C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / FA (0.1 M) as the mobile phase; Preparative Method F: The compounds were purified by preparative HPLC using a Waters HSS C18 OBD column (5 μm, 100 × 10 mm ID) using a gradient of MeCN in HO / FA (0.1 M) as the mobile phase. Preparative Method G: Compounds were purified by preparative HPLC using a WATERS SUNFIRE C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in HO / FA (0.1 M, pH 3) as the mobile phase; Preparative Method H: Compounds were purified by preparative HPLC using a WATERS XBRIDGE C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in HO / NH3 (0.2%, pH 10) as the mobile phase. Preparative Method I: Compounds were purified by preparative HPLC using a WATERS XSELECT CSH Fluoro Phenyl column (5 μm, 100×10 mm ID) using a gradient of MeCN in HO / FA (0.Preparative Method J: Compounds were purified by preparative HPLC using an XBRIDGE C18 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN / MeCN / NH3 (95 / 5 / 0.2) in HO as the mobile phase; Preparative Method K: Compounds were purified by preparative HPLC using an XBRIDGE Prep OBD C18 column (5 μm, 30 × 150 mm) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase. Preparative method L: Compounds were purified by preparative HPLC using a YMC-ACTUS TRIART C18 column (5 μm, 30 × 250 mm) using a gradient of MeCN in HO / NH3 (0.05%) as the mobile phase; Preparative method M: Compounds were purified by preparative HPLC using a WATERS XSELECT CSH Fluoro Phenyl column (5 μm, 100 × 10 mm ID) using a gradient of MeCN in HO / TFA (0.05%) as the mobile phase; Preparative method N: Compounds were purified by preparative HPLC using a WATERS XSELECT CSH OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / FA (0.1%) as the mobile phase; Preparative method O: Compounds were purified by preparative HPLC using a YMC-Actus Triart C18 ExRS column (5 μm, 30 × 150 mm ID) using a gradient of MeCN in HO / TFA (0.1%) as the mobile phase. Preparative method P: Compounds were purified by preparative HPLC using an XBRIDGE C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) + 0.1% NH4OH as the mobile phase; Preparative method Q: Compounds were purified by preparative HPLC using a WATERS SUNFIRE C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (0.Preparative Method R: Compounds were purified by preparative HPLC using an XBRIDGE SHIELD RP18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in HO / NHHCO (10 mM) as the mobile phase; Preparative Method S: Compounds were purified by preparative SFC using a Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) using a gradient of MeOH / NH (20 mM) in CO as the mobile phase; Preparative Method T: Compounds were purified by preparative HPLC using a WATERS XSELECT CSH OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in HHO / FA (0.1 M) as the mobile phase; Preparative Method U: Compounds were purified by preparative SFC using a PHENOMENEX Luna Preparative Method V: Compounds were purified by preparative SFC using a Hilic column (5 μm, 250×30 mm ID) using EtOH / FA (20 mM) in CO as the mobile phase; Preparative Method V: Compounds were purified by preparative HPLC using a Waters Xselect CSH OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in HO / FA (0.1 M) as the mobile phase; Preparative Method X: Compounds were purified by preparative HPLC using an XBridge™ C18 OBD column (5 μm, 250×30 mm ID) using a gradient of MeCN in HO / NH4HCO3 (10 mM) + 0.1% NH4OH as the mobile phase; Preparative Method Y: Compounds were purified by preparative HPLC using an XBridge™ C18 Preparative HPLC was performed using an OBD column (5 μm, 150×30 mm ID) with a gradient of MeCN in HO / NHHCO (10 mM) + 0.1% NHOH as the mobile phase; Preparative Method Z: Compounds were purified by preparative HPLC using an XBridge™ C18 ODB column (5 μm, 150×30 mm ID) with a gradient of MeCN in HO / AcOH (0.1%) as the mobile phase. SFC Preparative Methods: Preparative Method SFC-A: Compounds were purified by preparative SFC using a Waters™ BEH (5 μm, 250×30 mm ID) with MeOH / HO (NHHCO 50 mM) (97 / 3) in CO as the mobile phase.

[0221] In some instances, the compound may 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 give 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 Na2SO4 or using a phase separator and then concentrated under reduced pressure to give the purified compound.

[0223] (ix) Chiral preparative chromatography was performed using HPLC or SFC using standard HPLC or SFC equipment, respectively, and using isocratic or gradient run mobile phases as described below; (x) the yield, if any, is not necessarily the maximum achievable, and if necessary, the reaction may be repeated if more reaction product is required; (xi) When a particular compound is obtained as an acid addition salt, e.g., a monohydrochloride or dihydrochloride salt, the stoichiometry of the salt is based on the number and nature of basic groups in the compound, and the exact stoichiometry of the salt is generally not determined by, e.g., elemental analysis data; (xii) In general, 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 300, 400, 500 and 600 MHz, respectively. 1Measurements were made on a BRUKER AVANCE III 300, 400, 500, and 600 spectrometer operating at H frequencies on a delta scale. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as the internal standard. Protons on heteroatoms, such as NH and OH protons, may be unlisted because they are reported only when detected in NMR. In certain instances, protons may be hidden or partially hidden by solvent peaks and therefore are unlisted, unreported, or reported as solvent-overlapping multiplets. The following abbreviations (and their derivatives, e.g., dd, doublet of doublet, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, quintet. In some instances, the structure of the final product of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peak of the major rotamer is reported. In certain instances, the structures of intermediates and / or final products of Formula (I) may appear as rotamers in NMR spectra; in such cases, peaks for all rotamers are reported, with only the total number of protons reported. The ratio of major to minor rotamers is reported when known. Electrospray mass spectral data was obtained using a WATERS ACQUITY UPLC coupled to a WATERS single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, with generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data was obtained using a WATERS XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, with generally only ions associated with the parent structure being reported; (xiii) intermediates were not necessarily completely purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xv) In general, examples and intermediate compounds are named using CHEMDRAW PROFESSIONAL version 20.1.1.125 from PerkinElmer. CHEMDRAW PROFESSIONAL version 20.1.1.125 generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules of stereochemistry and adheres as closely as possible to IUPAC rules when generating chemical names. Stereoisomers differ from each other in the stereodesignators referenced in the names and are assigned according to the CIP rules. The prefix "rac-" indicates that the compound is racemic.

[0224] (xvi) In addition to those previously mentioned, the following abbreviations and units have been used: AcOH acetic acid Aq water-based Boc tert-butyloxycarbonyl tBuOH tert-butanol Brine Saturated sodium chloride solution Calcd calculation CBz benzyloxycarbonyl COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (CAS Registry Number 1075198-30-9) 18-Crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane DABAL-Me3CAS Registration Number 137203-34-0 DCM dichloromethane DEAD Diethyl azodicarboxylate DIC Diisopropylmethanediimine DIPEA N-ethyl-N-isopropyl-propan-2-amine DMAP N,N-dimethylpyridin-4-amine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPA Diphenylphosphorazine EDC 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine ESI electrospray ionization Et2O 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 Me3Al 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 Carbon PPh3 Triphenylphosphane sat saturation SFC Supercritical Fluid Chromatography TBTU 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography UPLC Ultra High Performance Liquid Chromatography UV ultraviolet light 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 [ka] 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 (28.6 g, 340.60 mmol) in DMF (150 mL) under a N (g) atmosphere. The resulting solution was stirred at 100 °C for 1 h. The reaction mixture was filtered through CELITE, and the filtrate was concentrated, diluted with DCM (300 mL), and washed with water (300 mL). The organic layer was dried over Na SO , filtered, and evaporated. The crude product was purified by flash chromatography on a C18 column (gradient 50-60% MeCN / water (FA)) to give the title compound (7.0 g, 21%) as a white solid; MS (ESI) m / z [M+H] + 289; 1H NMR(300MHz,DMSO-d6)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 (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 approximately 4 L below 50 °C, and then toluene (14.5 L) was added. This process of concentration and toluene addition was repeated twice, after which toluene (14.5 L) was added to the resulting mixture, which was then concentrated to approximately 3 L below 50 °C to give 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 h and then heated to 55-65 °C. The mixture was then heated to 140 °C for a residence time of 45 min under flow (see Figure 1). After heating, the reaction mixture was quenched under flow with a mixture of EtOH (1.4 L) and water (1.4 L) preheated to 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) over 6 h at 5-15 °C. EtOAc (14 L) was added, and the mixture was stirred at 20-30 °C for 2 h. The organic layer was then separated, and the aqueous layer was extracted with EtOAc (14 L). The combined organic layers were then concentrated under vacuum at 35-45°C, followed by the addition of EtOH (14 L). This process of concentration and EtOH addition was repeated, after which the mixture was concentrated under vacuum at 35-45°C. The mixture was then 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, rinsed with water (2.8 L) and n-heptane (4.2 L), and the resulting filter cake was stirred at 30-40°C for 16 hours to afford 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 over two steps).

[0227] Intermediate 2: 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid [ka] LiOH (0.482 g, 20.13 mmol) dissolved in water (10 mL) was added to ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 1 (1.45 g, 5.03 mmol) in THF (10 mL) at 20° C. The solution was stirred at room temperature for 2 hours and then at 60° C. for 1 hour. The THF was evaporated, and the aqueous layer was cooled to 0° C., acidified with 1 M HCl, and then lyophilized overnight. The white solid was dissolved in EtOAc and washed with a small amount of 1 M HCl. The organic layer was passed through a phase separator and concentrated to give the title compound (1.08 g, 83%) as a white-beige solid; MS m / z (ESI) [MH] - 259.0; 1 H NMR(500MHz,DMSO-d6)δ 6.93-7.21(1H,m),10.60(1H,s).

[0228] Intermediate 3: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone [ka] 5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid intermediate 23 (22 mg, 0.08 mmol), NaHCO (20 mg, 0.24 mmol), HOBt (17 mg, 0.09 mmol), and EDC (25 mg, 0.13 mmol) were dissolved in DMF (0.4 mL) in a vial and stirred for 5 min. A solution of (R)-3-phenylpyrrolidine HCl (14 mg, 0.08 mmol) in DMF (0.4 mL) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with sat. NHCl (aq., 2 mL), and the mixture was extracted with DCM (×3). The combined organic layers were washed with 1 M KHSO and brine, passed through a phase separator, and concentrated. The crude product was purified by flash chromatography on silica (gradient: 10-50% EtOAc / heptane) to give the title compound (17 g, 53%) as a yellow solid; MS (ESI) m / z [M+H] + 418.1.

[0229] Intermediate 4: (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycinate ethyl ester [ka] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (600 g, 3.0 mol) and ethyl benzylglycinate (600 g, 3.0 mol) in 5 L of DCM was added TEA (597 g, 6.0 mol) and TBTU (1043 g, 3.3 mol). The solution was stirred overnight at room temperature and then diluted with 10% HCl (1 L). The organic layer was separated, washed with sat. NaHCO (1 L) and brine (1 L), and dried over MgSO. The crude product was purified by flash chromatography on silica (0–10% EtOAc / PE) to give the title compound (1005 g, 90%) as a yellow liquid; MS (ESI) m / z [M+H] + 401.1.

[0230] Intermediate 5: (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycinate ethyl [ka] The reaction was carried out in three parallel reactions. To a 2 L solution of (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)ethyl glycinate intermediate 4 (357 g, 0.94 mol) in anhydrous THF, BH (10 M, 240 mL) was added dropwise within 2 h at 0 °C under a N (g) atmosphere. The reaction mixture was stirred overnight at 35 °C. The reaction was quenched with MeOH (100 mL) and water (500 mL), and the mixture was extracted with DCM (3 × 500 mL). The combined organic layers were dried over MgSO and evaporated in vacuo. The crude product was purified by flash chromatography on silica (gradient: 0-5% EtOAc / PE) to give the title compound (110 g, 32%) as a yellow liquid; MS (ESI) m / z [M+H] + 365.1.

[0231] Intermediate 6: (S)-4-benzyl-6-ethylpiperazin-2-one [ka] To a solution of (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)ethyl glycinate intermediate 5 (300 g, 0.82 mol) dissolved in dry DCM (500 mL) was added TFA (500 mL) dropwise at 0 °C. The solution was stirred at 20 °C for 10 h. The solvent was removed, sat. Na2CO3 (500 mL) was added, and the solution was stirred for an additional 10 h. The mixture was extracted with DCM (3 x 200 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to give the title compound (144 g, 80%) as a pale yellow solid; MS (ESI) m / z [M+H] + 218.9.

[0232] Intermediate 7: (S)-6-ethylpiperazin-2-one [ka] To a solution of (S)-4-benzyl-6-ethylpiperazin-2-one intermediate 6 (87 g, 0.4 mol) in MeOH was added Pd / C (17 g, 16 mmol). The mixture was stirred at 50 °C under H2(g) (50 Psi) for 2 days. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (42 g, 82%) as a white solid; MS (ESI) m / z [M+H] + 129.1.

[0233] Intermediate 8: 4-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-ol [ka] A solution of 1,6-dioxaspiro[2.5]octane (100 g, 0.877 mol) and 2-aminomethan-1-ol (64 g, 1.05 mol) in dry EtOH (1 L) was stirred at 50° C. for 14 h. The mixture was concentrated in vacuo to give the title compound (110 g, 92%); MS (ESI) m / z [M+H] + 176.

[0234] Intermediate 9: (2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzylcarbamate [ka] To the crude 4-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-ol intermediate 8 (180 g, 1.02 mol) and TEA (203 g, 2.01 mol) in dry DCM (2 L) was added benzyl carbonochloridate (183 g, 1.07 mol) dropwise at 0° C. After the addition, the reaction was stirred at 25° C. for 3 h. The reaction mixture was concentrated and purified by flash chromatography (PE:EtOAc, 2:1) to give the title compound (280 g, 88%); MS (ESI) m / z [M+Na] + I got 332.

[0235] Intermediate 10: Benzyl 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylate [ka] The crude (2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzyl carbamate intermediate 9 (140 g, 0.45 mol) and PPh3 (140 g, 0.53 mol) were dissolved in dry THF (1800 mL) under N2 (g) atmosphere, and the mixture was stirred at 25 °C. A solution of DEAD (94 g, 0.53 mol) in dry THF (200 mL) was added dropwise, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated and purified by flash column chromatography (PE: EtOAc, 3:1) to give the title compound (100 g, 76%). 1 H NMR(CDCl3,400MHz)7.29-7.33(m,5H);5.11-5.12(m,2H);4.08-4.16(m,6H),3.47(br s,2H);3.33(br s,2H);2.01-2.02(d,2H);1.71-1.74(m,2H).

[0236] Intermediate 11: 1,9-Dioxa-4-azaspiro[5.5]undecane [ka] 1,9-Dioxa-4-azaspiro[5.5]undecane-4-carboxylate benzyl intermediate 10 (60 g, 210 mmol) and Pd / C (10 g) in THF (1 L) were stirred under H2(g) (40 psi) at 25 °C for 12 h. The suspension was filtered, and the filtrate was concentrated to dryness to give the crude product. EtOAc / HCl (100 mL) was added, and the mixture was stirred at room temperature for 2 h. The solid was filtered off and dried under vacuum to give the title compound (22.5 g, 58%) as the HCl salt; MS (ESI) m / z [M+H] + 158.

[0237] Intermediate 12: tert-butyl 4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate [ka] 5-Bromo-2-chloropyridine (8.36 g, 43.42 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (10 g, 43.42 mmol), KOH (4.87 g, 86.84 mmol), and 18-crown-6 (0.459 g, 1.74 mmol) were dissolved in toluene (150 mL) and heated to reflux for 4 h. The reaction mixture was cooled and 80% of the solvent was evaporated. The reaction was quenched with water (100 mL) and extracted with EtO (3 × 100 mL). The organic layer was dried over MgSO, filtered, and evaporated to give a yellow liquid. The crude gum was triturated with EtO and then evaporated to give the title compound (16.45 g, 98%) as an off-white solid; MS (ESI) m / z [M+H] + 388.0.

