Amide heteroaromatics for treatment of liver disease

Abstract

The present specification relates to compounds of formula (I) and to pharmaceutically acceptable salts thereof, to processes and intermediates for preparing them, to pharmaceutical compositions containing them and to their use in the treatment of diseases such as liver disease. # imgabs0 #

Description

[0001] Cross-references to related patent applications

[0002] This specification claims the priority benefit of U.S. Provisional Patent Application Nos. 63 / 364,976 (filed on May 19, 2022), 63 / 367,843 (filed on July 7, 2022), and 63 / 383,982 (filed on November 16, 2022). The entire text of the above patent application is incorporated into this specification by reference.

[0003] The present invention 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. The present invention also relates to methods and intermediate compounds involved in the preparation of these amide heteroaromatic compounds, and pharmaceutical compositions containing these amide heteroaromatic compounds. Background Art

[0004] Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases, ranging from simple steatosis (nonalcoholic fatty liver) to nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis. Hepatic steatosis is defined as fat accumulation of more than 5% in the liver caused by causes other than alcohol intake. NASH is defined as hepatic steatosis accompanied by inflammation and hepatocellular damage, with or without fibrosis. It is estimated that approximately 25% of the global population has NAFLD, and mortality due to NAFLD-related diseases is expected to increase significantly by 2030.

[0005] To date, there are no approved treatments for NAFLD (such as NASH), and therapeutic interventions focus on addressing comorbidities that contribute to the pathogenesis of NAFLD, including treatment of insulin resistance, obesity, type 2 diabetes, and dyslipidemia.

[0006] Recently, variants of the 17βHSD13 gene have been associated with reduced serum aminotransferase levels and a reduced risk of liver disease, including alcoholic and non-alcoholic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in an allele-dose-dependent manner (Abul-Husn et al., NEngl J Med. 2018, 378(12), 1096-106, Wang et al., Eur Rev Med Pharmacol Sci 2020, 24(17), 8997-9007). The 17βHSD13 splice variant (rs72613567:TA) produces a truncated, unstable, and enzymatically inactive protein and is therefore characterized as a 17βHSD13 loss-of-function (LoF) variant (Ma et al., Hepatology 2019, 69(4), 1504-19). The association between LoF 17βHSD13 (rs72613567:TA) and reduced disease severity has been replicated in other cohorts with histologically confirmed NAFLD and was also associated with lower plasma transaminases, reduced risk of cirrhosis, HCC, and liver-related mortality in a study of 111,612 individuals in the Danish general population (Gellert-Kristensen et al., Hepatology, 2020, 71(1), 56-66). Interestingly, the protective effect of the LoF 17βHSD13 (rs72613567:TA) variant on plasma transaminase levels appears to be amplified by several key risk factors for liver disease, such as obesity, alcohol consumption, as well as established genetic risk factors, such as, but not limited to, the (rs738409C>G) variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3). In addition, two other 17βHSD13 LoF variants (rs62305723) and (rs143404524) have been reported to protect against chronic liver disease progression (Kozlitina et al., NEngl JMed [New England Journal of Medicine], 2018, 379(19), 1876-7). Overall, the LoF 17βHSD13 protective variants were more strongly associated with liver fibrosis and liver disease progression, but not with steatosis.

[0007] Based on the genetic validation that the 17βHSD13 LoF variant confers a protective effect on liver disease risk and progression, inhibiting the activity of 17βHSD13 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 steatosis), liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV), and hepatocellular carcinoma (HCC) in individuals who, for example, have several key risk factors for liver disease (e.g., obesity, alcohol consumption) as well as established genetic risk factors such as the (rs738409C>G) variant of PNPLA3.

[0008] The compounds of the present disclosure provide anti-hepatic effects at least by acting as 17βHSD13 inhibitors. In addition, the compounds of the present disclosure can selectively inhibit 17βHSD13 compared to 17βHSD4 and / or 17βHSD9.

[0009] Fifteen members of 17βHSD (HSD17B) have been identified in humans. Sequence homology between different members is low, but the overall structure appears to be conserved. 17β-Hydroxysteroid dehydrogenases are primarily involved in sex hormone metabolism. Some 17βHSD enzymes also play key roles in cholesterol and fatty acid metabolism (Labrie et al. Journal of Molecular Endocrinology, 2000, 25, 1–16, Wen Su et al. Molecular and Cellular Endocrinology, 2019, 489, 119–125). A clear off-target spectrum is an advantage of 17βHSD13 inhibitors, which can avoid potential toxicity caused by off-target activity. This includes selectivity for other 17βHSD members.

[0010] 17βHSD4 / D-bifunctional protein (DBP) is involved in fatty acid β-oxidation and steroid metabolism. 17βHSD4 is widely expressed and plays an important role in estrogen inactivation in a large number of peripheral tissues. 17βHSD4 mutations are known to cause DBP deficiency, an autosomal recessive peroxisomal fatty acid β-oxidation disorder that is usually fatal within the first two years of life. Homozygous missense variants in 17βHSD4 have been identified in Perrault syndrome, a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in males and females, and in some patients, neurological manifestations (Pierce et al. Am. J. Hum. Genet. [American Journal of Human Genetics], 2010, 87, 282-8; and Chen et al. BMC Med Genet. [BMC Medical Genetics], 2017, 18, 91).