[0238] Intermediate 13: 1-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine [ka] tert-Butyl 4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate Intermediate 12 (16.6 g, 42.97 mmol) and 6.0 M HCl in propan-2-ol (91 mL, 3.00 mol) were stirred at 25 °C overnight to give a white solid. EtO (50 mL) was added to the reaction mixture, and the precipitate was collected by filtration, washed with EtO, and dried under vacuum to give the title compound (15 g, 97%) as a white solid; MS (ESI) m / z [M+H] + 287.9.

[0239] Intermediate 14: 2,4,5-trifluoro-N,3-dimethoxy-N-methylbenzamide [ka] To 2,4,5-trifluoro-3-methoxybenzoic acid (1 g, 4.85 mmol) and HATU (2.214 g, 5.82 mmol) in DMF (14 mL) was added DIPEA (2.54 mL, 14.55 mmol) and N,O-dimethylhydroxylamine HCl (0.6 g, 6.15 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1 M HCl (aq), 1 M NaHCO3 (aq), water, and brine. The organic phase was separated using a phase separator and then concentrated. The crude oil was purified by flash chromatography on silica (gradient: 30-70% EtOAc / heptane) to give the title compound (1.03 g, 85%) as a pale yellow oil; MS (ESI) m / z [M+H] + 250.1.

[0240] Intermediate 15: 1-(2,4,5-trifluoro-3-methoxyphenyl)ethan-1-one [ka] MeMgBr (3.4 M, 5.31 mL, 18.06 mmol) in THF was added dropwise to 2,4,5-trifluoro-N,3-dimethoxy-N-methylbenzamide intermediate 14 (0.9 g, 3.61 mmol) in THF (12 mL) under N2(g) at 0°C. The solution was stirred at room temperature for 1 h. The reaction was quenched by pouring into ice-cold 1 M HCl (aq, 15 mL) and THF (10 mL). The mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and evaporated to give the crude title compound (0.736 g, 100%) as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ 2.63 (3H, d), 4.07 (3H, t), 7.38-7.47 (1H, m).

[0241] Intermediate 16: Ethyl 2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoate [ka] LiHMDS (1 M, 4 mL, 4.00 mmol) in toluene was added to 1-(2,4,5-trifluoro-3-methoxyphenyl)ethan-1-one intermediate 15 (0.736 g, 3.61 mmol) in THF (10 mL) and cooled to 20 °C under a N2(g) atmosphere. The mixture was stirred at -20 °C for 40 min. Diethyl oxalate (0.5 mL, 3.68 mmol) was added, and the solution was stirred at room temperature for 40 min. The reaction was quenched by adding 1 M HCl (aq, 15 mL) followed by EtOAc. The phases were separated, and the organic layer was washed with water and then concentrated to give a yellow solid. The crude residue was purified by flash chromatography on silica (gradient: 30-50% EtOAc (containing 1% AcOH) / heptane) to give the title compound (0.924 g, 84%) as a beige solid; MS (ESI) m / z [M+H] + 305.0.

[0242] Intermediate 17: Ethyl 5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate [ka] Ethyl 2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoate intermediate 16 (0.924 g, 3.04 mmol) was dissolved in EtOH (99%, 10 mL) and hydroxylamine HCl (0.488 g, 7.02 mmol) was added. The yellow solution was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed once with 1 M HCl (aq) and once with water. The phases were separated using a phase separator, and the organic layer was concentrated. The crude product was purified by flash chromatography on silica (gradient: 20-40% EtOAc / heptane) to give the title compound (0.585 g, 64%) as a white solid; MS (ESI) m / z [M+H] + 302.0.

[0243] Intermediate 18: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone [ka] (2R,6S)-2,6-Dimethylmorpholine (0.102 g, 0.89 mmol) was dissolved in dry toluene (1 mL), and MeAl in toluene (2 M, 0.830 mL, 1.66 mmol) was added dropwise at room temperature under a N2(g) atmosphere. The resulting clear solution was stirred at room temperature for 45 minutes. To a stirred solution of ethyl 5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate intermediate 17 (0.2 g, 0.66 mmol) in toluene (1.3 mL) was added dropwise at room temperature under a N2(g) atmosphere. The solution was heated to 60 °C for 20 hours. Tartaric acid (30%, aq, 5 mL) was added dropwise until two clear phases appeared. The mixture was extracted with EtOAc. The phases were separated. The aqueous phase was extracted again with EtOAc. The organic layers were combined and concentrated. The residue was purified by preparative HPLC, Prep Method D, (gradient: 15-65%) to give the title compound (143 mg, 58%) as a yellow oil that solidified upon standing; MS (ESI) m / z [M+H] + 371.2.

[0244] Intermediate 19: 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazinyl)-2-oxoacetate methyl ester [ka] Methyl 2-chloro-2-oxoacetate (5.60 mL, 60.8 mmol) was added dropwise to 4-fluoro-3-hydroxybenzohydrazide (WO 2009105214) (6.9 g, 40.55 mmol) in 1,4-dioxane (200 mL) and THF (200 mL) under a N2(g) atmosphere at 5 °C. The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was removed under reduced pressure to give the title compound (10.20 g, 98%) as a white solid; MS (ESI) m / z [M+H] + 257.

[0245] Intermediate 20: 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate methyl ester [ka] A mixture of 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazinyl)-2-oxoacetate methyl intermediate 19 (10 g, 39.03 mmol) in POCl3 (150 mL) was stirred at 90 °C for 1 h. The solvent was removed under reduced pressure, and water was added to the residue. The precipitate was collected by filtration, washed with water (20 mL), and dried under vacuum to give the title compound (6.40 g, 69%) as a light brown solid; MS (ESI) m / z [M+H] + 239.

[0246] Intermediate 21: 1,2,4-trifluoro-5-iodo-3-methoxybenzene [ka] An oven-dried 20 mL microwave vial was charged with 2,4,5-trifluoro-3-methoxybenzoic acid (0.5 g, 2.43 mmol), KPO (0.515 g, 2.43 mmol), iodine (2.463 g, 9.70 mmol), and a stir bar. The vial was stoppered, evacuated, and backfilled with N. 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% NaSO(aq) was added until the dark color disappeared. A second batch was prepared as above, and the reaction mixtures were combined and extracted with DCM (x3). The combined organic layers were washed with 8% NaCO(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 give the title compound (0.841 g, 60%) as a nearly colorless oil; MS (ESI) m / z [M+H] + 288.0.

[0247] Intermediate 22: tert-Butyl 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate [ka] A 20 mL microwave vial was charged with 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), 2 M KCO(aq) (2.12 mL, 4.24 mmol), and a stir bar. The vial was stoppered, evacuated, and refilled with N(g) (×3), then heated at 80 °C for 1.5 h. EtOAc and water were added, and the mixture was washed with 8% NaHCO(aq). The aqueous layer was extracted with EtOAc, and the combined organic layers were passed through a phase separator and concentrated. The residue was purified by normal-phase flash chromatography on silica (gradient: 0 to 30% EtOAc / heptane). Fractions containing the title compound were pooled and concentrated, and the residue was dissolved in MTBE (approximately 10 mL) and treated with SILIAMETS thiol (1 g, loading: 1.4 mmol / g) at 40° C. for 30 minutes. 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 give the title compound (176 mg, 36%); 1 H NMR (500MHz, CDCl3) 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 [ka] TFA (0.5 mL) was added to a solution of tert-butyl 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate (167 mg, 0.48 mmol) in DCM (1 mL), and the solution was stirred at room temperature for 1.5 h, during which time a precipitate formed. The volatiles were removed in vacuo, and the crude product was further azeotroped with MeCN (×3) to give the title compound (137 mg, 98%) as an off-white solid; MS m / z (ESI) [MH]- 287.1.

[0249] Intermediate 24: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone [ka] 5-(2,4,5-Trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid intermediate 23 (130 mg, 0.45 mmol) and DIPEA (0.236 mL, 1.35 mmol) were dissolved in a mixture of MeCN (3 mL) and EtOAc (3 mL) and stirred. HATU (206 mg, 0.54 mmol) was added, and the resulting solution was stirred at room temperature for 2–3 min. (2R,6S)-2,6-Dimethylmorpholine (0.074 mL, 0.59 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was diluted with EtOAc and washed sequentially with saturated Na2CO3 (aq) and water. The organic layer was passed through a phase separator and concentrated. The residue was purified by preparative HPLC, Preparative Method F (gradient: 40–85%). Fractions containing the title compound were pooled and concentrated to near dryness, then partitioned between DCM and water using a phase separator. The organic layer was concentrated to give the title compound (145 mg, 83%) as a solid; MS m / z (ESI) [M+H] + 386.2.

[0250] Intermediate 25: tert-butyl (1-cyclohexyl-1H-pyrazol-5-yl)carbamate [ka] To a stirred solution of 1-cyclohexyl-1H-pyrazole-5-carboxylic acid (800 mg, 4.12 mmol) in t-BuOH (10 mL), DPPA (2267 mg, 8.24 mmol) was added slowly at 15 °C, followed by TEA (2296 μL, 16.47 mmol). The resulting solution was stirred at 80 °C under a N2(g) atmosphere for 16 h. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 6-59% MeCN / water) followed by preparative HPLC, Prep Method Q (gradient: 48-60%), to give the title compound (0.352 g, 32%) as a white solid; MS m / z (ESI) [M+H] + 266.

[0251] Intermediate 26: tert-butyl (1-cyclohexyl-1H-pyrazol-5-yl)(methyl)carbamate [ka] NaH (60%, 249 mg, 6.22 mmol) was added to tert-butyl (1-cyclohexyl-1H-pyrazol-5-yl)carbamate Intermediate 25 (330 mg, 1.24 mmol) in DMF (4 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. MeI (0.101 mL, 1.62 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched by adding cooled 2 M NH4Cl (aq, 30 mL, 60 mmol) at 10 °C. The reaction mixture was concentrated, diluted with EtOAc (50 mL), and then washed with sat. NH4Cl (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (0.340 g, 98%) as a yellow solid; 1 H NMR(300MHz,DMSO-d6)δ 1.11-1.45(11H,m),1.61-1.88(7H,m),3.05(3H,s),3.46-3.63(1H,m),3.72-3.84(1H,m),6.09(1H,d),7.40(1H,d).

[0252] Intermediate 27: 1-Cyclohexyl-N-methyl-1H-pyrazol-5-amine [ka] 4M HCl in 1,4-dioxane (3 mL, 12 mmol) was added to tert-butyl 1-cyclohexyl-1H-pyrazol-5-yl)(methyl)carbamate Intermediate 26 (340 mg, 1.22 mmol) in 1,4-dioxane (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 5 hours. The solvent was removed under reduced pressure to give the title compound (0.250 mg, 95%) as a yellow oil; MS m / z (ESI) [M+H] + 180.

[0253] Intermediate 28: tert-butyl 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate [ka] Tert-Butyl propionate (373 mg, 2.96 mmol) was added to 4-fluoro-3-methoxybenzaldehyde oxime (200 mg, 1.18 mmol), KCl (88 mg, 1.18 mmol), and OXONE (1090 mg, 1.77 mmol) in MeCN (2 mL) and HO (2 mL) cooled to 0 °C. The temperature was allowed to reach room temperature, and the resulting suspension was stirred at 10 °C for 15 h. The reaction mixture was filtered through CELITE. This process was repeated 17 times using a total of 21.4 mmol of 4-fluoro-3-methoxybenzaldehyde oxime. The combined filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 16–63% MeCN / HO) to give the title compound (0.397 g, 6%) as a light brown solid; MS m / z (ESI) [M+H] + 294.

[0254] Intermediate 29: 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid [ka] TFA (5 mL, 64.90 mmol) was added to tert-butyl 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate Intermediate 28 (390 mg, 1.33 mmol) in DCM (10 mL) at 15° C. The resulting solution was stirred at 15° C. for 2.5 h. The solvent was removed under reduced pressure to give the title compound (0.325 g, 99%) as a beige solid; MS m / z (ESI) [M+H] + 238.

[0255] Intermediate 30: N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamide [ka] DIC (215 μL, 1.38 mmol) was added to a stirred solution of 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid intermediate 29 (170 mg, 0.69 mmol), TFA (170 mg, 0.69 mmol), and 1-cyclohexyl-N-methyl-1H-pyrazol-5-amine intermediate 27 (148 mg, 0.83 mmol) in DMF (2 mL) at 15° C. The resulting solution was stirred at 80° C. for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated brine (10×20 mL), dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:2) followed by reverse-phase flash chromatography on a C18 column (gradient: 0-69% MeCN / water) to give the title compound (0.109 g, 40%) as a colorless oil (solidified upon standing); MS m / z (ESI) [M+H] + 399.

[0256] Intermediate 31: (3-(4-fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone [ka] DIPEA (255 μl, 1.46 mmol) was added to 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid intermediate 29 (120 mg, 0.49 mmol), 3-phenylpyrrolidine (86 mg, 0.58 mmol), and HATU (370 mg, 0.97 mmol) in DMF (2.5 mL) at 15° C. The resulting solution was stirred at 15° C. for 2 h. The reaction mixture was diluted with sat. NaHCO (aq, 20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed sequentially with sat. brine (5×20 mL) and water (20 mL). The organic layers were dried over NaSO, filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:PE, 1:1) to give the title compound (0.119 g, 67%) as a beige solid; MS m / z (ESI) [M+H] + 367.

[0257] Intermediate 32: Ethyl 4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate [ka] LiHMDS (1M, 14.27 ml, 14.27 mmol) in THF was added dropwise to 1-(4-fluoro-3-hydroxyphenyl)ethan-1-one (1.0 g, 6.49 mmol) in THF (15 mL) at −20° C., and the reaction mixture was stirred at −20° C. for 1 hour. Diethyl oxalate (2.84 g, 19.46 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding 2 M HCl (10 mL), and the reaction mixture was diluted with EtOAc (150 ml) and washed with 2 M HCl (2×50 ml). The organic layer was dried over Na SO , filtered, and evaporated to give the title compound (1.50 g, 91%) as a solid. 1 H NMR(300MHz, CDCl3)δ 15.17(s,1H),7.70(dd,1H),7.58(ddd,1H),7.22(dd,1H),7.04(s,1H),5.56(s,1H),4.43(q,2H),1.44(t,3H).

[0258] Intermediate 33: Ethyl 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate [ka] A mixture of hydroxylamine HCl (274 mg, 3.94 mmol) and ethyl 4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate Intermediate 32 (500 mg, 1.97 mmol) in AcOH (20 mL) was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (50 mL) and washed with sat. NaHCO (2 × 20 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was washed with EtO (50 mL) and dried to give the title compound (0.150 g, 30%) as a light brown solid; MS m / z (ESI) [M+H] + 252.

[0259] Intermediate 34: 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid [ka] A solution of NaOH (191 mg, 4.78 mmol) in water (2 mL) was added to ethyl 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate intermediate 33 (400 mg, 1.59 mmol) in EtOH (2 mL). The reaction mixture was vigorously stirred at 50° C. for 4 hours. The reaction mixture was adjusted to pH 2 with 0.1 M HCl. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase flash chromatography on a C18 column (gradient 0-40% MeCN / water containing 0.1% FA) to give the title compound (0.280 g, 79%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 7.23-7.35 (m, 2H), 7.39 (ddd, 1H), 7.48 (dd, 1H), 10.44 (s, 1H).

[0260] Intermediate 35: 3-ethynyl-2,5,6-trifluorophenol [ka] Dimethyl (1-diazo-2-oxopropyl)phosphonate (2.62 g, 13.63 mmol) was added to 2,4,5-trifluoro-3-hydroxybenzaldehyde (1.6 g, 9.09 mmol) and K2CO3 (3.77 g, 27.26 mmol) in MeOH (20 mL) at 20 °C, and the resulting solution was stirred at 20 °C for 4 h. The reaction mixture was filtered through CELITE, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM, 1:15) to give the title compound (0.450 g, 29%) as a yellow oil; MS m / z (ESI) [M+H] - 171.