[0011] 17βHSD9 / RDH5 (retinol dehydrogenase 5) is involved in retinoid metabolism. The enzyme is mainly expressed in retinal pigment epithelial cells. The RDH5 gene encodes an enzyme that is part of the visual cycle, namely 11-cis retinol dehydrogenase, which catalyzes the reduction of 11-cis-retinol to 11-cis-retinal. Mutations in the RDH5 gene can lead to progressive cone dystrophy or macular dystrophy and night blindness. White spot fundus is a rare congenital night blindness with damage to the rod system, characterized by the presence of many small white-yellow retinal lesions. This disorder is mainly caused by mutations in the RDH5 gene (Hotta et al. Am. J. Ophthalmol. [American Journal of Ophthalmology], 2003, 135, 917-9; and Skorczyk-Werner et al. J. Appl. Genet. [Journal of Applied Genetics], 2015, 56, 317-27).

[0012] Compared with other known 17βHSD13 inhibitors, the compounds of the present specification may also exhibit favorable physical properties (e.g., lower lipophilicity, higher water solubility, higher permeability, lower plasma protein binding, and / or higher chemical stability), and / or favorable toxicity characteristics (e.g., reduced activity on hERG), and / or favorable metabolism or pharmacokinetic characteristics. Therefore, such compounds may be particularly suitable as therapeutic agents, for example, for the treatment of liver diseases. Summary of the invention

[0013] According to one aspect of the present specification, there is provided a compound having formula (I);

[0014]

[0015] in,

[0016] A is selected from

[0017]

[0018] Each R A are independently selected from H, halo, R X 、-OR x and -CN, where each R X is independently C optionally substituted with one to three F 1-3 alkyl;

[0019] R B is halogenated, -CHF2, -CF3, -OCHF2 or -OCF3;

[0020] X 1 , X 2 and X 3 one of which is selected from NH, O and S, and X 1 , X 2 and X 3 The other two are independently selected from N and CR Y , where each R Y are independently H, -CN, -C(=O)N(R 7 )2 or R XA , where R XA is independently C optionally substituted with one to three F 1-3 alkyl;

[0021] R 1 and R 2 This is so that;

[0022] (i)R 1 and R 2 Together with the N atom to which they are attached, they form a ring system, wherein the ring system is optionally substituted by one or more R C Substitute, where each R C Independently selected from 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;

[0023] (ii) R 1 Selected from R 8 and R 4A , and R 2 Selected from R 8A and H; or

[0024] (iii) R 1 YesR 5A And R 2 YesR 8B ;

[0025] Each R 3 Independently C 1-4 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by one or more independently selected from R 4X , R 5x 、-O(R 4X )、-O(R 5X ) and F are substituted by groups;

[0026] Each R 3X Independently C 1-4 Alkyl or C 3-6 cycloalkyl, each of which is optionally substituted with one or more F;

[0027] Each R 4 and R 4B is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, each of which is optionally substituted by one or more independently selected from 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 halogenated group substitution;

[0028] R 4A is a 5-membered monocyclic heteroaryl group, which is optionally substituted by one or more independently selected from 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 halogenated group substitution;

[0029] Each R 5 , R 5A and R 5B is independently phenyl, each of which is optionally substituted by one or more independently selected from R 4X 、-O(R 4X ), R 5X 、-O(R5X )、-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 halogenated group substitution;

[0030] Each R 4X is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, each of which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3X and halogenated group substitution;

[0031] Each R 5X are independently phenyl, each of which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x and halogenated group substitution;

[0032] R 6 It is C 1-4 Alkoxy, which is optionally substituted by one or more independently selected from R 4X , R 5x and group substitution of F;

[0033] Each R 7 , R 7A , R 7B and R 7C Independently H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0034] R 8 , R 8A , R 8B Independently C 1-4 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by one or more independently selected from 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 group substitution;

[0035] wherein the ring system is a saturated or partially saturated, monocyclic, bicyclic or tricyclic 4-13 membered ring comprising one N atom and optionally one or two additional heteroatoms independently selected from N, O and S; and

[0036] wherein each heteroaryl is independently an aromatic ring containing one or more heteroatoms independently selected from N, O and S,

[0037] or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0039] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0040] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating liver disease.

[0041] In another aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

[0042] In another aspect, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating liver disease.

[0043] In another aspect, a method of treating a liver disease in a patient is provided, the method comprising administering to the patient an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, provided are intermediates useful for synthesizing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0045] definition

[0046] In order to make this specification more easily understood, certain terms are explicitly defined below. In addition, definitions are set forth throughout the detailed description as appropriate.

[0047] As used herein, the term "alkyl" refers to straight-chain and branched saturated hydrocarbon groups having the specified number of carbon atoms.

[0048] In this specification, the prefix C x-y (For example, in terms such as "C x-y alkyl" etc.)) where x and y are integers represents the numerical range of carbon atoms present in the group. Suitable C 1-3 Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl. Suitable C 1-4Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0049] In this specification, the prefix X-membered-Y-membered as used in terms such as "X-membered-Y-membered ring" and the like (wherein X and Y are integers) indicates a numerical range of atoms (ie, carbon atoms and heteroatoms) present in the group.

[0050] 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. Suitable C 1-3 Examples of alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr) and isopropoxy (O i Pr). Suitable C 1-4 Examples of alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr), isopropoxy (O i Pr), n-butoxy (O n Bu), isobutyloxy (O i Bu), sec-butyloxy (O s Bu) and tert-butyloxy (O t Bu).