[0261] Intermediate 36: Ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate [ka] TEA (1215 μL, 8.72 mmol) was added to 3-ethynyl-2,5,6-trifluorophenol intermediate 35 (300 mg, 1.74 mmol) and ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (1.32 g, 8.72 mmol) in DCM (5 mL) at 20° C., and the resulting solution was stirred at 45° C. for 70 h. The reaction mixture was concentrated, diluted with EtOAc (25 mL), and washed with water (25 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:15) to give the title compound (0.300 g, 60%) as a raw solid. 1 H NMR (300MHz, DMSO-d6) δ 1.13-1.30 (m, 3H), 4.23-4.40 (m, 2H), 7.27 (d, 1H), 7.57 (m, 1H), 11.48 (s, 1H). ;

[0262] Intermediate 37: 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid [ka] LiOH (117 mg, 4.87 mmol) was added to ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate intermediate 36 (280 mg, 0.97 mmol) in a mixture of EtOH (3 mL) and water (0.75 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 h. The reaction mixture was adjusted to pH 7 with 0.1 M HCl. The solvent was removed under reduced pressure to give the title compound (0.250 g, 99%) as a yellow solid; MS m / z (ESI) [M+H] - 258.

[0263] Intermediate 38: Ethyl 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate [ka] NaHCO3 (1.908 g, 22.71 mmol) was added to 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carboxylic acid (1.568 g, 7.57 mmol), EDC (2.90 g, 15.14 mmol), and HOBt monohydrate (2.046 g, 15.14 mmol) in DMF (30 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. A solution of (Z)-2-amino-2-(hydroxyimino)ethyl acetate (1 g, 7.6 mmol) in DMF (10 mL) was added, and the resulting mixture was stirred at 25 °C for 30 min and then at 80 °C for 3 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (4 × 300 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 30-60% MeCN / water) to give the title compound (0.940 g, 41%) as a white solid; MS m / z (ESI) [M+H] + 304.

[0264] Intermediate 39: Ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate [ka] EDC (2.90 g, 15.1 mmol) was added to ethyl (Z)-2-amino-2-(hydroxyimino)acetate (1.00 g, 7.57 mmol), 4-fluoro-3-hydroxybenzoic acid (1772 mg, 11.35 mmol), and NaHCO (1.91 g, 22.7 mmol) in DMF (20 mL), and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (750 mL) and extracted with EtOAc (3 × 250 mL). The combined organic layers were dried over NaSO, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 40–50% EtOAc / PE) to give the title compound (1.200 g, 63%) as a white solid; MS m / z (ESI) [M+H] + 253.

[0265] Intermediate 40: 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid [ka] Ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 39 (470 mg, 1.86 mmol) and 2 M LiOH (aq, 9.32 mL, 18.6 mmol) in EtOH (10 mL) were stirred at 60 °C for 1 h. The organic solvent was removed under reduced pressure, and the reaction mixture was adjusted to pH 5-6 with 2 M HCl. The mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (0.400 g, 96%); MS m / z (ESI) [M+H] + 225.

[0266] Intermediate 41: 2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid [ka] Methyl 2-bromooxazole-5-carboxylate (470 mg, 2.28 mmol), (4-fluoro-3-hydroxyphenyl)boronic acid (391 mg, 2.51 mmol), KPO 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(g). THF (10 mL) and water (10 mL) were added, and the reaction mixture was flushed with N(g) again. The reaction mixture was heated at 60 °C in a preheated heating block overnight. 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 combined reaction mixture was diluted with EtOAc and sat. NH4Cl(aq). The aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The aqueous layer was then acidified to pH ∼1 with 2M HCl and extracted with EtOAc (x4). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a second residue. The combined residues were purified by normal phase flash chromatography on silica (gradient: 0-10% MeOH / EtOAc). The product-containing fractions were combined, concentrated, and dissolved in EtOAc. The organic layer was extracted with 0.1M NaOH (aq). The aqueous layer was acidified with 2M HCl and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered, and the solvent 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 [ka] MeCN (0.62 mL, 1.18 mmol) was added to a stirred suspension of NaH (60% in oil, 0.094 g, 2.35 mmol) in THF (1 mL), and the resulting mixture was stirred at room temperature for 10 min. Methyl 4-fluoro-3-hydroxybenzoate (0.100 g, 0.59 mmol) was added, and the resulting mixture was heated to 50 °C for 70 h. HO was added, and the mixture was acidified with 3.8 M HCl and extracted with EtOAc. The organic layer was concentrated, and the residue was purified by normal-phase flash chromatography on silica (gradient: 0-100% EtOAc / heptane) to give the title compound (0.075 g, 71%) as a white solid; MS (ESI) m / z [M+H] - 311.

[0268] Intermediate 43: Ethyl 4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate [ka] TEA (0.117 mL, 0.84 mmol) was added to a stirred suspension of 3-(4-fluoro-3-hydroxyphenyl)-3-oxopropanenitrile intermediate 42 (0.075 g, 0.42 mmol) in EtOH (99.5%, 1.5 mL), and the resulting mixture was stirred at room temperature for 10 minutes. (Z)-2-Chloro-2-(hydroxyimino)ethyl acetate (0.063 g, 0.42 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by normal-phase flash chromatography on silica (gradient: 0-50% EtOAc / heptane) to give the title compound (0.056 g, 48%) as a white solid; MS (ESI) m / z [M−H] - 275.

[0269] Intermediate 44: Ethyl 4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate [ka] MeCN (1.53 mL, 29.1 mmol) was added to a stirred suspension of NaH (60% in oil, 2.33 g, 58.2 mmol) in THF (24 mL), and the resulting mixture was stirred at room temperature for 15 min. Methyl 2,4,5-trifluoro-3-hydroxybenzoate (3.00 g, 14.6 mmol) in THF (6 mL) was added dropwise, and the resulting mixture was heated to 50 °C for 20 h. HO (450 mL) was added, and the mixture was washed with heptane, acidified with 3.8 M HCl, and extracted with EtOAc. The organic layer was concentrated, and the residue was suspended in EtOH (99.5%, 75 mL). TEA (4.66 mL, 33.4 mmol) was added, and the resulting mixture was stirred at room temperature for 10 min. Ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (2.53 g, 16.7 mmol) was added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was purified by normal-phase flash chromatography on silica (gradient: 8-13% EtOAc / heptane). The impure product was combined with another batch of crude product prepared as above starting with methyl 2,4,5-trifluoro-3-hydroxybenzoate (1.32 g, 6.14 mmol), and the combined crude product was resolidified from DCM to give the title compound (0.900 g, 12%) as a white solid; MS (ESI) m / z [M−H] - 311; 1 H NMR(500MHz,CD3OD)δ 7.37(ddd,1H),4.53(q,2H),1.47(t,3H).

[0270] Intermediate 45: N-methyl-1-phenyl-1H-tetrazol-5-amine [ka] A solution of 5-chloro-1-phenyl-1H-tetrazole (2 g, 11.07 mmol) in methanamine (33% in EtOH, 2 mL) was stirred at 25 °C for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 0-60% EtOAc / PE) to give the title compound (1.2 g, 61%) as a white solid; MS (ESI) m / z [M+H] + =176.0

[0271] Intermediate 46: tert-butyl (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prophosphate [ka] To 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid intermediate 23 (424 mg, 1.47 mmol), tert-butyl prophosphate (252 mg, 1.47 mmol), and HATU (1398 mg, 3.68 mmol) in DMF (10 mL) cooled to 10 °C under a N atmosphere, DIPEA (771 μL, 4.41 mmol) was slowly added. The resulting solution was stirred at 20 °C for 14 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with saturated brine (1 × 100 mL), saturated NaHCO (1 × 100 mL), and water (1 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (DCM:MeOH; 1:3) to give the title compound (0.255 g, 39%) as a pale yellow solid; MS (ESI) m / z [M+H] + 442.0

[0272] Intermediate 47: (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline [ka] A solution of HCl (4 M in dioxane, 60.8 μL, 2 mmol) in 1,4-dioxane (0.5 mL) was added dropwise to a stirred solution of tert-butyl (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)prophosphate intermediate 46 (120 mg, 0.27 mmol) in 1,4-dioxane (0.5 mL) cooled to 10° C. The resulting solution was stirred at 20° C. for 14 h. The solvent was removed under reduced pressure. The crude product was purified by crystallization from EtOAc to give the title compound (0.105 g, 100%) as a white solid; MS (ESI) m / z [M+H] + =386.0

[0273] Intermediate 48: N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide [ka] EDC (80 mg, 0.42 mmol) and HOBt (56.1 mg, 0.42 mmol) were added to (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline intermediate 47 (80 mg, 0.21 mmol), dimethylamine HCl (16.93 mg, 0.21 mmol), and DIPEA (109 μL, 0.62 mmol) in DMF (1 mL) under a N atmosphere at 20° C. The resulting solution was stirred at 20° C. for 2 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), and washed sequentially with water (20 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM; 1:10) to give the title compound (0.060 g, 70%) as a white solid; MS (ESI) m / z [M+H] + =413

[0274] Intermediate 49: (Z)-4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl [ka] 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 approximately 10 minutes, after which a solution / mixture of (Z)-N'-hydroxyisobutylimidamide (176 mg, 1.72 mmol) in DCM (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then washed with 8% NaHCO3 (aq, 3 x 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 [ka] A solution of sodium acetate (0.784 mL, 2.15 mmol) in water (0.784 mL) was added to a mixture of tert-butyl (Z)-4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate intermediate 49 (610 mg, 1.96 mmol) in EtOH (6 mL), and the mixture was stirred at 86 °C for 5.5 h. 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, Prep 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 [ka] TFA (3 mL) was added to a solution of tert-butyl 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (325 mg, 1.11 mmol) in DCM (3 mL) at room temperature, and the solution was stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with 1 M NaOH (aq) and water. The organic layer was concentrated to give the title compound (204 mg, 95%) as a light brown oil; MS (ESI) m / z [M+H] + =194.2

[0277] Intermediate 52: Methyl 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate [ka] A mixture of 2,4,5-trifluoro-3-hydroxybenzonitrile (249 mg, 1.44 mmol), hydroxylammonium chloride (120 mg, 1.73 mmol), and NaHCO (193 mg, 2.30 mmol) in MeOH (2.5 mL) was stirred at 50 °C for 23 h. The reaction mixture was concentrated, and the residue was suspended in pyridine and cooled to 0 °C. Methyl 2-chloro-2-oxoacetate (0.199 mL, 2.16 mmol) was added, and the mixture was stirred at room temperature for 20 min and then at 50 °C for 1.5 h. The reaction mixture was cooled to room temperature and poured onto ice and 4 M HCl (aq, 7 mL). The resulting mixture was extracted with EtOAc, and the organic layer was washed with water and brine, passed through a phase separator, and concentrated. The residue was purified by preparative HPLC, Prep Method J (gradient: 20-65%) to give the title compound (153 mg, 39%) as a white solid; MS m / z (ESI) [M+H] + 273.0.

[0278] Intermediate 53: Ethyl 5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate [ka] Oxalyl dichloride (4.09 mL, 47.7 mmol) and a catalytic amount of DMF (0.154 mL, 1.99 mmol) were added to a stirred suspension of 3,4-difluoro-5-hydroxybenzoic acid (3.46 g, 19.9 mmol) in DCM (50 mL) at room temperature, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and coevaporated twice from toluene. The residue was dissolved in THF (20 mL) and added dropwise to a stirred solution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (2.63 g, 19.9 mmol) in pyridine (40 mL, 494 mmol) at room temperature. The resulting mixture was heated to 70°C for 5 days, cooled to room temperature, and poured onto a stirred mixture of 3.8 M HCl (150 mL) and ice (400 mL). The mixture was stirred at room temperature for 1 hour. The solid was filtered off and washed with HO to give the crude product as a brown solid. The crude product was dissolved in DCM (approximately 50 mL) and loaded onto a plug of silica (14 g). The product was extracted with DCM (40 mL) and heptane / EtOAc (1:1, 100 mL). The impure product was combined with crude product from another batch prepared as above starting with 3,4-difluoro-5-hydroxybenzoic acid (1.00 g, 5.74 mmol), and the combined crude product was resolidified from DCM to give the title compound (1.75 g, 25%) as an off-white solid; MS (ESI) m / z [M−H] - 269.

[0279] Intermediate 54: 2,4,5-trifluoro-3-methoxybenzothioamide [ka] Lawesson's reagent (1.774 g, 4.39 mmol) was added to a solution of 2,4,5-trifluoro-3-methoxybenzamide (1.5 g, 7.31 mmol) in THF (30 mL), and the reaction mixture was heated at 50° C. for 50 min. The reaction mixture was concentrated, and the residue was purified by normal phase flash chromatography on silica (0-20% EtOAc / heptane) to give the title compound (1.225 g, 76%) as a yellow solid; MS m / z (ESI) [MH] - 220.1.

[0280] Intermediate 55: Ethyl 2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate [ka] A solution of 2,4,5-trifluoro-3-methoxybenzothioamide intermediate 54 (1.095 g, 4.95 mmol) and ethyl 2-chloro-3-oxopropanoate (0.820 g, 5.45 mmol) in toluene (25 mL) was heated at 105-110° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by normal phase flash chromatography on silica (0-30% EtOAc / heptane) to give an orange solid, which was further purified by trituration with heptane to give the title compound (282 mg, 18%) as a pale orange solid; MS m / z (ESI) [M+H] + 318.1.

[0281] Intermediate 56: ((2R,6S)-2,6-dimethylmorpholino)(2-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanone [ka] MeAl (2M in toluene) (0.989 ml, 1.98 mmol) was added dropwise to a solution of (2R,6S)-2,6-dimethylmorpholine (0.140 mL, 1.11 mmol) in anhydrous toluene (1.1 mL) at room temperature under a N2(g) atmosphere. The reaction mixture was stirred at room temperature for 1 hour and then added dropwise to a stirred slurry of ethyl 2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate Intermediate 55 (251 mg, 0.79 mmol) in toluene (1.6 mL) at room temperature under a N2(g) atmosphere. The resulting solution was heated at 60°C for 9 hours and then cooled to 0°C. Tartaric acid (30%, aq, 10 mL) was added dropwise, and the mixture was then extracted with EtOAc (x2). The combined organic layers were washed with water, dried over Na2SO4, 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] + 387.2.

[0282] Example 1: (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone [ka] DIPEA (0.440 mL, 2.52 mmol) was added dropwise 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) under a N2(g) atmosphere at 25 °C, and the reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method B (gradient: 42-52%) to give the title compound (61 mg, 41%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 17Calculated value of FN3O3: 354.1248, Measured value: 354.1254; 1 H NMR (300 MHz, DMSO-d6) δ 1.97-2.18 (1H, m), 2.22-2.45 (solvent overlap, m), 3.41-3.72 (solvent overlap, 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 [ka] COMU (1.08 g, 2.51 mmol) was added to 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (436 mg, 1.68 mmol), DIPEA (2.93 mL, 16.8 mmol), and 3-phenoxyazetidine (250 mg, 1.68 mmol) in DMF (2.5 mL) under a N2(g) atmosphere. The resulting mixture was stirred at 25 °C for 3 h. Brine (75 mL) was added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 40–60% MeCN / water) to give the title compound (0.089 g, 14%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 18 H 13 Calculated value of F3N3O4: 392.0852, Found value: 392.0840; 1 H NMR(400MHz,DMSO-d6)δ 11.71(s,1H),7.68(ddd,1H),7.38-7.28(m,2H),7.05-6.96(m,1H),6.93-6.85(m, 2H),5.15(ddd,1H),5.00(ddd,1H),4.62(ddd,1H),4.47(ddd,1H),4.08(ddd,1H).

[0284] Example 3: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone [ka] BBr3 (1 M, 1.06 mL, 1.06 mmol) in DCM was added dropwise to a solution of ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone intermediate 24 (136 mg, 0.35 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with DCM and water was carefully added. The layers were separated, and the aqueous layer was acidified with 1 M KHSO4 and extracted with EtOAc (×2). The combined organic layers were passed through a phase separator and concentrated. The residue was purified by preparative HPLC, Prep Method J (gradient: 30-70%) to give the title compound (110 mg, 84%) as a white solid; HRMS (ESI) m / z [M+H] + C 17 H 17 Calculated value of F3NO3S: 372.0876, Measured value: 372.0892; 1 H NMR (500 MHz, DMSO-d6) δ 1.11 (6H, d), 2.66 (solvent overlap, bs), 3.33 (1H, s), 3.52-3.62 (2H, m), 4.16 (2H, s), 7.44 (1H, ddd), 7.48 (1H, dd), 7.59 (1H, d), 11.17 (1H, s).