[0051] As used herein, the term "cycloalkane" refers to a saturated carbon ring. 3-6 Examples of cycloalkane groups are cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0052] As used herein, the term "cycloalkylidyne" refers to a 1,1-diradical of a cycloalkane. 3-6 An example of a cycloalkylidene group is a cyclopropylene group (i.e. ), cyclobutylene (i.e. ), cyclopentylene (i.e. ) and cyclohexylene (i.e. ).

[0053] Unless otherwise indicated, "halo" is selected from Cl, F, Br and I. In embodiments, halo is selected from Cl and F.

[0054] The term "heteroatom" refers to N, O or S.

[0055] Unless otherwise indicated, the term "heteroaryl" is an aromatic, monocyclic or bicyclic 5- to 9-membered ring containing one or more heteroatoms independently selected from N, O and S. Wherein the compounds disclosed herein contain more than one heteroaryl group, and these heteroaryl groups may be the same or different. The heteroaryl group may be a 5- or 6-membered monocyclic heteroaryl. Examples of suitable 5-membered heteroaryl groups include pyrrolyl, furanyl, thienyl, 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. Examples of 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 group can be a 9-membered bicyclic heteroaryl group. When the heteroaryl group is bicyclic, one or both rings can be aromatic. Examples of suitable 9-membered heteroaryl groups include indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, indolinyl, isoindolyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, 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).

[0056] Unless otherwise indicated, the term "heterocycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic ring containing one N atom and one additional heteroatom selected from N, O and S. For the avoidance of doubt, the other atoms of the ring are carbon. Examples of suitable heterocycloalkyl groups 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.

[0057] The term "4-8 membered monocyclic heterocycloalkyl" refers to a saturated 4-8 membered monocyclic ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur, and for the avoidance of doubt, the other atoms of the ring are carbon. Suitable 4-membered heterocycloalkyl is azetidin-1-yl. Suitable 5-membered heterocycloalkyl is pyrrolidin-1-yl. Examples of suitable 6-membered heterocycloalkyl groups include piperidin-1-yl, piperazin-1-yl, morpholine-4-yl and thiomorpholine-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-oxazoc-4-yl, 1,5-oxazoc-5-yl, 1,4-thiazocanyl and 1,5-thiazocanyl.

[0058] The term "8-11 yuan spiro ring bicyclic heterocycloalkyl" refers to a saturated 8-11 yuan bicyclic spiro ring, which contains a nitrogen atom and optionally one additional heteroatom selected from N, O and S, and for the avoidance of doubt, the other atoms of the ring are carbon. Examples of suitable 8-yuan spiro ring heterocycloalkyl groups include 5-azaspiro [2.5] octane-5-yl, 4,7-diazaspiro [2.5] octane-7-yl, 4-oxa-7-azaspiro [2.5] octane-7-yl and 4-thia-7-azaspiro [2.5] octane-7-yl. Examples of suitable 9-yuan spiro ring 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]dec-7-yl, 6,9-diazaspiro[4.5]dec-9-yl, 6-oxa-9-azaspiro[4.5]dec-9-yl and 6-thia-9-azaspiro[4.5]dec-9-yl. Examples of suitable 11-membered spirocyclic heterocycloalkyl groups include 2-azaspiro[5.5]undec-2-yl, 1,4-diazaspiro[5.5]undec-4-yl, 1-oxa-4-azaspiro[5.5]undec-4-yl and 1-thia-4-azaspiro[5.5]undec-4-yl.

[0059] The term "7-10 membered fused bicyclic heterocycloalkyl" refers to a saturated 7-10 membered bicyclic fused ring comprising one nitrogen atom and optionally one further heteroatom selected from N, O and S, for the avoidance of doubt the other atoms of the ring being carbon. Examples of suitable 7 membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.1.0]hept-2-yl, 2,5-diazabicyclo[4.1.0]hept-2-yl, 2-oxa-5-azabicyclo[4.1.0]hept-5-yl and 2-thia-5-azabicyclo[4.1.0]hept-5-yl. Examples of suitable 8-membered fused bicyclic heterocycloalkyl groups include 2-azabicyclo[4.2.0]oct-2-yl, 2,5-diazabicyclo[4.2.0]oct-2-yl, 2-oxa-5-azabicyclo[4.2.0]oct-5-yl and 2-thia-5-azabicyclo[4.2.0]oct-5-yl. Examples of suitable 9-membered fused bicyclic heterocycloalkyl groups include octahydro-1H-cyclopenta[b]pyridin-1-yl, octahydro-1H-cyclopenta[b]pyrazin-1-yl, octahydrocyclopenta[b][1,4]oxazin-4-yl and octahydrocyclopenta[b][1,4]thiazin-4-yl. Examples of suitable 10-membered fused bicyclic heterocycloalkyl groups include decahydroquinolin-1-yl, decahydroquinoxalin-1-yl, octahydro-2H-benzo[b][1,4]oxazin-4-yl and octahydro-2H-benzo[b][1,4]thiazin-4-yl.

[0060] The term "8-10 membered bridged bicyclic heterocycloalkyl" refers to a saturated 8-10 membered bicyclic bridged ring comprising one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein the remaining atoms of the 8-10 membered fused bicyclic heterocycloalkyl group are carbon. Examples of suitable 8-10 membered bridged bicyclic heterocycloalkyl groups include 3-azabicyclo[3.2.1]oct-3-yl, 3-azabicyclo[3.2.2]nonane and 3-azabicyclo[3.3.2]decane-3-yl.

[0061] The term "oxo" refers to an oxygen atom forming a double bond (ie, =0) to a suitable atom (eg, carbon).

[0062] Unless otherwise indicated, 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 of the ring are carbon. When the ring system is bicyclic, it may be spirocyclic, fused or bridged. Examples of suitable monocyclic ring systems include 4-6 membered heterocycloalkyl. Examples of suitable bicyclic ring systems include 8-11 membered spirocyclic bicyclic heterocycloalkyl, 7-10 membered fused bicyclic heterocycloalkyl and 8-10 membered bridged bicyclic heterocycloalkyl.

[0063] The term "saturated or partially saturated" ring system refers to a ring system which is aliphatic or which contains at least one aliphatic ring and one or two aromatic rings.

[0064] Unless expressly stated otherwise, the bonding atom of a group may be any suitable atom of the group; for example, propyl includes prop-1-yl and prop-2-yl.

[0065] For the avoidance of doubt, where a plurality of substituents are independently selected from a given group, the selected substituents may comprise the same substituent or different substituents from the given group.

[0066] For the avoidance of doubt, a circle is used within a 5-membered ring to indicate that the 5-membered ring is an aromatic ring. By way of example only, Indicates selected from Aromatic ring.

[0067] For the avoidance of doubt, the formulas used in this specification are represents the point of attachment between different groups. By way of example only, represents a 3-hydroxyphenyl group which is attached to a different group via the carbon atom in the meta position of the OH substituent.

[0068] For the avoidance of doubt, use of a bond between a substituent and the center of a ring indicates that the substituent may replace any hydrogen atom directly attached to the ring, whether or not that hydrogen atom is attached to a C or N atom. By way of example only, Indicates selected from The group.

[0069] Where any embodiment within this specification includes a group that is referred to as being "optionally substituted," another embodiment will include embodiments where the group is unsubstituted.

[0070] For the avoidance of doubt, where a plurality of substituents are independently selected from a given group, the selected substituents may comprise the same substituent or different substituents from the given group.

[0071] Units, prefixes and symbols are expressed in their form accepted by the International System of Units (SI). Numerical ranges are inclusive of the numbers defining the range.

[0072] 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 the present disclosure belongs. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, Revised edition, 2000, Oxford University Press provide a general dictionary reference to many of the terms used in the present disclosure for a skilled artisan. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Embodiments and experiments illustrating the principles of the present disclosure will now be discussed with reference to the accompanying drawings, in which:

[0074] Figure 1 The synthetic scheme of intermediate 1 is illustrated.

[0075] Detailed Description

[0076] In one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

[0077] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0078] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is an aliphatic, monocyclic or bicyclic 4-11 membered ring (wherein the ring system is optionally replaced by one or more R) containing one N atom and optionally one or two additional heteroatoms independently selected from N, O and S. C replace).

[0079] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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 is optionally separated by one or more R C replace).

[0080] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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 is optionally replaced by one or more R C replace).

[0081] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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 is optionally replaced by one or more R C replace).

[0082] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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 is optionally replaced by one or more R C replace).

[0083] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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 is optionally separated by one or more R C replace).

[0084] In an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is an aliphatic, monocyclic 5-8 membered ring containing one N atom and one O atom (wherein the ring system is optionally replaced by one or more R C replace).

[0085] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is a 4-8 membered monocyclic heterocycloalkyl, which is optionally substituted by one or more R C replace.

[0086] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is a 5-7 membered monocyclic heterocycloalkyl, which is optionally substituted by one or more R C replace.

[0087] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is an 8-11 membered spirobicyclic heterocycloalkyl, which is optionally substituted by one or more R C replace.

[0088] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is a 7-10 membered fused bicyclic heterocycloalkyl, which is optionally substituted by one or more R C replace.

[0089] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is an 8-10 membered bridged bicyclic heterocycloalkyl optionally substituted by one or more R C replace.

[0090] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is optionally replaced by one or more R C In other embodiments, the ring system is optionally substituted by one to three R C In other embodiments, the ring system is optionally replaced by one or two R C In other embodiments, the ring system is unsubstituted.

[0091] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein each R C Independently selected from F, R 3 , R 4 、-O(R 4 )、-O(R 5 ), R 5 , R 6 , -OH, -CN and -C(=O)N(R 7A)2. In another embodiment, each R C Independently selected from R 3 , R 4 、O(R 4 )、-O(R 5 ), R 5 and R 6 In another embodiment, each R C Independently selected from R 3 , R 4 and R 5 In another embodiment, each R C Independently R 3 In another embodiment, each R C Independently C 1-4 alkyl, which is optionally substituted with one or more (e.g., one to three) F. In further embodiments, each R C Independently selected from C 1-4 In other embodiments, each R C Independently C 1-4 In another embodiment, each R C It is CH3.

[0092] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0093]

[0094] Where x is selected from 0 to 3, and each R 9 Independently selected from R 3 , R 4 and R 5 .

[0095] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0096]

[0097] Where x is selected from 0 to 3, and each R 9 Independently selected from R 3 , R 4 and R 5 .

[0098] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R2 is a group selected from the following,

[0099]

[0100] Where x is selected from 0 to 3, and each R 9 Independently selected from R 3 , R 4 and R 5 .

[0101] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 yes

[0102]

[0103] Where x is selected from 0 to 3, and each R 9 Independently selected from R 3 , R 4 and R 5 .