[0285] Example 4: (3-(2-methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (2-Methoxyphenyl)pyrrolidine HCl (0.102 g, 0.48 mmol) was suspended in EtOAc and washed with 10% Na2CO3. The organic layer was concentrated, and toluene (1 mL) and Me3Al in toluene (2 M, 0.599 mL, 1.20 mmol) were added to the residue under a N2 (g) atmosphere, and the resulting mixture was stirred at room temperature for 1 h. This mixture was added to a stirred slurry of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 1 (0.138 g, 0.48 mmol) in toluene (1.5 mL), and the resulting mixture was heated to 60 °C for 22 h. The mixture was cooled to room temperature, tartaric acid (30%, aq, 5 mL) was added, and the mixture was extracted with EtOAc (5 mL). The organic layer was concentrated and the residue was purified by reverse phase HPLC, preparative method C (gradient 20-80%) to give the title compound (120 mg, 60%) as a colorless syrup; HRMS (ESI) m / z [M+H] + C 20 H 17 Calculated value of F3N3O4: 420.1166, Found value: 420.1164; 1 H NMR(500MHz,CDCl3)2.15-2.28(1H,m),2.30-2.40(1H,m),3.64-3.94(6H,m),4.00-4.1(1H,m), 4.21-4.31(1H,m),6.89(1H,ddd),6.94(1H,tdd),7.19(1H,dd),7.22-7.31(1H,m),7.37(1H,m).

[0286] Example 5: N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide [ka] BBr3 (1 M, 10 mL, 10.00 mmol) in DCM 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 a N2(g) atmosphere. The resulting solution was stirred at 15 °C for 2 h. To the above solution cooled to 0 °C, additional BBr3 (1 M, 20 mL, 20.00 mmol) in DCM was slowly added under a N2(g) atmosphere. The resulting solution was stirred at 15 °C for 2 h. The reaction mixture was poured into 2 M NaOH (aq, 50 mL) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:2) followed by further purification by preparative HPLC, preparative method N (gradient 45-55%) to give the title compound (0.014 g, 16%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated value of FN4O3: 385.1670, Measured value: 385.1674; 1 H NMR(300MHz,DMSO-d6)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 [ka] BBr3 (1 M, 5 mL, 5 mmol) in DCM was added slowly over 5 min to a stirred solution of (3-(4-fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone intermediate 31 (110 mg, 0.30 mmol) in anhydrous DCM (4 mL) cooled to 0 °C under a N2(g) atmosphere. The resulting solution was stirred at 15 °C for 3 h under a N2(g) atmosphere. The reaction mixture was poured into saturated NaHCO3 (aq, 20 mL) cooled to 0 °C and extracted with EtOAc (4 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method F (gradient: 46-56%) to give the title compound (0.050 g, 47%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 18 Calculated value of FN2O3: 353.1296, Measured value: 353.1304; 1 H NMR(300MHz,DMSO-d6)δ 1.94-2.2(m,1H),2.24-2.42(1H,m),3.41-4.29(5H,m),7.2-7.47(7H,m),7.51-7.61(2H,m),10.27(1H,s).

[0288] Example 7: N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide [ka] (COCl)2 (50.8 mg, 0.40 mmol) was added slowly to a mixture of 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid intermediate 34 (100 mg, 0.45 mmol) and DMF (1 μL, 0.01 mmol) in DCM (5 mL) cooled to 5 °C under a N2 (g) atmosphere. The resulting solution was stirred at 28 °C for 0.5 h. 1-Cyclohexyl-N-methyl-1H-pyrazol-5-amine intermediate 27 (80 mg, 0.45 mmol) and TEA (836 μL, 6 mmol) were added at 20 °C. The resulting solution was stirred at 28 °C for 45 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC, preparative method O (gradient: 28-61%) to give the title compound (1.1 mg, 1%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated value of FN4O3: 385.1670, Measured value: 385.1680; 1 H NMR (400 MHz, DMSO-d6) δ 1.14-1.48 (6H, m), 1.61-1.86 (7H, m), 3.30 (solvent overlap, S), 6.17 (1H, d), 7.00 (1H, s), 7.23-7.34 (3H, m), 7.37 (1H, s).

[0289] Example 8: (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone [ka] EDC (118 mg, 0.62 mmol), DMAP (7.54 mg, 0.06 mmol), and HOBt (83 mg, 0.62 mmol) were added to 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid intermediate 37 (80 mg, 0.31 mmol), (R)-3-(4-chlorophenyl)pyrrolidine (56 mg, 0.31 mmol), and DIPEA (162 μL, 0.93 mmol) in DMF (2 mL) at 20° C. The resulting solution was stirred at 60° C. under a N2(g) atmosphere for 2 h. The reaction mixture was concentrated, diluted with EtOAc (25 mL), and washed with water (25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:10) and further purified by preparative HPLC, preparative method P (gradient 60-85%) to give the title compound (0.025 g, 19%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 15 Calculated value for ClF3N2O3: 423.0718, Found value: 423.0718; 1 H NMR (400MHz, DMSO-d6, 80℃) δ 2.01 (m, 1H), 2.23-2.36 (m, 1H), 3.45-4.25 (m, 5H), 6.96-7.08 (m, 2H), 7.27-7.39 (m, 4H).

[0290] Example 9: 4-(3-(3-phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one [ka] MeAl (2 M, 0.5 mL, 1.00 mmol) in toluene was added to a solution of 3-phenylpyrrolidine (73 mg, 0.49 mmol) in toluene (0.5 mL) stirred at 25 °C for 40 min. The resulting solution was added to a suspension of ethyl 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate Intermediate 38 (100 mg, 0.33 mmol) in toluene (0.5 mL) under a N2 (g) atmosphere, and the mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with water (75 mL) and filtered through a pad of CELITE. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method Q (gradient: 50-62%) to give the title compound (34 mg, 25%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 16 Calculated value of F3N4O3: 405.1168, Measured value: 405.1166; 1 H NMR(300MHz,DMSO-d6)δ 2.00-2.18(1H,m),2.22-2.38(1H,m),3.42-4.18(m,5H),7.20-7.40(5H,m),7.57(1H,d),7.83(1H,d),12.65(1H,s).

[0291] Example 10: 4-(3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one [ka] DABAL-Me3 (127 mg, 0.49 mmol) was added portionwise to 1-(3-methoxyphenyl)piperazine HCl (95 mg, 0.42 mmol) in THF (1 mL). The resulting mixture was stirred at 80° C. for 2 hours under a N2(g) atmosphere. A solution of ethyl 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate Intermediate 38 (100 mg, 0.33 mmol) in THF (1 mL) was added portionwise to the mixture at 50° C. under a N2(g) atmosphere. The resulting solution was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with DMSO and filtered through a syringe filter. The filtrate was collected and purified by preparative HPLC, Prep Method Q (gradient: 33-63%) to give the title compound (72 mg, 48%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 20 H 19 Calculated value of F3N5O4: 450.1384, Found value: 450.1380; 1 H NMR(300MHz,DMSO-d6)δ 2.94-3.11(4H,m),3.62-3.71(2H,m),3.79(3H,s),3.81-3.89(2H,m),6.83-7.06(4H,m),7.58(1H,s),7.85(1H,s),12.60(1H,s).

[0292] Example 11: (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone [ka] (R)-3-Phenylpyrrolidine HCl (295 mg, 1.61 mmol), 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 40 (300 mg, 1.34 mmol), HOBt hydrate (246 mg, 1.61 mmol), and EDC (385 mg, 2.01 mmol) were suspended in DMF (8 mL) under N (g) min. The resulting mixture was stirred at room temperature for 2 h and then purified by reverse-phase flash chromatography on a C18 column (gradient: 40–50% MeCN / water (0.1% NH4HCO3)) to give the title compound (0.188 g, 40%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 17 Calculated value of FN3O3: 354.1248, Measured value: 354.1256; 1 H NMR(400MHz,CD3OD)δ 2.10-2.24(1H,m),2.36-2.48(1H,m),3.49-3.78(2H,m),3.79-4.39(3H,m), 7.23-7.32(2H,m),7.32-7.38(4H,m),7.64-7.70(1H,m),7.71-7.78(1H,m).

[0293] Example 12: N-(1-cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide [ka] 2-(4-Fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid intermediate 41 (70 mg, 0.31 mmol), 1-cyclohexyl-1H-pyrazol-5-amine (52 mg, 0.31 mmol), and HATU (131 mg, 0.35 mmol) were dissolved in DMF (2.95 mL). 2,6-Dimethylpyridine (183 μL, 1.57 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO (10 mL) and brine (3 × 10 mL). The organic layer was dried over MgSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase HPLC, preparative method S (gradient 20-25%) to give the title compound (0.012 g, 10%); HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated value of FN4O3: 371.1514, Measured value: 371.1516; 1 H NMR(600MHz,DMSO-d6)δ 1.13-1.22(1H,m),1.27-1.38(2H,m),1.59-1.66(1H,m),1.73-1.88(6H,m),4-4.09(1H,m),6 .18(1H,d),7.38(1H,dd),7.47(1H,d),7.62(1H,s),7.74(1H,dd),8.07(1H,s),10.40(2H,s).

[0294] Example 13: 5-(4-fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile [ka] MeAl in toluene (2 M, 0.185 mL, 0.37 mmol) was added to a stirred solution of 3-phenylpyrrolidine (0.054 g, 0.37 mmol) in toluene (0.3 mL) under a N2(g) atmosphere, and the resulting mixture was stirred at room temperature for 1 h. The mixture was added to ethyl 4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate Intermediate 43 (0.034 g, 0.12 mmol), and the resulting mixture was heated to 60 °C for 22 h and then cooled to room temperature. Tartaric acid (30%, aq, 2 mL) was added, and the mixture was extracted with EtOAc (5 mL). The organic layer was concentrated, and the residue was purified by normal-phase flash chromatography on silica (gradient: 0–100% EtOAc / heptane) to give the title compound (22 mg, 47%) as a white solid; HRMS (ESI) m / z [M+H] + ;C 21 H 17 Calculated for FN3O3: 378.1248, Found: 378.1248; mixture of rotamers, major:minor ratio 1.2:1 1 H NMR (500MHz, DMSO-d6) δ 2.08(p), 2.26-2.39(m), 3.42-3.56(m), 3.56-3.7(m), 3.75-3.9(m), 4-4.13(m), 4.27(dd), 7.19-7.29(m), 7.29-7.4(m), 7.44-7.6(m), 7.66(ddd), 10.78(s). Total number of protons in the spectrum: 16.

[0295] The following Examples 14-29 were prepared in a similar manner to Example 13 from ethyl 4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate intermediate 44 using the appropriate commercially available amine. The HCl and AcOH salts of the amines were dissolved in MeOH, passed through a 5 g ISOLUTE NH ion exchange column, and concentrated before use. The crude products were purified as specified.

[0296] Example 14: 3-(4-(3-(4-fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (24 mg, 37%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 24 H 21 Calculated value of F4N4O4: 505.1494, Found value: 505.1486; 1 H NMR(500MHz,CD3OD)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 [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (9 mg, 16%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 20 H 15 Calculated value of F3N5O3: 430.1122, Measured value: 430.1126; 1 H NMR(500MHz,CD3OD)δ 3.68(dt,4H),3.93(q,4H),6.73(dd,1H),6.89(d,1H),7.35(ddd,1H),7.61(ddd,1H),8.09-8.17(m,1H).

[0298] Example 16: 3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (25 mg, 43%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 22 H 18 Calculated value of F3N4O4: 459.1274, Found value: 459.1258; 1 H NMR (500MHz, CD3OD) δ 3.27(dt,4H),3.76(s,3H),3.89-3.99(m,4H),6.46(dd,1H),6.53(t,1H),6.59(dd,1H),7.15(t,1H),7.35(ddd,1H).

[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 [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (20 mg, 29%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 21 H 13 Calculated value of F6N8O3: 539.1008, Measured value: 539.1016; 1 H NMR(500MHz,CD3OD)δ 3.85(dt,4H),4.01(dt,4H),7.36(ddd,1H),7.56(d,1H),8.11(d,1H).

[0300] Example 18: 3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (12 mg, 27%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 19 H 10 Calculated for F4N3O3: 404.0652, Found: 404.0638; mixture of rotamers, major:minor ratio 1:1: 1 H NMR (500 MHz, CD3OD) δ 5.00 (d), 5.26 (d), 7.04-7.14 (m), 7.17 (d), 7.31-7.45 (m), total number of protons in the spectrum: 8.

[0301] Example 19: N-(tert-butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide [ka] The crude product was purified by preparative HPLC, Preparative Method A (gradient: 5-95%) to give the title compound (2 mg, 4%); HRMS (ESI) m / z [M+H] + ;C 21 H 18 Calculated value of F3N4O3: 431.1326, Measured value: 431.1334; 1 H NMR(600MHz,DMSO-d6)δ 1.39(s,9H),4.85(s,2H),7.29(m,2H),7.38(d,1H),7.78(td,1H),8.54(d,1H),11.88(s,1H).

[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 [ka] The crude product was purified by preparative HPLC, Prep Method U to give the title compound (12 mg, 23%); HRMS (ESI) m / z [M+H] + ;C 21 H 17 Calculated for F3N5O3: 444.1278, Found: 444.1276; Mixture of rotamers: Major:Minor ratio 2:1: 1 H NMR (600 MHz, DMSO-d6) δ 0.64-0.68 (m), 0.7-0.73 (m), 0.73-0.77 (m), 0.81-0.85 (m), 1.66 (tt), 1.79 (tt), 2.79 (q), 3.91 (t), 3.98 (t), 4.68 (s), 4.72 (s), 7.48-7.56 (m), 11.86 (s), total number of protons in the spectrum: 13.

[0303] Example 21: (S)-3-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (18 mg, 36%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 21 H 14 Calculated for ClF3N3O3: 448.0670, Found: 448.0682; Mixture of rotamers: Major:Minor ratio: 1:1 1H NMR (500 MHz, DMSO-d6) δ 2.06 (p), 2.26-2.39 (m), 3.42-3.55 (m), 3.56-3.68 (m), 3.75-3.88 (m), 3.99-4.12 (m), 4.26 (dd), 7.33-7.44 (m), 7.45-7.56 (m), 11.81 (s). Total number of protons in the spectrum: 13.

[0304] Example 22: 3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (5 mg, 9%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 17 H 15 Calculated value of F3N3O4: 382.1008, Found value: 382.1008; 1 H NMR(500MHz,CD3OD)δ 1.16(d,3H),1.25(d,3H),2.61-2.71(m,1H),2.98(dd,1H),3.6-3.75(m,2H),4.13(dt,1H),4.50(dt,1H),7.34(ddd,1H).

[0305] Example 23: 3-(4-(benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (23 mg, 38%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 22 H 15 Calculated value of F3N5O4: 470.1070, Found value: 470.1048;1 H NMR(500MHz,CD3OD)δ 3.84(dt,4H),4.00(q,4H),7.08(td,1H),7.19(td,1H),7.29-7.4(m,3H).

[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 [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (5 mg, 7%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 25 H 18 Calculated value of F4N5O4: 528.1290, Found value: 528.1276; 1 H NMR (500 MHz, CD3OD) δ 1.9-2.16 (m, 4H), 3.10 (td, 1H), 3.38-3.49 (m, 1H), 4.3-4.46 (m, 2H), 4.80-4.87 (m, 1H, hidden by solvent OH), 6.97 (s, 1H), 7.04-7.14 (m, 2H), 7.29-7.38 (m, 1H), 7.46-7.53 (m, 2H).