[0104] In an embodiment, the compound of formula (I) is a compound of formula (II):

[0105]

[0106] in

[0107] J is selected from O, S, CH2, NH and a covalent bond,

[0108] G is absent or, together with the carbon atom to which it is attached, forms C 3-6 Cycloalkane ring;

[0109] Z is such that

[0110] (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 Cycloalkylene,

[0111] (ii) when G is absent and J is NH, Z is selected from CH2, CH2CH2, C 3-6 Cycloalkylene and C(═O), and

[0112] (iii) When G and the carbon atom to which it is attached form C 3-6 In the case of a cycloalkane ring, Z is CH2;

[0113] x is selected from 0 to 3; and

[0114] Each R 9 Independently selected from R 3 , R4 and R 5 ,

[0115] or a pharmaceutically acceptable salt thereof.

[0116] In an embodiment, the compound of formula (II) is a compound of formula (IIA) or formula (IIB):

[0117]

[0118] Where X 1 , X 2 , X 3 , A, J, R 9 and x are as defined for the compound having formula (II).

[0119] In an embodiment, the compound of formula (II) is a compound of formula (IIC)

[0120]

[0121] Where X 1 , X 2 , X 3 , A, J, R 9 and x are as defined for the compound having formula (II).

[0122] In an embodiment, the compound of formula (II) is a compound of formula (IID)

[0123]

[0124] Where X 1 , X 2 , X 3 , A, J, R 9 and x is as defined for the compound having formula (II), and y is an integer from 1 to 4.

[0125] In an embodiment, the compound of formula (II) is a compound of formula (IIE)

[0126]

[0127] Where X 1 , X 2 , X 3 , A, J, R 9 and x are as defined for the compound having formula (II), and z is an integer from 1 to 4.

[0128] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R2 is a group selected from the following

[0129]

[0130] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0131]

[0132] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0133]

[0134] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0135]

[0136] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 is a group selected from the following

[0137]

[0138] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is selected from

[0139]

[0140] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is selected from

[0141]

[0142] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the ring system is selected from

[0143]

[0144] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 1 Selected from R 8 and R4A , and R 2 Selected from R 8A and H.

[0145] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 1 YesR 8 , and R 2 Selected from R 8A and H.

[0146] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 8 It is C 1-4 Alkyl or C 3-6 Cycloalkyl (e.g. C 1-4 alkyl), each of which is optionally substituted by one or more independently selected from 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 is substituted with a group (e.g., one to three groups). In another embodiment, R 8 It is C 1-4 Alkyl (eg CH3), which is optionally substituted by one or two independently selected from 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 is substituted with a group (e.g., a group). In another embodiment, R 8 It is C 1-4 Alkyl (eg CH3), which is optionally substituted by one or two independently selected from R 4B (For example, R 4x ) and R 5B (For example, R 5x ) is substituted with a group (e.g., a group). In another embodiment, R 8 It is C 1-4 Alkyl (e.g. CH3), which is optionally substituted by 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, wherein the heteroaryl and phenyl are optionally substituted by one or more selected from C 1-4 Alkyl (e.g. CH3), C 3-6The cycloalkyl (eg, cyclohexyl) and phenyl groups (eg, one or two groups) are substituted.

[0147] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 8 It is C 1-4 Alkyl or C 3-6 Cycloalkyl (e.g. C 1-4 alkyl), each of which is independently selected from 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 is substituted with a group (e.g., one to three groups). In another embodiment, R 8 It is C 1-4 Alkyl (eg CH3), which is composed of one or two independently selected 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 is substituted with a group (e.g., a group). In another embodiment, R 8 It is C 1-4 Alkyl (eg CH3), which is composed of one or two independently selected R 4B (For example, R 4x ) and R 5B (For example, R 5x ) is substituted with a group (e.g., a group). In another embodiment, R 8 It is C 1-4 Alkyl (e.g. CH3), which is substituted by phenyl or monocyclic or bicyclic 5- to 9-membered heteroaryl, wherein the phenyl or monocyclic or bicyclic 5- to 9-membered heteroaryl is optionally substituted by one or two independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are substituted.

[0148] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 4A is a 5-membered monocyclic heteroaryl group, which is optionally substituted by one or more independently selected from R 4X 、-O(R 4X ), R 5X 、-O(R5X )、-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 halogenated groups (e.g., one to three groups). In another embodiment, R 4A is a 5-membered monocyclic heteroaryl group, which is optionally substituted by one or two independently selected from R 4X , R 5X and R 3X In another embodiment, R 4A is a 5-membered monocyclic heteroaryl group, which is optionally substituted by one or two selected from C 1-4 Alkyl, C 3-6 In another embodiment, R 4A is 1H-pyrazolyl (e.g. 3-1H-pyrazolyl), tetrazolyl (e.g. 5-tetrazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl) or 1H-benzo[d]imidazolyl (e.g. 2-1H-benzo[d]imidazole), each of which is optionally substituted by one or more selected from C 1-4 Alkyl (e.g. CH3), C 3-6 The cycloalkyl (eg cyclohexyl) and phenyl groups are substituted.

[0149] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 4A yes

[0150]

[0151] Where R 10 For R 3 or R 5x , and X 4 and X 5 are independently N or CH. In another embodiment, X 4 is CH. In another embodiment, X 5 It is CH.

[0152] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein each R 4B is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, which is optionally substituted by one or more independently selected from R 4X 、-O(R 4X ), R 5X 、-O(R 5X )、-OH、-CN、C 1-4 Alkoxy, -C(=O)OH, -C(=O)O(C1-4 alkyl), -C(=O)N(R 7B 2. R 3 and halogenated groups (e.g., one to three groups). In another embodiment, each R 4B is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (eg, a monocyclic 5- or 6-membered heteroaryl), which is optionally substituted by one or more (eg, one to three) independently selected from halo, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 In another embodiment, R 4B is 1H-pyrazolyl (e.g. 3-1H-pyrazolyl), tetrazolyl (e.g. 5-tetrazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl) or 1H-benzo[d]imidazolyl (e.g. 2-1H-benzo[d]imidazole), each of which is optionally substituted by one or two selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl groups are substituted.

[0153] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 8A It is C 1-4 In another embodiment, R 8A It is CH3, CH(CH3)2 or C(CH3)3.

[0154] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 1 YesR 5A And R 2 YesR 8B .

[0155] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 5A is phenyl, which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x and halogenated groups (e.g., one to three groups). In another embodiment, R 5A is phenyl, which is optionally substituted by one or two independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x In another embodiment, R 5A is phenyl, which is optionally substituted by one or two independently selected from -CN, C1-4 Alkoxy, R 3x In another embodiment, R 5A is phenyl, which is optionally substituted with -CN.

[0156] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 5B is phenyl, which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x and halogenated groups (e.g., one to three groups). In another embodiment, R 5B is phenyl, which is optionally substituted by one or two independently selected from -CN, C 1-4 Alkoxy, R 3x In another embodiment, R 5B is phenyl, which is optionally replaced by C 1-4 Alkoxy substitution.

[0157] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 8B It is C 1-4 In another embodiment, R 8B It is CH3, CH(CH3)2 or C(CH3)3.

[0158] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein NR 1 R 2 Selected from

[0159]

[0160] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE) or a pharmaceutically acceptable salt thereof is provided, wherein each R A are independently selected from H, halo, R X 、-OR x and -CN, where each R X is independently C optionally substituted with one to three F 1-3 In another embodiment, each R A are independently selected from H, halo, C 1-3 Alkyl, C 1-3 In another embodiment, each R Ais independently selected from H, F and Cl. In another embodiment, each R A Independently selected from H and F.

[0161] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE) or a pharmaceutically acceptable salt thereof is provided, wherein A is selected from

[0162]

[0163] Where R A As defined above.

[0164] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE) or a pharmaceutically acceptable salt thereof is provided, wherein A is

[0165]

[0166] Where R A and R B As defined above. In another embodiment, R B is F, Cl or CF3. In another embodiment, one or more R A is F. In another embodiment, two or more R A is F. In another embodiment, each R A It's F.

[0167] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE) or a pharmaceutically acceptable salt thereof is provided, wherein A is

[0168]

[0169] Where R A As defined above. In another embodiment, each R A R is independently H, F or Cl. In another embodiment, each R A It is H or F.

[0170] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID) or (IIE) or a pharmaceutically acceptable salt thereof is provided, wherein A is

[0171]

[0172] Where R E is H or halogenated.

[0173] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (III):

[0174]

[0175] in

[0176] J is selected from O, S, CH2, NH and a covalent bond,

[0177] x is selected from 0 to 3;

[0178] Each R 9 Independently selected from R 3 , R 4 and R 5 ;as well as

[0179] R E is H or halogenated,

[0180] or a pharmaceutically acceptable salt thereof.

[0181] In embodiments, the compound of formula (III) is a compound of formula (IIIA), (IIIB) or (IIIC)

[0182]

[0183] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , R E , R 9 and x are as defined for compounds of formula (III). In further embodiments, each R 9 Independently selected from C 1-4 In other embodiments, x is selected from 1, 2, and 3.

[0184] In an embodiment, the compound of formula (III) is a compound of formula (IIID)

[0185]

[0186] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and R E As defined for compounds of formula (III), and each R 11 Independently selected from H, R 3 , R 4 and R 5 In another embodiment, each R 11 Independently H, R3 , R 4x or R 5x In another embodiment, each R 11 Independently H, R 3x , R 4x or R 5X In another embodiment, each R 11 independently H or R 3x In another embodiment, each R 11 independently H or C 1-4 In another embodiment, each R 11 are independently H or CH3.

[0187] In an embodiment, a compound having Formula (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein R E is H, F or Cl. In another embodiment, R E It is H or F.

[0188] In an 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 X 1 , X 2 and X 3 One of them is O, and X 1 , X 2 and X 3 The other two are selected from N and CR Y In another embodiment, R Y It's H.

[0189] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is S, and X 1 , X 2 and X 3 The other two are selected from N and CR Y In another embodiment, R Y It's H.

[0190] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is O, and X 1 , X 2 and X 3 The other two in are both N.

[0191] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is O, X 1 , X 2 and X 3 One of them is N, and X 1 , X 2 and X 3 One of them is CR Y In another embodiment, R Y is H or -CN.

[0192] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is S, and X 1 , X 2 and X 3 The other two in are both N.

[0193] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is S, X 1 , X 2 and X 3 One of them is N, and X1 , X 2 and X 3 One of them is CR Y In another embodiment, R Y It's H.

[0194] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 , X 2 and X 3 One of them is S, and X 1 , X 2 and X 3 The other two are CR Y In another embodiment, each R Y It's H.