[0307] Example 25: 3-(4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (32 mg, 53%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 22 H 18Calculated value of F3N4O5: 475.1224, Measured value: 475.1216; 1 H NMR(500MHz,CD3OD)δ 1.82-1.94(m,2H),2.06-2.16(m,2H),3.73(ddd,1H),3.77-3.87(m,4H),3.96(ddd, 1H),4.02(ddd,1H),5.19-5.27(m,1H),6.76(d,1H),7.29-7.39(m,2H),7.77(d,1H).

[0308] Example 26: 3-(4-hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (9 mg, 16%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 17 H 12 Calculated value of F6N3O4: 436.0726, Found value: 436.0732; 1 H NMR(500MHz,CD3OD)δ 1.79-1.93(m,4H),3.24(td,1H),3.56(td,1H),4.15-4.25(m,1H),4.59-4.7(m,1H),7.32(ddd,1H).

[0309] Example 27: 3-(3-cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (10 mg, 23%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 17 H 12Calculated value of F4N3O3: 382.0810, Measured value: 382.0816; 1 H NMR(500MHz,CD3OD)δ 0.49-0.58(m,2H),0.63-0.73(m,2H),1.44(dddd,1H),4.14-4.28(m,2H),4.5-4.66(m,2H),7.33(ddd,1H).

[0310] Example 28: 5-(2,4,5-trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method U, to give the title compound (10 mg, 24%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 15 Calculated value of H8F6N3O3: 392.0464, Found value: 392.0450; 1 H NMR (500 MHz, CD3OD) δ 1 H NMR δ 3.65(m,1H),4.21-4.26(m,1H),4.41-4.48(m,1H),4.59-4.66(m,1H),4.77-4.83(m,1H),7.15(ddd,1H).

[0311] Example 29: 3-(7-cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile [ka] The crude product was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (17 mg, 34%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 21 H 12Calculated for F3N4O3: 425.0856, Found: 425.0828; mixture of rotamers, major:minor ratio 1.5:1: 1 H NMR (500 MHz, CD3OD) δ 3.10 (t), 4.04 (td), 4.97 (s), 5.04 (s), 7.35 (dddd), 7.40 (dd), 7.53 (s), 7.56 (dd), 7.66 (s), total number of protons in the spectrum: 10.

[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 [ka] A mixture of 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile Example 66 (0.006 g, 0.01 mmol) and NBS (5 mg, 0.03 mmol) in AcOH (0.5 mL) was stirred at 80° C. for 1 h. The mixture was concentrated, and the residue was purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (3 mg, 42%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 11 Calculated for BrF3N4O3: 478.9960, found: 478.9970; mixture of rotamers, major:minor ratio 2:1: 1 H NMR (500 MHz, DMSO-d6) δ 3.09 (q), 3.87 (t), 4.01 (t), 4.85 (s), 4.93 (s), 7.40 (t), 7.46 (t), 7.50 (d), 7.67 (d), 7.75 (dd), 12.08 (s), total number of protons in the spectrum: 10.

[0313] Example 31: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile [ka] 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 overnight at room temperature. The reaction mixture was diluted with DMSO and purified by preparative HPLC, Prep Method A (gradient: 5-95%) to give the title compound (15 mg, 26%); HRMS (ESI) m / z [M+H] + C 19 H 12 Calculated value for F3N4O3: 401.0856, Found: 401.0834; Mixture of rotamers, major:minor ratio: 1:0.6 1 H NMR (600 MHz, DMSO-d6) 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 [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (40 mg, 0.15 mmol), HATU (70 mg, 0.18 mmol), and DMF (1 mL) were mixed in a vial. DIPEA (0.081 mL, 0.46 mmol) was added, followed by 2,2,6,6-tetramethylmorpholine (33 mg, 0.23 mmol). The resulting yellow solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with DMSO and purified by preparative HPLC, Prep Method B (gradient: 5-95%) to give the title compound (17 mg, 29%); HRMS (ESI) m / z [M+H] + C 17 H 19 Calculated value of F3N3O4: 386.1322, Found value: 386.1324; 1 H NMR (600MHz, DMSO-d6) δ 1.09 (6H, s), 1.17 (6H, s), 3.32 (2H, s), 3.49 (2H, s), 6.99-7.12 (1H, m).

[0315] Example 33: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone [ka] BBr3 (1 M, 122 μL, 0.12 mmol) in DCM was added dropwise to a solution of (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone intermediate 3 (17 mg, 0.04 mmol) in DCM (0.8 mL) at 0 °C. The reaction was stirred at room temperature for 2.5 h. The yellow reaction mixture was diluted with DCM, and water was carefully added. The organic phase was separated. 1 M KHSO4 was added to the aqueous phase, which was extracted with EtOAc (×3). The organic phases were combined, dried using a phase separator, and concentrated to give a white solid. The residue was purified by preparative HPLC, Prep Method C (gradient 25-65%) to give the title compound (12 mg, 73%); HRMS (ESI) m / z [M+H] + C 21 H 17Calculated for F3NO2S: 404.0926, Found: 404.0924; Mixture of rotamers: 1 H NMR (500 MHz, DMSO-d6) δ 1.95-2.21 (1H, m), 2.23-2.44 (1H, m), 3.42-3.64 (2H, m, overlap with water peak), 3.77 (1H, t), 3.84-4.08 (1H, m), 4.23 (1H, t), 7.21-7.3 (1H, m), 7.3-7.49 (5H, m), 7.54-7.73 (2H, m), 11.17 (1H, bs). Total number of protons in the spectrum: 16.

[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) in DMF 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 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 purified by preparative HPLC using one of the following methods: 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 preparation 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, was added to a vial containing the appropriate amine (0.12 mmol, 2 eq). The reaction mixture was shaken overnight at room temperature. 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: Preparative Method 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 [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (93 mg, 0.36 mmol), HATU (272 mg, 0.72 mmol), and DMF (3 mL) were mixed in a vial. 3-(Azetidin-3-yl)benzonitrile HCl (80 mg, 0.41 mmol) was added, followed by DIPEA (375 μL, 2.15 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC, Preparative Method D (gradient 20-60%). Pure fractions were combined, and MeCN was evaporated. The remaining aqueous phase was extracted with EtOAc (×2). The organic layers were combined and concentrated to give a yellow oil, which was purified by preparative HPLC, Preparative Method D (gradient 30-80%). Relevant fractions were combined and evaporated. The residue was dissolved in MeCN and purified by preparative HPLC, preparative method J (gradient 15-55%). Pure fractions were combined and evaporated by lyophilization overnight. The residue was dissolved in EtOAc and washed with 1M KHSO4. The aqueous phase was extracted with EtOAc (x2). The organic layers were combined and evaporated. The residue was dissolved in MeCN / water and lyophilized overnight to give the title compound (8.4 mg, 6%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 12 Calculated value of F3N4O3: 401.0856, Found value: 401.0846; 1 H NMR (500MHz, DMSO-d6)7.97-8.02(1H,m),7.73-7.82(2H,m),7.58(1H,t),7.38(1H,s),4.94(1H,t),4.49-4.62(2H,m),4.03-4.21(2H,m).

[0329] Example 86: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (80 mg, 0.31 mmol), HATU (234 mg, 0.62 mmol), and DMF (1 mL) were mixed in a vial. 1,2,3,4-Tetrahydroisoquinoline-7-carbonitrile (54 mg, 0.34 mmol) was added, followed by DIPEA (322 μL, 1.85 mmol). The resulting yellow solution was stirred at room temperature for 4 h. The reaction mixture was filtered and purified by preparative HPLC, Preparative Method D (gradient 15-55%). Pure fractions were combined, and MeCN was evaporated. The remaining aqueous phase was extracted with EtOAc (×2). The organic layers were combined and concentrated to give a beige oil. The oil was dissolved in MeCN, and water was added. The compound was lyophilized overnight to give a solid. Water was added to give a slurry, which was sonicated for 5 min. The slurry was lyophilized overnight to give the title compound (76 mg, 62%) as a beige solid; HRMS (ESI) m / z [M+H] + C 19 H 12 Calculated value of F3N4O3: 401.0856, Found value: 401.0838; Mixture of rotamers: Major:Minor ratio: 1:0.6; 1 H NMR (500 MHz, DMSO-d6) δ 3.01 (2H, dt), 3.79 (1.2H, t), 3.93 (0.8H, t), 4.79 (0.8H, s), 4.90 (1.2H, s), 7.4-7.49 (1H, m), 7.5-7.64 (1H, m), 7.64-7.71 (1H, m), 7.84 (1H, s), 11.81 (1H, bs). Total number of protons in the spectrum: 11.

[0330] Example 87: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (2R,6S)-2,6-Dimethylmorpholine (0.520 g, 4.51 mmol) was suspended in dry toluene (12 mL) and MeAl (2 M, 4.34 mL, 8.68 mmol) in toluene was added under an N2 (g) atmosphere. The resulting mixture was stirred at room temperature for 1 h. The above mixture was added to a stirred slurry of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 1 (1 g, 3.47 mmol) in toluene (12 mL). The resulting solution was heated at 60 °C for 20 h. The mixture was cooled to room temperature, tartaric acid (30%, aq, 100 mL) was added, and the mixture was extracted with EtOAc. The organic layer was concentrated and the residue was purified by preparative HPLC, Prep Method D (gradient: 20-80%) to give the title compound (1.01 g, 81%) as a white solid; HRMS (ESI) m / z [M+H] + C 15 H 15 Calculated value of F3N3O4: 358.1008, Found value: 358.0978; 1 H NMR(500MHz,CD3OD)δ 1.14(3H,d),1.25(3H,d),2.65(1H,dd),2.96(1H,dd),3.57-3.79(2H,m),3.98(1H,dt),4.52(1H,dt),7.43-7.67(1H,m).

[0331] Example 88: ((2R,6R)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] The title compound was prepared from (2R,6R)-2,6-dimethylmorpholine and ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 1 in a manner analogous to Example 87. The crude product was purified by preparative HPLC, Prep Method D (gradient 20-80%) to give the title compound (59 mg, 48%); HRMS (ESI) m / z [M+H] + C 15 H 15Calculated value of F3N3O4: 358.1008, Found value: 358.1008; 1 H NMR(500MHz,CD3OD)δ 1.20(3H,d),1.26(3H,d),3.43(1H,dd),3.52(1H,dd),3.76(1H,dd),3.88(1H,dd),4.02-4.1(1H,m),4.1-4.18(1H,m),7.46-7.64(1H,m).

[0332] Example 89: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone [ka] The title compound was prepared from ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone intermediate 18 in a manner analogous to Example 33, but using 6 eq of BBr3 (1M) in DCM. The crude product was purified by preparative HPLC, preparative method D (gradient 15-55%) to give the title compound (74 mg, 57%); HRMS (ESI) m / z [M+H] + C 16 H 16 Calculated value of F3N2O4: 357.1056, Measured value: 357.1066; 1 H NMR (500 MHz, DMSO-d6) δ 1.05 (3H, d), 1.16 (3H, d), 2.55 (1H, dd, overlapping with water peak), 2.88 (1H, dd), 3.52-3.62 (2H, m), 3.90 (1H, dt), 4.38 (1H, td), 7.14 (1H, d), 7.48-7.57 (1H, m), 11.47 (1H, s).

[0333] The following compounds, Examples 90 to 111, were also prepared in a similar manner to that described above.

[0334] Example 90: (5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone [ka] A solution of methyl 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate intermediate 20 (100 mg, 0.42 mmol) and 5-oxa-8-azaspiro[3.5]nonane (160 mg, 1.26 mmol) in DMF (5 mL) was stirred at 80 °C for 4 h. The crude product was purified by preparative HPLC, Prep Method E (gradient: 38-50%) to give the title compound (42 mg, 30%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 17 Calculated value of FN3O4: 334.1198, Measured value: 334.1176; 1 H NMR(300MHz,DMSO-d6)δ ppm 1.54-1.85(2H,m)1.87-2.12(4H,m)3.58-3.67(3H,m)3.71(1H,s)3.91-4.02(2 H,m)7.35-7.47(1H,m)7.47-7.56(1H,m)7.61-7.70(1H,m)10.49-10.75(1H,m).

[0335] Example 91: 5-(4-fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide [ka] MeAl (1 M in heptane, 2.52 mL, 2.52 mmol) was added dropwise to a mixture of methyl 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate intermediate 20 (200 mg, 0.84 mmol) and N-methyl-1-phenyl-1H-tetrazol-5-amine intermediate 45 (441 mg, 2.52 mmol) in DCM (2 mL) and THF (10 mL) under a N2(g) atmosphere at 25 °C. The resulting mixture was stirred at 25 °C for 3 days. The reaction mixture was poured into aqueous 0.1 M HCl (100 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method V (gradient: 50-65%) to afford the title compound (112 mg, 35%) as a white solid. HRMS(ESI)m / z[M+H] + C 17 H 13 Calculated value of FN7O3: 382.1058, Measured value: 382.1036; 1 H NMR(300MHz,DMSO-d6)δ ppm 3.35(3H,s)7.32-7.45(2H,m)7.47-7.64(6H,m)10.65(1H,s)..

[0336] Example 92: 5-(4-fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide [ka] MeAl (2 M in hexane, 3425 μL, 6.85 mmol) was added to a mixture of ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 39 (288 mg, 1.14 mmol) and N-methyl-1-phenyl-1H-tetrazol-5-amine intermediate 45 (200 mg, 1.14 mmol) in THF (20 mL). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into 2 M HCl (10 mL) and extracted with DCM (3 × 25 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude orange oil was purified by flash chromatography on silica (gradient: 40-50% EtOAc / PE) to give the title compound (0.225 g, 51%) as a white solid; HRMS (ESI) m / z [M+H] + C 17 H 13 Calculated value of FN7O3: 382.1058, Measured value: 382.1058; 1 H NMR (400MHz, CD3OD) δ 3.45 (3H, s), 7.22-7.30 (1H, m), 7.44-7.57 (2H, m), 7.62 (5H, s).

[0337] Example 93: (S)-(3-phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (S)-3-Phenoxypyrrolidine (250 mg, 1.53 mmol) was added to a mixture of DIPEA (990 mg, 7.66 mmol), HATU (1165 mg, 3.06 mmol), and 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (598 mg, 2.30 mmol) in DMF (5 mL). The reaction mixture was vigorously stirred at 25 °C for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over MgSO, filtered, and evaporated. The solid was purified by preparative HPLC, Prep Method Z (gradient: 50-65%) to give the title compound (0.040 g, 6%) as an off-white solid; HRMS (ESI) m / z [M+H] + C 19 H 15 Calculated value of F3N3O4: 406.1008, Found value: 406.1008; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.09-2.37(2H,m)3.52-4.17(4H,m)5.05-5.22(1H,m)6.88-7.04(3H,m)7.23-7.37(2H,m)7.52-7.72(1H,m).

[0338] Example 94: (3-(benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] 3-(Benzyloxy)piperidine (1 g, 5.23 mmol) was added to a mixture of DIPEA (3.38 g, 26.14 mmol), HATU (3.98 g, 10.46 mmol), and 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (2.040 g, 7.84 mmol) in DMF (20 mL). The reaction mixture was vigorously stirred at 25 °C for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over MgSO, filtered, and evaporated. The solid was purified by preparative HPLC, Prep Method X (gradient: 28-38%) to give the title compound (33.5 mg, 1%) as an off-white solid; HRMS (ESI) m / z [M+H] + C 21 H 19 Calculated value of F3N3O4: 434.1322, Found value: 434.1314; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.37-1.56(1H,m)1.66-1.98(2H,m)3.37-3.65(4H,m)3.73-3.84(2H,m)4.41(1H,s)4.49-4.67(1H,m)6.76-7.92(5H,m).

[0339] Example 95: (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] COMU (884 mg, 2.06 mmol) was added to a mixture of (R)-3-(4-chlorophenyl)pyrrolidine (250 mg, 1.38 mmol), 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (358 mg, 1.38 mmol), and DIPEA (2.40 mL, 13.76 mmol) in DMF (2.5 mL) under a N2(g) atmosphere. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated brine (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The yellow oil was purified by flash chromatography on a C18 column (gradient: 40-60% MeCN / water) to give the title compound (0.076 g, 13%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 19 H 14 Calculated value for ClF3N3O3: 424.0670, Found value: 424.0668; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.96-2.15(1H,m)2.25-2.39(1H,m)3.40-3.99(4H,m)4.02-4.22(1H,m)7.30-7.46(4H,m)7.59-7.78(1H,m)11.68(1H,s).

[0340] Example 96: (3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] MeAl (2 M in toluene, 3460 μL, 6.92 mmol) was added to a mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (300 mg, 1.15 mmol) and 3-phenylpyrrolidine (340 mg, 2.31 mmol) in THF (3 mL) under a N2(g) atmosphere at 25 °C. The resulting solution was stirred at 60 °C for 3 h. The reaction mixture was acidified with 2 M HCl and then concentrated. The residue was diluted with EtOAc and washed successively with water and sat. NaHCO3. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method E (gradient: 55-70%) to give the title compound (0.030 g, 6%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 15 Calculated value of F3N3O3: 390.1060, Found value: 390.1070; 1 H NMR(400MHz,DMSO-d6)δ ppm 2.04-2.13(1H,m)2.29-2.36(1H,m)3.46-3.51(1H,m)3.55-3.65(1H,m)3.73-3.86(1H,m)3.90-3.99 (1H,m)4.06-4.20(1H,m)7.21-7.29(1H,m)7.30-7.41(4H,m)7.58-7.71(1H,m)11.61-11.77(1H,m).

[0341] Example 97: (3-(benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] MeAl (2 M in toluene, 4613 μL, 9.23 mmol) was added to 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (400 mg, 1.54 mmol) and 3-(benzyloxy)pyrrolidine (273 mg, 1.54 mmol) in DMF (5 mL) under a N2(g) atmosphere at 25 °C. The resulting solution was stirred at 25 °C for 2 h. The reaction mixture was acidified with 2 M HCl and then concentrated. The residue was diluted with EtOAc and washed sequentially with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC, Prep Method V (gradient: 50-62%) to give the title compound (0.048 g, 7%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 17 Calculated value of F3N3O4: 420.1166, Found value: 420.1168; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.99-2.22(2H,m)3.53-3.88(4H,m)4.23-4.36(1H,m)4.45-4.65(2H,m)7.26-7.45(5H,m)7.49-7.73(1H,m)11.43(1H,s).

[0342] Example 98: (R)-(3-phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (R)-3-phenoxypyrrolidine (300 mg, 1.84 mmol) was added to a mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (1.195 g, 4.60 mmol), HATU (1.398 g, 3.68 mmol), and DIPEA (963 μL, 5.51 mmol) in DMF (10 mL) at 0° C. under a N2(g) atmosphere. The resulting mixture was heated at 25° C. for 3 h. The reaction mixture was concentrated, diluted with DCM (50 mL), and washed successively with water (3 × 50 mL) and saturated brine (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (DCM:MeOH, 20:1) and then by preparative HPLC, preparative method N (gradient: 50-65%) to give the crude compound. The crude compound was diluted with DCM (100 mL) and washed sequentially with sat. NaHCO (3 x 100 mL) and water (3 x 100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue still contained impurities, so it was diluted again with DCM, washed with sat. NaHCO and water as above, dried over NaSO, filtered, and evaporated to give the title compound (0.031 g, 34%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 15 F3N3O4: 406.1008, Measured: 406.1040; 1 H NMR(400MHz,DMSO-d6)δ ppm 2.12-2.32(2H,m)3.59-3.71(1H,m)3.72-4.10(3H,m)5.15(1H,br s)6.90-7.06(3H,m)7.24-7.39(2H,m)7.57-7.77(1H,m)11.52(1H,br s).

[0343] Example 99: N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide [ka] 1-Cyclohexyl-1H-pyrazol-5-amine (120 mg, 0.73 mmol) was added to a mixture of HATU (387 mg, 1.02 mmol), DIPEA (634 μL, 3.63 mmol), and 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid intermediate 34 (211 mg, 0.94 mmol) in DMF (5 mL). The resulting mixture was stirred at 25 °C for 3 h. Water was added, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with sat. NaHCO (aq., ×2), dried over anhydrous NaSO, and evaporated to dryness. The residue was purified by preparative TLC (PE: EtOAc, 1:1) followed by flash chromatography on a C18 column (gradient: 0-100% MeCN / water) to give the title compound (0.072 g, 26%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated value of FN4O3: 371.1514, Measured value: 371.1514; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.09-1.42(3H,m)1.64(1H,br d)1.69-1.93(6H,m)4.01-4.18(1H,m)6.21(1H,d)7.32-7.40(1H,m)7.41-7.48(3H,m)7.51(1H,dd)10.43(1H,br s)10.74(1H,br s).

[0344] Example 100: N-((1-cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide [ka] 2,6-Dimethylpyridine (130 μL, 1.12 mmol) was added to a mixture of 2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid intermediate 41 (50 mg, 0.22 mmol), (1-cyclohexyl-1H-pyrazol-5-yl)methanamine (40.2 mg, 0.22 mmol), and HATU (94 mg, 0.25 mmol) in DMF (2.11 mL). The reaction was left at room temperature overnight. The reaction was diluted with EtOAc (20 mL) and washed with sat. NaHCO (10 mL) and brine (3 × 10 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, preparative method SFC-A, (gradient: 5-90%) to give the title compound (10.90 mg, 12%); HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated value of FN4O3: 385.1670, Measured value: 385.1660; 1 H NMR(600MHz,DMSO-d6)δ 9.18(t,1H),7.89(s,1H),7.69(dd,1H),7.56(ddd,1H),7.32-7.37(m,2H),6.17(d,1H),4.56(d, 2H),4.2-4.26(m,1H),4.09(s,1H),1.74-1.83(m,6H),1.64(d,1H),1.35(qt,2H),1.17(qt,1H).

[0345] Example 101: (R)-(5-(4-fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone [ka] (R)-3-Phenylpyrrolidine (100 mg, 0.68 mmol) was added to a mixture of COMU (291 mg, 0.68 mmol), DIPEA (263 mg, 2.04 mmol), and 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid intermediate 34 (182 mg, 0.82 mmol) in DMF (5 mL). The reaction mixture was stirred at 25 °C for 3 h. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on a C18 column (gradient: 0-60% MeCN / water) followed by preparative HPLC, preparative method Y (gradient: 32-62%) to give the title compound (0.037 g, 15%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 18 Calculated value of FN2O3: 353.1296, Measured value: 353.1304; 1 H NMR(300MHz,DMSO-d6)δ ppm 1.96-2.18(1H,m)2.22-2.43(1H,m)3.42-3.68(2H,m)3.71-3.88(1H,m)3.93-4.10(1H,m)4.23(1H,dd)6.90-7.82(9H,m).

[0346] Example 102: (3H-spiro[isobenzofuran-1,3'-pyrrolidin]-1'-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] DIC (89 μL, 0.57 mmol) was added to a mixture of 3H-spiro[isobenzofuran-1,3′-pyrrolidine] (50 mg, 0.29 mmol), 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) under a N2(g) atmosphere at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with sat. NaHCO3 (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na2SO4, 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 Calculated value of F3N3O4: 418.1008, Found value: 418.1014; 1 H NMR(400MHz,DMSO-d6)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 [ka] (S)-3-(4-chlorophenyl)pyrrolidine (200 mg, 1.10 mmol) was added to a mixture of DIPEA (427 mg, 3.30 mmol), HATU (837 mg, 2.20 mmol), and 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (430 mg, 1.65 mmol) in DMF (10 mL). The reaction mixture was vigorously stirred at room temperature for 3 h, then quenched with saturated brine (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and evaporated. The yellow oil was purified by preparative HPLC, Prep Method Y (gradient: 28–38%) to give the title compound (0.039 g, 8%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 14 Calculated value for ClF3N3O3: 424.0670, Found value: 424.0676; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.96-2.17(1H,m)2.25-2.42(1H,m)3.41-3.99(4H,m)4.12(1H,ddd)7.29-7.51(4H,m)7.53-7.82(1H,m)11.73(1H,br s).

[0348] Example 104: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone [ka] EDC (118 mg, 0.62 mmol) and HOBt (83 mg, 0.62 mmol) were added to a mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid intermediate 37 (80 mg, 0.31 mmol), (R)-3-phenylpyrrolidine (45.4 mg, 0.31 mmol), DIPEA (162 μL, 0.93 mmol), and DMAP (7.54 mg, 0.06 mmol) in DMF (2 mL) at 20 °C. The resulting solution was stirred at 60 °C for 3 h under a N2(g) atmosphere. The reaction mixture was concentrated, diluted with EtOAc (25 mL), and washed with water (25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:10) and then by preparative HPLC, Prep Method N (gradient: 45-55%) to give the title compound (0.018 g, 15%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 16 Calculated value of F3N2O3: 389.1108, Measured value: 389.1094; 1 H NMR(300MHz,DMSO-d6)δ ppm 1.96-2.19(1H,m)2.30-2.43(1H,m)3.40-4.29(5H,m)7.16(1H,d)7.22-7.31(1H,m)7.31-7.39(4H,m)7.40-7.64(1H,m)11.56(1H,br s).

[0349] Example 105: N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide [ka] BBr3 (1 M in DCM, 0.2 mL, 0.20 mmol) was added dropwise to N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide intermediate 48 (50 mg, 0.12 mmol) in DCM (1 mL) under a N2(g) atmosphere at 0 °C. The resulting solution was stirred at 20 °C for 8 h. The reaction was quenched with MeOH (2 mL). The residue was purified by preparative TLC (MeOH:DCM, 1:10) followed by preparative HPLC, preparative method N (gradient: 31-44%) to give the title compound (0.014 g, 29%) as a white solid. HRMS (ESI) m / z [M+H] + C 18 H 18 Calculated for F3N2O3S: 399.0984, Found: 399.0976; Mixture of rotamers: 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.69-1.84 (1H, m), 1.89-2.11 (2H, m), 2.14-2.31 (1H, m), 2.76-2.88 (3H, m), 2.96-3.17 (3H, m), 3.53-3.72 (0.4H, m), 3.78-4.02 (1.6H, m), 4.96 (0.8H, dd), 5.27 (0.2H, dd), 7.18-7.79 (3H, m), 11.27 (1H, s). Total number of protons in the spectrum: 17.

[0350] Example 106: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (34 mg, 0.13 mmol), HATU (99 mg, 0.26 mmol), and DMF (0.5 mL) were mixed in a vial. Isoindoline-5-carbonitrile HCl (23.61 mg, 0.13 mmol) dissolved in DMF (0.500 mL) was added, followed by DIPEA (137 μL, 0.78 mmol). The resulting yellow solution was stirred overnight at room temperature. The reaction mixture was diluted with DMSO and purified by preparative HPLC, Prep Method C (gradient: 15-60%) to give the title compound (0.012 g, 24%) as a white solid; HRMS (ESI) m / z [M+H] + C 18 H 10 Calculated value of F3N4O3: 387.0700, Measured value: 387.0686; 1 H NMR (500MHz, DMSO-d6) δ 4.99(2H,d),5.22(2H,d),7.56-7.7(2H,m),7.77-7.84(1H,m),7.91(1H,d).

[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 [ka] MeAl (2 M in toluene, 0.985 mL, 1.97 mmol) was added to 3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazole Intermediate 51 (198 mg, 1.02 mmol) in toluene (2 mL) under a N2 (g) atmosphere. The resulting mixture was stirred at room temperature for 45 minutes. The mixture was added to a stirred slurry of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 1 (227 mg, 0.79 mmol) in toluene (2 mL). The resulting mixture was heated to 60 °C for 5 hours and then cooled to room temperature. Tartaric acid (30%, aq, 12 mL) was added, and the mixture was extracted with EtOAc (x2). The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative HPLC, Prep Method C (gradient: 35-75%) to give the title compound (209 mg, 61%) as an off-white solid; HRMS (ESI) m / z [M+H] + C 19 H 17 Calculated for F3N5O4: 436.1228, Found: 436.1210; Mixture of rotamers: 1 H NMR (500 MHz, MeOD): 1.33 (6H, dd), 2.74-2.82 (2H, m), 3.03-3.12 (1H, m), 3.92 (1.3H, t), 4.05 (0.7H, t), 4.51-4.57 (2H, m), 6.95-7 (0.4H, m), 7.07-7.11 (0.6H, m), 7.51-7.6 (1H, m). Total number of protons in the spectrum: 15.

[0352] Example 108: ((2S,6R)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] ((2S,6R)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone Example 87 (29 mg, 0.08 mmol) and NIS (73.0 mg, 0.32 mmol) in AcOH (2 mL) were stirred at room temperature for 20 h. The mixture was concentrated, and the residue was diluted with MeCN and DMSO and purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (27 mg, 68%) as a brown-yellow solid; HRMS (ESI) m / z [M+H] + C 15 H 14 Calculated value of F3IN3O4: 483.9976, Found value: 483.9962; 1 H NMR(500MHz,CDCl3)δ 1.22(3H,d),1.29(3H,d),2.6-2.72(2H,m),3.00(1H,dd),3.6-3.81(2H,m),4.20(1H,dt),4.63(1H,dt).

[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 [ka] A mixture of 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile Example 66 (0.149 g, 0.24 mmol) and NIS (0.218 g, 0.97 mmol) in AcOH (10 mL) was stirred at room temperature for 20 hours. The mixture was concentrated, and the residue was purified by preparative HPLC, Prep Method D (gradient: 20-80%) to give the title compound (0.063 mg, 50%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 11 Calculated value of F3IN4O3: 526.9822, Found value: 526.9808; 1H NMR(500MHz,CDCl3)3.26(2H,t),4.14(2H,t),5.01(2H,s),7.38(1H,t),7.46(1H,d),7.59(1H,d),9.23(1H,s)..

[0354] Example 110: ((2R,6S)-2,6-dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone [ka] MeAl (2 M in toluene, 0.347 mL, 0.69 mmol) was added dropwise to a solution of (2R,6S)-2,6-dimethylmorpholine (0.048 mL, 0.38 mmol) in anhydrous toluene (0.5 mL) under a N(g) atmosphere at room temperature. The reaction mixture was stirred at room temperature for 1 h and then added dropwise to a stirred mixture of methyl 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate intermediate 52 (80 mg, 0.29 mmol) in toluene (0.75 mL) under a N(g) atmosphere at room temperature. The resulting solution was heated at 60 °C for 6 h and then cooled to 0 °C. Tartaric acid (30%, aq, 4 mL) was added dropwise, and the resulting mixture was extracted with EtOAc (×2). The combined organic layers were washed with HO (×2), passed through a phase separator, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Prep Method D (gradient: 25-65%) to give the title compound (52 mg, 49%) as a white solid; HRMS (ESI) m / z [M+H] + C 15 H 15 Calculated value of F3N3O4: 358.1008, Found value: 358.1022; 1 H NMR(500MHz,DMSO-d6)δ 1.08(3H,d),1.17(3H,d),2.64(1H,dd),2.95(1H,dd),3.56-3.66(2H,m),4.1-4.17(1H,m),4.32-4.38(1H,m),7.48(1H,ddd),11.50(1H,s).