[0195] In an 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

[0196] (i)X 1 It is N, X 2 is O and X 3 It is N,

[0197] (ii)X 1 It is N, X 2 is N and X 3 It is O;

[0198] (iii)X 1 Yes CR Y , X 2 Yes CR Y And X 3 It is S;

[0199] (iv)X 1 It's O, X 2 is N and X 3 Yes CR Y ;

[0200] (v)X 1 It is N, X 2 is O and X 3 Yes CR Y ;

[0201] (vi)X 1Yes CR Y , X 2 is N and X 3 It is O;

[0202] (vii)X 1 It's O, X 2 is N and X 3 is N;

[0203] (viii)X 1 It is N, X 2 is N and X 3 is S; or

[0204] (ix)X 1 Yes CR Y , X 2 is S and X 3 Yes CR Y .

[0205] In an 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

[0206] (i)X 1 It is N, X 2 is O and X 3 It is N,

[0207] (ii)X 1 It is N, X 2 is N and X 3 It is O;

[0208] (iii)X 1 Yes CR Y , X 2 Yes CR Y And X 3 It is S;

[0209] (iv)X 1 It's O, X 2 is N and X 3 Yes CR Y ;

[0210] (v)X 1 It is N, X 2 is O and X 3 Yes CR Y ;

[0211] (vi)X 1 Yes CR Y , X 2is N and X 3 It is O;

[0212] (vii)X 1 It's O, X 2 is N and X 3 is N;

[0213] (viii)X 1 It is N, X 2 is N and X 3 It is S;

[0214] (ix)X 1 Yes CR Y , X 2 is S and X 3 Yes CR Y or

[0215] (x)X 1 Yes CR Y , X 2 is N and X 3 It’s S.

[0216] In an 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

[0217] (i)X 1 It is N, X 2 is O and X 3 It is N,

[0218] (ii)X 1 It is N, X 2 is N and X 3 It is O;

[0219] (iii)X 1 It is CH, X 2 is CH and X 3 It is S;

[0220] (iv)X 1 It's O, X 2 is N and X 3 It is CH;

[0221] (v)X 1 It is N, X 2 is O and X 3 It is CH;

[0222] (vi)X 1 It is CH, X 2 is N and X3 It is O;

[0223] (vii)X 1 It's O, X 2 is N and X 3 is N;

[0224] (viii)X 1 It is N, X 2 is N and X 3 is S; or

[0225] (ix)X 1 It is CH, X 2 is S and X 3 It is CH.

[0226] In an 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

[0227] (i)X 1 It is N, X 2 is O and X 3 It is N,

[0228] (ii)X 1 It is N, X 2 is N and X 3 It is O;

[0229] (iii)X 1 It is CH, X 2 is CH and X 3 It is S;

[0230] (iv)X 1 It's O, X 2 is N and X 3 It is CH;

[0231] (v)X 1 It is N, X 2 is O and X 3 It is CH;

[0232] (vi)X 1 It is CH, X 2 is N and X 3 It is O;

[0233] (vii)X 1 It's O, X 2 is N and X 3 is N;

[0234] (viii)X 1 It is N, X 2 is N and X 3 It is S;

[0235] (ix)X 1 It is CH, X 2 is S and X 3 is CH; or

[0236] (x)X 1 It is CH, X 2 is N and X 3 It’s S.

[0237] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 It is N, X 2 is O and X 3 It is N.

[0238] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 It is N, X 2 is N and X 3 It's O.

[0239] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 It is N, X 2 is N and X 3 It’s S.

[0240] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 It is N, X 2 is O and X 3 Yes CR Y In another embodiment, R Y is H or -CN.

[0241] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 Yes CR Y , X 2 is N and X 3 is 0. In another embodiment, each R Y It's H.

[0242] In an embodiment, a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC) or (IIID) or a pharmaceutically acceptable salt thereof is provided, wherein X 1 Yes CR Y , X 2 is S and X 3 Yes CR Y In another embodiment, each R Y It's H.

[0243] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (IV):

[0244]

[0245] x is selected from 0 to 3;

[0246] Each R 9 Independently selected from R 3 , R 4 and R 5 ;as well as

[0247] R E is H or halogenated,

[0248] or a pharmaceutically acceptable salt thereof.

[0249] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (V):

[0250]

[0251] x is selected from 0 to 3;

[0252] Each R 9 Independently selected from R 3 , R 4 and R 5 ;as well as

[0253] R E is H or halogenated,

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (VI):

[0256]

[0257] x is selected from 0 to 3;

[0258] Each R 9 Independently selected from R 3 , R 4 and R 5 ;as well as

[0259] R E is H or halogenated,

[0260] or a pharmaceutically acceptable salt thereof.

[0261] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (VII):

[0262]

[0263] x is selected from 0 to 3;

[0264] Each R 9 Independently selected from R 3 , R 4 and R 5 ;as well as

[0265] R E is H or halogenated,

[0266] or a pharmaceutically acceptable salt thereof.

[0267] In embodiments, compounds are provided having Formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), wherein each R 9 Independently selected from C 1-4 Alkyl, C 3-6 In other embodiments, each R 9 Independently C 1-4 In another embodiment, each R 9 It is CH3.

[0268] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 3 Independently C 1-4 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by one or more (e.g., one to three) independently selected from R 4X , R 5x 、-O(R 4X )、-O(R 5X ) and F are substituted with a group. In another embodiment, each R 3 Independently C 1-4 Alkyl, which is optionally substituted by one to three (eg, one or two) independently selected from R 4X , R 5x In embodiments, in further embodiments, each R 3 Independently C 1-4 Alkyl, CF3, CHF2 or CH2F.

[0269] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 3 YesR 3X .