[0355] Example 111: ((3R,5S)-3,5-dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone [ka] The title compound was prepared 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) in a manner similar to that described in Example 110. The crude product was purified by preparative HPLC, Prep Method D (gradient: 35-75%) to give the title compound (67 mg, 65%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 17 Calculated value of F3N3O3: 356.1216, Measured value: 356.1224; 1 H NMR(500MHz,DMSO-d6)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 [ka] (4aR,7aS)-Octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol) was dissolved in MeOH and passed through an Isolute NH column (1 g). The compound was eluted with MeOH. MeOH was evaporated, and the residue was dissolved in dry toluene (0.5 mL). MeAl (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under a N2(g) atmosphere. The solution was stirred at room temperature for 45 minutes and then added dropwise 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) at room temperature under nitrogen. 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 re-extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, Prep 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 Calculated for F3N3O4: 370.1014, Found: 370.0996; Mixture of rotamers: 1 H NMR (500 MHz, DMSO-d6) 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 [ka] (4aS,7aR)-Octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol) was dissolved in MeOH and passed through an Isolute NH ion-exchange column (1 g). The compound was eluted with MeOH. MeOH was evaporated, and the residue was dissolved in dry toluene (0.5 mL). MeAl (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under a N2(g) atmosphere. The solution was stirred at room temperature for 45 minutes and then added dropwise 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) under a N2(g) atmosphere at room temperature. 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 Calculated for F3N3O4: 370.1014, Found: 370.1002; Mixture of rotamers: 1 H NMR (500 MHz, DMSO-d6) δ 1.44-2.04 (6H, m), 3.08-3.21 (0.6H, m), 3.36-3.51 (1.4H, m), 3.55-3.61 (0.4H, m), 3.71-3.8 (1H, m), 3.83-3.99 (1.6H, m), 4.16 (0.6H, dd), 4.43-4.65 (0.4H, m), 7.52-7.82 (1H, m), 11.68 (1H, s). Total number of protons in the spectrum: 14.

[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 [ka] (4aR,7aR)-Octahydrocyclopenta[b][1,4]oxazine (0.040 g, 0.32 mmol) was dissolved in dry toluene (0.5 mL). MeAl (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under a N2(g) atmosphere. The solution was stirred at room temperature for 45 minutes and then added dropwise 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) under a N2(g) atmosphere at room temperature. The solution was heated at 60 °C for 20 hours. Tartaric acid (30%, aq, 5 mL) was added dropwise, and 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, Prep Method C (gradient: 30-100%) to give the title compound (0.023 g, 26%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 15 Calculated for F3N3O4: 370.1014, Found: 370.1024; mixture of rotamers. 1 H NMR (500 MHz, DMSO-d6) δ 1.03-2.01 (6H, m), 3.03-3.28 (2H, m), 3.37-3.52 (1H, m), 3.54-3.78 (1.7H, m), 3.8-4.11 (1H, m), 4.32-4.46 (0.3H, m), 7.57-7.8 (1H, m), 11.70 (1H, s). Total number of protons in the spectrum: 14.

[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 [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (0.08 g, 0.31 mmol), HATU (0.234 g, 0.62 mmol), and DMF (1.2 mL) were mixed in a vial. (4aS,7aS)-Octahydrocyclopenta[b][1,4]oxazine HCl (Bioorganic & Medicinal Chemistry Letters (2015), 25(5), 1086-1091) (0.050 g, 0.31 mmol) was added, followed by DIPEA (0.322 mL, 1.85 mmol). The resulting yellow solution was stirred at room temperature for 4 h. The reaction mixture was diluted with DMSO and purified by preparative HPLC, Prep Method D (gradient: 30-100%) to give the title compound (0.039 g, 34%) as a pale yellow solid. HRMS(ESI)m / z[M+H] + C 16 H 15 Calculated for F3N3O4: 370.1014, found: 370.0981; mixture of rotamers. 1 H NMR (500 MHz, DMSO-d6) δ 0.98-2.01 (6H, m), 2.98-3.27 (2H, m), 3.36-3.53 (1H, m), 3.51-3.79 (1.7H, m), 3.79-4.19 (1H, m), 4.40 (0.3H, s), 7.51-7.84 (1H, m), 11.70 (1H, s). Total number of protons in the spectrum: 14.

[0360] Example 116: (5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone [ka] MeAl (2 M in toluene, 0.407 mL, 0.81 mmol) was added to a stirred solution of (2S,6R)-2,6-dimethylmorpholine (0.076 mL, 0.63 mmol) in toluene (1 mL) under a N2(g) atmosphere, and the resulting mixture was stirred at room temperature for 1 h. The mixture was added to a stirred slurry of ethyl 5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 53 (0.100 g, 0.37 mmol) in toluene (1 mL), and the resulting mixture was heated to 60 °C for 22 h, then cooled to room temperature. Tartaric acid (30%, aq, 5 mL) was added, and the mixture was extracted with EtOAc (5 mL). The organic layer was concentrated and the residue was purified by preparative HPLC, Prep Method C (gradient: 50-80%) to give the product (65 mg, 52%) as an off-white solid; HRMS (ESI) m / z [M+H] + ;C 15 H 16 Calculated value of F2N3O4: 340.1104, Found value: 340.1124; 1 H NMR(500MHz,DMSO-d6)δ 1.04(3H,d),1.16(3H,d),2.59(1H,dd),2.86(1H,dd),3.55(2H,dddt),3.77(1H,d),4.36(1H,d),7.55(1H,d),7.62(1H,ddd),11.29(1H,s).

[0361] Example 117: (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone [ka] 2,2,6-Trimethylmorpholine (0.041 g, 0.32 mmol) was dissolved in toluene (0.5 mL). MeAl (2 M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under a N2(g) atmosphere. The resulting solution was stirred at room temperature for 45 minutes and then added dropwise 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) under a N2(g) atmosphere at room temperature. 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, Prep Method D (gradient: 35-85%) to give the title compound (0.034 g, 38%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 17 Calculated for F3N3O4: 372.1166, Found: 372.1158; Mixture of rotamers: 1 H NMR (500 MHz, DMSO-d₆) 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-oxa-7-azaspiro[2.5]octan-7-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] 5-(2,4,5-Trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (64 mg, 0.25 mmol), HATU (122 mg, 0.32 mmol), and DMF (1 mL) were mixed in a vial. DIPEA (0.129 mL, 0.74 mmol) was added, followed by 4-oxa-7-azaspiro[2.5]octane HCl (55.2 mg, 0.37 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with DMSO and purified by preparative HPLC, Prep Method C (gradient: 20-80%) to give the title compound (20 mg, 23%) as a white solid; HRMS (ESI) m / z [M+H] + C 15 H 13 Calculated value of F3N3O4: 356.0852, Found value: 356.0854; 1 H NMR(500MHz,DMSO-d6)δ 0.56-0.61(1H,m),0.64-0.68(1H,m),0.68-0.74(1H,m),0.74-0.79(1H,m),3.50(1H,s),3. 65(2H,s),3.70(1H,s),3.71-3.76(1H,m),3.76-3.8(1H,m),7.5-7.82(1H,m),11.67(1H,s).

[0363] Example 119: ((3R,5S)-3,5-dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (2R,6S)-tert-Butyl 2,6-dimethylpiperazine-1-carboxylate (0.145 g, 0.68 mmol) was dissolved in dry toluene (1 mL). MeAl (2 M in toluene, 0.651 mL, 1.30 mmol) was added dropwise at room temperature under a N2 (g) atmosphere. The resulting solution was stirred at room temperature for 45 minutes and then added dropwise to a stirred solution of ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate Intermediate 1 (0.15 g, 0.52 mmol) in toluene (1.3 mL) under nitrogen. The solution was heated at 60°C for 20 hours. Tartaric acid (30%, aq, 5 mL) was added dropwise. The aqueous phase was washed with EtOAc. The aqueous phase was purified by preparative HPLC, Prep Method D (gradient: 5-45%) to give the title compound (0.126 g, 68%) as a white solid; HRMS (ESI) m / z [M+H] + C 15 H 16 Calculated value of F3N4O3: 357.1168, Measured value: 357.1158; 1 H NMR(500MHz,DMSO-d6)δ 1.03(3H,d),1.15(3H,d),2.56-2.69(1H,m),2.84-3.09(3H,m),3.86(1H,d),4.47(1H,d),7.16-7.46(1H,m).

[0364] Example 120: ((2R,6S)-2,6-dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone [ka] BBr3 (1 M in DCM, 1.025 mL, 1.02 mmol) was added dropwise to a solution of ((2S,6R)-2,6-dimethylmorpholino)(2-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanone intermediate 56 (132 mg, 0.34 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Further BBr3 (1 M in DCM, 1.025 mL, 1.02 mmol) was added dropwise and stirring was continued for 1.5 h. The reaction mixture was diluted with DCM, cooled in an ice bath, and water was carefully added. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were passed through a phase separator and concentrated. The residue was purified by preparative HPLC, Prep Method J (gradient: 30-70%) to give the title compound (86 mg, 68%) as a white solid; HRMS (ESI) m / z [M+H] + C 16 H 16 Calculated value of F3N2O3S: 373.0834, Measured value: 373.0821; 1 H NMR (500 MHz, DMSO, 25 °C) δ 0.72-1.35 (6H, m), 2.46-3.14 (solvent overlap, m), 3.54-3.64 (2H, m), 3.8-4.51 (2H, m), 7.62 (1H, ddd), 8.30 (1H, d), 11.45 (1H, s).

[0365] Example 121: rac-((2R,6S)-2-ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (racemic mixture) AlMe3 (2.17 mL, 4.34 mmol), 2 M in toluene, was added dropwise to a solution of rac-(2R,6S)-2-ethyl-6-methylmorpholine (314 mg, 2.43 mmol) in anhydrous toluene (2.5 mL) at room temperature under N2. The resulting solution was stirred for 1 h 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 (500 mg, 1.74 mmol) in anhydrous toluene (3.5 mL) at room temperature under N2. The resulting solution was stirred at 60 °C for 7.5 h. The reaction was cooled to room temperature overnight and then further cooled to 0 °C. 30% tartaric acid (aq, 25 mL) was added dropwise, and the resulting mixture was extracted with EtOAc (×2). The combined organic layers were washed with H2, passed through a phase separator, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Prep Method D (gradient 0-75%, then 100%) to give the title compound (62 mg, 10%) as a white solid; HRMS (ESI) m / z [M+H] + Calculated value for C16H17F3N3O4: 372.1171, Found value: 372.1156; 1 H NMR (500MHz, DMSO, 25℃, mixture of rotamers) δ 0.85(1.4H,t),0.93(1.6H,t),1.05(1.6H,d),1.17(1.4H,d),1.34-1.43(1H,m),1.46-1.56(1H,m),2.07(0H,s),2.62(1H,ddd ),2.89(1H,ddd),3.34-3.4(1H,m),3.46-3.61(1H,m),3.73-3.82(1H,m),4.34-4.42(1H,m),7.61-7.69(1H,m),11.68(1H,s).

[0366] Example 122 rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone [ka] (racemic mixture) 2 M AlMe3 (2.17 mL, 4.34 mmol) in toluene was added dropwise to a solution of rac-(2R,6S)-2-isopropyl-6-methylmorpholine (348 mg, 2.43 mmol) in anhydrous toluene (2.5 mL) at room temperature under N2. The resulting solution was stirred at room temperature for 1 h 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 (500 mg, 1.74 mmol) in anhydrous toluene (3.5 mL) at room temperature under N2. The resulting solution was stirred at 60 °C for 7.5 h. The reaction was cooled to room temperature overnight and then further cooled to 0 °C. 30% tartaric acid (aq, 25 mL) was added dropwise, and the mixture was extracted with EtOAc (×2). The combined organic layers were washed with HO, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Prep Method D (gradient 40-80%) to give the title compound (367 mg, 55%) as a white solid; HRMS (ESI) m / z [M+H] + Calculated for C17H19F3N3O4: 386.1328, Found: 386.1328; 1 H NMR (500MHz, DMSO, 25℃, mixture of rotamers) δ 0.83(1.3H,d),0.88(1.3H,d),0.93(1.7H,d),0.96(1.7H,d),1.05(1.7H,d),1.18 (1.3H,d),1.59-1.68(0.4H,m),1.69-1.77(0.6H,m),2.61(0.4H,dd),2.69(0.6H,d d),2.87(0.6H,dd),2.96(0.4H,dd),3.14-3.23(1H,m),3.45-3.62(1H,m),3.76(0 .6H,dt),3.84(0.4H,dt),4.34-4.45(1H,m),7.6-7.69(1H,m),11.5-11.88(1H,m).

[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 [ka] (racemic mixture) 2M AlMe3 (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 N2. 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 N2. The resulting solution was heated at 60 °C for 4 hours. The heat was removed and the reaction was allowed to cool 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 (x2). The organic layers were combined, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Prep Method J (gradient: 35-75%). The product-containing fractions were acidified to pH 5 with HOAc, and MeCN was removed under reduced pressure. The resulting aqueous oil / water mixture was extracted with DCM (x3). The combined organic layers were concentrated, and the residue was purified by preparative HPLC, Prep Method D (gradient: 35-75%) to give the title compound (208 mg, 63%) as a white solid; HRMS (ESI) m / z [M+H] + Calculated value for C17H17F3N3O4: 384.1171, Found value: 384.1185; 1 H NMR (500MHz, DMSO, 25℃, 3:2 mixture of 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 [ka] A mixture of ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone Example 87 (4.84 g, 13.6 mmol) and NBS (2.89 g, 16.26 mmol) in AcOH (50 mL) was stirred at 80° C. for 20 min. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in EtOAc (75 mL) and washed with water (5×50 mL). 30% NaCl(aq) (usually 1-3 mL) was added in small portions to hasten phase separation. The organic layer was washed with 30% NaCl(aq), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (5.91 g, 100%) as a pale yellow foamy solid.

[0369] A small amount of the title compound (200 mg) was further purified by preparative HPLC, Prep Method D, gradient (30-70%) to give the title compound (133 mg) as a white solid; HRMS (ESI) m / z [M+H] + Calculated value for C15H14BrF3N3O4: 436.0120, Found: 436.0116; 1 H NMR (500MHz, DMSO, 25℃) 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 17bHSD13 enzyme assay Ten concentrations of compound (0.2 μl) in DMSO were dispensed into a GREINER PP tube using an ECHO dispensing system (BECKMAN COULTER). 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 17bHSD13, 0.5 mM NAD, 20 μM estradiol, and various concentrations of compounds in buffer (5 mM EDTA (TEKNOVA E0306), 0.01% DDM (AFFYMETRIX) in 50 mM Tris-Cl (pH 7.4)). 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 LC-MS / MS system with the following settings: Samples were chromatographed on a WATERS, SYMMETRY, C8, 3.5 μm, 2.1 x 50 mm column at a constant flow rate of 0.5 mL / min. The mobile phase consisted of A (water with 0.2% formic acid) and B (acetonitrile with 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.5 min, linear increase to 100% B from 0.5 to 1 min, hold at 100% B from 1 to 1.6 min, then return to 50% B from 1.6 to 2 min. The run time was 2 min, and the retention times of estradiol and estrone were approximately 0.8 and 1.07 min, 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 multiple reaction monitoring (MRM) mode with an APCI probe in positive polarity. The MRM pairs were m / z 273.1 to m / z 107.0 and m / z 271.3 to m / z 107.0 for estradiol and estrone, respectively. The dwell time was 100 ms for each transition, and the depolarization and collision energies were 100 and 40, respectively. Data from the MS signals were analyzed 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 measuring the conversion of estradiol to estrone by LCMS / MS.

[0373] Cells were plated at 10 kJ / w in 30 μl of culture medium (DMEM with Glutamax + 10% FBS) in 384-well plates (GREINER CELL Culture Plate 384w Black / Clear Poly-D-Lysine). After allowing cells to attach for 6 hours, 0.15 μl of 10 concentrations of compound and 0.03 μl of 10 mM estradiol (Sigma, E8875) in DMSO were added using an ECHO dispensing system (Beckman Coulter). After culturing 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. 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 on a SCIEX API 5000 LC-MS / MS system with the following settings: Samples were chromatographed on a WATERS, symmetry, C8, 3.5 μm, 2.1 x 50 mm column at a constant flow rate of 0.5 mL / min. The mobile phase consisted of A (water with 0.2% formic acid) and B (acetonitrile with 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.5 min, linear increase to 100% B from 0.5 to 1 min, hold at 100% B from 1 to 1.6 min, then return to 50% B from 1.6 to 2 min. The run time was 2 min, and the retention times of estradiol and estrone were approximately 0.8 and 1.07 min, 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 multiple reaction monitoring (MRM) mode with an APCI probe in positive polarity. The MRM pairs were m / z 273.1 to m / z 107.0 and m / z 271.3 to m / z 107.0 for estradiol and estrone, respectively. The dwell time was 100 ms for each transition, and the depolarization and collision energies were 100 and 40, respectively. Data from the MS signals were analyzed using the area under the curve (AUC). Ratio = estrone / (estrone + estradiol).

[0375] In vitro 17bHSD4 enzyme assay Ten concentrations of compound (0.2 μl) in DMSO were added to a GREINER FLUOTRAC 200 384-well plate (781076) using an ECHO dispensing system (Beckman Coulter). 80 nl of 10 mM estradiol (Sigma, E8875) was added using an ECHO dispensing system. The enzymatic reaction was initiated by adding 40 μl of a mixture containing recombinant 17bHSD4 (M1-N311) and NAD using a MULTIDROP COMBI dispensing system (Thermo Fisher). The final assay conditions were 40 nM 17bHSD4, 0.125 mM NAD, 15 μM estradiol, and various concentrations of compound in buffer (5 mM EDTA (TEKNOVA E0306), 0.01% DDM (AFFYMETRIX D310) in 50 mM Tris-Cl (pH 7.4)). After each addition, the plate was centrifuged at 150 × g for 1 min (EPPENDORF, 5810R, A-4-81). NADH formation was measured by fluorescence intensity (FI) (Ex360 / Em460) at time 0 (t0) and 1.5 h (t1) using a PHERASTAR FSX (BMG LABTECH). FI for each sample was calculated as FI at t1 minus FI at t0.

[0376] In vitro 17bHSD9 cell assay Inhibition of 17bHSD9 was measured in a cell-based assay using HSD17β9 overexpressed in HEK293S cells and measuring the conversion of retinol to retinal by LCMS / MS.

[0377] Cells were plated at 10 kJ / w in 30 μl of culture medium (DMEM with Glutamax + 10% FBS) in 384-well plates (GREINER CELL Culture Plate 384w Black / Clear Poly-D-Lysine). After allowing cells to attach for 6 hours, 0.15 μl of 10 concentrations of compound and 0.015 μl of 10 mM all-trans-retinol (CAYMAN CHEMICAL, 20241) in DMSO were added using an ECHO dispensing system (BECKMAN COULTIER). After culturing 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. 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 LC-MS / MS system with the following settings: Samples were chromatographed on a WATERS, symmetry, C8, 3.5 μm, 2.1 x 50 mm column at a constant flow rate of 0.5 mL / min. The mobile phase consisted of A (water with 0.2% formic acid) and B (acetonitrile with 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, holding at 100% B from 0.8 to 1.5 min, then returning to 50% B from 1.5 to 1.6 min, for the duration of the run. The run time was 2 min, and the retention times of retinol and retinal were approximately 1.54 and 1.62 min, 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 multiple reaction monitoring (MRM) mode with an ESI probe in positive polarity. The MRM pairs were m / z 269.3 to m / z 93.0 and m / z 285.2 to m / z 161.0 for retinol and retinal, respectively. The dwell time was 100 ms for each transition, and the depolarization and collision energies were 50 and 25, respectively. Data from the MS signals were analyzed using the area under the curve (AUC). Ratio = retinal / (retinal + retinol).

[0379] Data analysis Curve fitting and IC 50 The values ​​were calculated using GENEDATA SCREENER. The effect of the compound was calculated using the following formula: Compound Effect % = -100 x [(X - Min) / (Max - Min)] where X represents the effect in the presence of the test compound, min is DMSO, and max 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 presented in Table 3 can be the results from a single 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 by 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, which is incorporated herein by reference. 6Cryopreserved hepatocytes were used at 10 ... 6 The mean (cell) was calculated from the slope of the natural logarithm regression analysis of the parent concentration versus time curve.

[0387] Assay B: Cytochrome P450 Inhibition 2C9 Inhibition of 2C9 was determined using a fluorescence-based method in a 96-well format (Crespi, CL 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, which 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 into fluorescent metabolites were used as probes for each individual CYP. The levels of formed metabolites were measured using a fluorescence plate reader (SPECTRAMAX GEMINIXS, MOLECULAR DEVICES, Sunnyvale, California, USA). A dilution series of the test substrate was prepared at eight different concentrations. For each CYP, a mixture of the enzyme, the corresponding coumarin substrate, potassium phosphate buffer pH 7.4, and water (concentration and volume dependent on the CYP) was added to each well of a black 96-well plate. Varying concentrations of the test substrate were then added. After a 10-minute preincubation, the reaction was initiated by adding the cofactor NADPH. After 20–50 minutes (dependent on the CYP and substrate), the reaction was terminated by adding Tris base / MeCN (20:80). The plate was transferred to a fluorescence plate reader with wavelengths individually set for the different coumarin substrates and their respective fluorescent metabolites. Responses were exported to Excel, and IC values ​​were calculated. 50 Curves were plotted (% inhibition vs. concentration) and IC values ​​were calculated for each test substrate and enzyme using XLfit. 50 was calculated.

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

[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 either HBSS (basal control), 30 nM (stimulated control) or various concentrations of a reference agonist (EC 50 (determined) or test compound. The adenylyl cyclase activator NKH 477 is then added to a final concentration of 3 μM. After 20 minutes of incubation at 37°C, 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 60 minutes at room temperature, the fluorescence transfer is measured using a microplate reader (RUBYSTAR, BMG) at gex = 337 nm and gem = 620 and 665 nm. The cAMP concentration is determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). Results are expressed as a percentage of the control response to 30 nM CP55940. The standard reference agonist is CP55940, which is tested at several concentrations in each study to generate a concentration-response curve from which its EC 50 Calculate.

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

[0391] [Table 16]

[0392] [Table 17]

[0393] [Table 18]

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

[0395] metabolic research In vitro studies to identify the metabolites of Example 87 yielded Metabolite 1 and Metabolite 2, defined below. Metabolites 1 and 2 were subsequently 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 [ka] A solution of ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Example 87 (60 mg, 0.17 mmol) and TEA (38 μL, 0.27 mmol) in anhydrous DCM (2.76 mL) was treated with pyridine-sulfur trioxide (1 / 1) (160 mg, 1.01 mmol), and the reaction mixture was stirred at room temperature for 5 min. The solid formed was removed by filtration, water was added to the filtrate, and the aqueous phase was washed with DCM. The pH of the aqueous phase was adjusted to 7-8 with NaHCO3. Lyophilization afforded the sodium salt of the desired product (23 mg, 30%). HRMS (ESI) m / z [M+H] + C 15 H 14 Calculated value of F3N3O7S: 436.0426, measured value: 436.0429.

[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 [ka] To a solution of ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone, Example 87 (1 eq), and (2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.9 eq) in MeCN (0.1 M) in a reaction vessel covered with aluminum foil, AgO (2.5 eq) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through CELITE, and the filtrate was diluted with EtOAc and then concentrated under reduced pressure. The crude compound was purified by preparative HPLC on an XBRIDGE C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase. The ethyl acetate group and ester were hydrolyzed by treatment with TEA (12 eq) and LiBr (40 eq) in MeCN (0.07 M) at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was acidified with HCl. The mixture was concentrated under reduced pressure, and the crude compound was purified by preparative HPLC, Prep Method D (gradient: 0-100%) to give the title compound; HRMS (ESI) m / z [M−H] - C 21 H 21 F3N3O 10 Calculated value: 532.1179, measured value: 532.1195.

[0398] The foregoing description of exemplary embodiments is intended solely to inform others skilled in the art of Applicant's specification, its principles, and its practical application, so that they may readily adapt and apply the specification in its numerous forms, as may be best suited to the requirements of a particular application. This description and its specific examples, while describing embodiments of the specification, are intended for illustrative purposes only. Accordingly, the specification is not limited to the exemplary embodiments set forth herein, as such may vary. Furthermore, it will be understood that various features of the specification, which are for clarity described in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the specification, which are for brevity described in the context of a single embodiment, may also be combined to form subcombinations thereof.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, A is, 【Chemistry 2】 Selected from: Each R Ａ are independently H, halo, R Ｘ , -OR ｘ and -CN, where each R Ｘ is independently C optionally substituted with 1 to 3 F １～３ alkyl); R Ｂ is halo, -CHF ２ , -CF ３ , -OCHF ２ or -OCF ３ and X １ , X ２ and X ３ is selected from NH, O and S, and X １ , X ２ and X ３ The other two are independently N and CR Ｙ where each R Ｙ are independently H, —CN, —C(═O)N(R ７ ) ２ or R ＸＡ and R ＸＡ is independently C optionally substituted with 1 to 3 F １～３ alkyl); R １ and R ２ teeth, (i) R １ and R ２ together with the N atom to which they are attached form a ring system, wherein said ring system optionally contains one or more R Ｃ and each R Ｃ are independently F, R ３ , R ４ , -O(R ４ ), -O(R ５ ), R ５ , R ６ , —OH, —CN, oxo and —C(═O)N(R ７Ａ ) ２ selected from: (ii) R １ is R ８ and R ４Ａ and R ２ is R ８Ａ and H; or (iii) R １ is R ５Ａ and R ２ is R ８Ｂ is It is; Each R ３ is independent, C １～４ Alkyl or C ３～６ cycloalkyl, each of which is optionally R ４Ｘ , R ５ｘ , -O(R ４Ｘ ), -O(R ５Ｘ ) and F; Each R ３Ｘ is independent, C １～４ Alkyl or C ３～６ cycloalkyl, each of which is optionally substituted with one or more F; Each R ４ and R ４Ｂ are independently monocyclic or bicyclic 5-9 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 halo; 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; Each R ５ , R ５Ａ and R ５Ｂ are independently phenyl, 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 halo; Each R ４Ｘ are independently monocyclic or bicyclic 5-9 membered heteroaryl, each of which is optionally selected from —OH, —CN, —C １～４ Alkoxy, —C(═O)OH, —C(═O)N(R ７Ｂ ) ２ , R ３Ｘ and halo; Each R ５Ｘ are independently phenyl, each of which optionally is —OH, —CN, —C １～４ Alkoxy, —C(═O)OH, —C(═O)N(R ７Ｂ ) ２ , R ３ｘ and halo; R ６ is optionally R ４Ｘ , R ５ｘ and C substituted with one or more groups independently selected from F １～４ is alkoxy; Each R ７ , R ７Ａ , R ７Ｂ and R ７Ｃ are independently H, C １～４ Alkyl or C ３～６ is cycloalkyl; R ８ , R ８Ａ , R ８Ｂ is independent, C １～４ Alkyl or C ３～６ cycloalkyl, each of which is optionally R ４Ｂ , R ５Ｂ , F, -OH, -CN, C １～４ Alkoxy, —C(═O)O(C １～４ alkyl) and —C(═O)N(R ７Ｃ ) ２ substituted with one or more groups independently selected from the ring system is a saturated or partially saturated monocyclic, bicyclic or tricyclic 4-13 membered ring containing one N atom and optionally containing one or two additional heteroatoms independently selected from N, O and S; 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.

2. (i) X １ is N and X ２ is O and 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 and X ２ is N and X ３ is CR Ｙ is; (v) X １ is N and X ２ is O and X ３ is CR Ｙ is; (vi) X １ is CR Ｙ and X ２ is N and X ３ is O; (vii) X １ is O and X ２ is N and 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 is; or (x) X １ is CR Ｙ and X ２ is N and X ３ is S, 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. X １ , X ２ and X ３ One of them is O and the other is X １ , X ２ and X ３ The other two are independently N and CR Ｙ 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

4. X １ is N and X ２ is O and X ３ is N, or a pharmaceutically acceptable salt thereof.

5. X １ , X ２ and X ３ One of them is S and the other is X. １ , X ２ and X ３ The other two are independently CR Ｙ 2. The compound of formula (I) according to claim 1, wherein:

6. Each R Ａ is independently H or halo, or a pharmaceutically acceptable salt thereof.

7. Each R Ａ is independently H or F, or a pharmaceutically acceptable salt thereof.

8. A is, 【Transformation 3】 The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. R Ｂ The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein

10. R １ and R ２ together with the N atom to which they are attached form a ring system, wherein said ring system optionally contains one or more R Ｃ 10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the ring system is an aliphatic monocyclic or bicyclic 4- to 11-membered ring containing one N atom and optionally one further heteroatom selected from N, O and S.

12. R １ and R ２ are taken together with the N atom to which they are attached to form a ring system selected from 4-8 membered monocyclic heterocycloalkyl, 8-11 membered spirocyclic bicyclic heterocycloalkyl, and 7-10 membered fused bicyclic heterocycloalkyl, wherein said ring system is optionally fused to one or more R Ｃ and heterocycloalkyl is a saturated ring containing one N atom and optionally one further heteroatom selected from N, O and S), a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

13. R １ and R ２ together with the N atom to which they are attached, optionally one or more R Ｃ 11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound forms a ring system which is a 4-8 membered monocyclic heterocycloalkyl substituted with , wherein the heterocycloalkyl is a saturated ring containing one N atom and optionally one further heteroatom selected from N, O and S.

14. R １ and R ２ together with the N atom to which they are attached, optionally one or more R Ｃ 11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound forms a ring system which is a 5-7 membered monocyclic heterocycloalkyl substituted with , wherein the heterocycloalkyl is a saturated ring containing one N atom and one further heteroatom selected from N, O and S.

15. The ring system may optionally be R ３ , R ４ and R ５ 15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 groups independently selected from:

16. Formula (II): 【Chemistry 4】 [In the formula, J is O, S, CH ２ , NH, and a covalent bond; G is absent or, together with the carbon atom to which it is attached, forms C ３～６ forming a cycloalkane ring; Z is (i) G is absent and J is O, S, or CH ２ and a covalent bond, Z is CH ２ , C.H. ２ CH ２ and C ３～６ cycloalkylidynes, (ii) When G is absent and J is NH, Z is CH ２ , C.H. ２ CH ２ , C ３～６ selected from cycloalkylidyne and C(═O), and (iii) G, together with the carbon atom to which it is attached, forms C ３～６ When forming a cycloalkane ring, Z is CH ２ is It is; x is selected from 0 to 3; and Each R ９ are independently ３ , R ４ and R ５ Selected from 8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

17. Formula (III): 【Transformation 5】 [In the formula, J is O, S, CH ２ , NH, and a covalent bond; x is selected from 0 to 3; Each R ９ are independently ３ , R ４ and R ５ is selected from: R Ｅ is H or halo] 6. The compound of formula (I) according to any one of claims 1 to 5, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

18. 18. The compound of formula (I) according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein J is O.

19. R １ is R ８ and R ４Ａ and R ２ is R ８Ａ and H. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

20. R ８ is R ４Ｂ and R ５Ｂ C substituted with 1 or 2 groups independently selected from １～４ 20. The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

21. R ４Ａ teeth, 【Transformation 6】 (In the formula, X ４ and X ５ are independently N or CH, and R １０ is R ３ or R ５ｘ 20. The compound of formula (I) according to claim 19, wherein:

22. R ８Ａ is C １～４ The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 19 to 21, wherein R is alkyl.

23. R １ is R ５Ａ and R ２ is R ８Ｂ 10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

24. R ８Ｂ is C １～４ 24. The compound of formula (I) according to claim 23, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

25. Each R ３ is independently C optionally substituted with 1 to 3 F １～４ 25. The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is alkyl.

26. Each R ４ and R ４Ｂ are independently monocyclic or bicyclic 5- to 9-membered heteroaryl, each of which is optionally 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 26. A compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, substituted with one or more groups independently selected from: and halo.

27. Each R ５ , R ５Ａ and R ５Ｂ are independently phenyl, each of which optionally is selected from the group consisting of OH, —CN, C １～４ Alkoxy, —C(═O)OH, —C(═O)O(C １～４ alkyl), —C(═O)N(R ７Ｂ ) ２ , R ３Ｘ 27. A compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, substituted with one or more groups independently selected from: and halo.

28. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 for use in therapy.

30. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 for use in the treatment of liver disease.

31. 28. The compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of a liver disease 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).

32. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 for use in the treatment of NASH.

33. 28. A method of treating liver disease in a patient, comprising administering to said patient a compound of formula (I) according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

Images