[0270] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 3X Independently C 1-4 Alkyl or C 3-6 cycloalkyl, each of which is optionally substituted with one or more (e.g., one to three) F. In further embodiments, each R 3X Independently C 1-4 alkyl, which is optionally substituted with one to three F. In further embodiments, each R 3X Independently C 1-4 In another embodiment, each R 3X It is C1-4 alkyl.

[0271] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 4 is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (eg, a monocyclic 5- or 6-membered heteroaryl), each of which is optionally substituted by one or more (eg, one to three) independently selected from 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 In another embodiment, each R 4 is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (eg, a monocyclic 5- or 6-membered heteroaryl), which is optionally substituted by one or more (eg, one to three) independently selected from halo (eg, F or Cl), C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 In another embodiment, each R 4 independently selected from [1,2,4]triazolo[4,3-b]pyridazinyl (e.g. 6-[1,2,4]triazolo[4,3-b]pyridazinyl), pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), benzo[d]oxazolyl (e.g. 2-benzo[d]oxazolyl), each of which is optionally substituted by one or more (e.g. one to three) independently selected from halo (e.g. F or Cl), C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and CN groups are substituted.

[0272] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 4Xis independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (eg, a monocyclic 5- or 6-membered heteroaryl), each of which is optionally substituted by one or more (eg, one to three) independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3X In another embodiment, each R 4x is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl (eg, a monocyclic 5- or 6-membered heteroaryl), which is optionally substituted by one or more (eg, one to three) independently selected from halo (eg, F or Cl), C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 In another embodiment, each R 4x independently is optionally C 1-4 Tetrazolyl (eg 5-tetrazolyl) substituted with an alkyl (eg CH3) group.

[0273] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 5 is independently phenyl, which is optionally substituted by one or more (e.g., one to three) independently selected from 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 In another embodiment, each R 5 is independently phenyl, which is optionally substituted by one or more (e.g., one to three) independently selected from halo (e.g., F or Cl), C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 In another embodiment, each R 5 It is phenyl.

[0274] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein each R 5X is independently phenyl, which is optionally substituted by one or more (e.g., one to three) independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x In another embodiment, each R 5X is independently phenyl, which is optionally substituted by one or more (e.g., one to three) independently selected from halo (e.g., F or Cl), C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 In another embodiment, each R 5X It is phenyl.

[0275] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided, wherein R 6 It is C 1-4 Alkoxy, which is optionally substituted by one or more independently selected from R 4X , R 5x and F are substituted with groups (e.g., one to three groups). In another embodiment, R 6 It is C 1-4 Alkoxy, which is optionally substituted with one or more (e.g., one to three) F. In further embodiments, R 6 It is C 1-4 Alkoxy.

[0276] In embodiments, compounds of Formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IV), (V), (VI), or (VII) are provided, wherein x is 0, 1, 2, or 3. In further embodiments, x is 1, 2, or 3.

[0277] In an embodiment, a compound having formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE) or a pharmaceutically acceptable salt thereof is provided, provided that when A is And X 3 When it is N, then X 1 It is N.

[0278] In an embodiment, a compound having formula (I), (II) or (IIA) or a pharmaceutically acceptable salt thereof is provided, provided that when A is And X 3 When it is N, then X 2 It's O.

[0279] In an embodiment, a compound of formula (I), (II) or (IIA) or a pharmaceutically acceptable salt thereof is provided, provided that the compound is not (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.

[0280] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is selected from:

[0281] (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone;

[0282] (3-phenoxyazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0283] ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone;

[0284] (3-(2-methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0285] N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide;

[0286] (3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

[0287] N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide;

[0288] (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;

[0289] 4-(3-(3-phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one;

[0290] 4-(3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one;

[0291] (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone;

[0292] N-(1-cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide;

[0293] 5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile;

[0294] 3-(4-(3-(4-fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0295] 3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0296] 3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0297] 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;

[0298] 3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0299] N-(tert-butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide;

[0300] 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;

[0301] (S)-3-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0302] 3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0303] 3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0304] 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;

[0305] 3-(4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0306] 3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0307] 3-(3-cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0308] 5-(2,4,5-trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile;

[0309] 3-(7-cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile;

[0310] 2-(5-(2-bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;

[0311] 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile;

[0312] (2,2,6,6-tetramethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0313] (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone;

[0314] (S)-6-ethyl-4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-one;

[0315] (3-isopropylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0316] ((3R,5S)-3,5-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0317] ((3R,5S)-3,5-dimethylpiperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0318] ((2R,5S)-2,5-dimethylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0319] Morpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0320] Thiomorpholino(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0321] (Hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0322] 3-(4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-2-yl)benzonitrile;

[0323] (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;

[0324] Piperidin-1-yl(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0325] (6-oxa-9-azaspiro[4.5]dec-9-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0326] (S)-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2-(trifluoromethyl)morpholino)methanone;

[0327] (2-isobutylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0328] (3,3-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0329] (R)-(2-(Fluoromethyl)morpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0330] ((2R,5R)-2,5-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0331] (R)-(7-methyl-1,4-oxazepan-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0332] (5-oxa-8-azaspiro[3.5]nonan-8-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0333] (1,9-dioxa-4-azaspiro[5.5]undec-4-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0334] ((2S,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0335] (4-(4-methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0336] 4-(1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidin-4-yl)benzonitrile;

[0337] (4-(3-(4-fluorophenoxy)propyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0338] (4-(pyridin-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0339] 4-(1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile;

[0340] (3-phenylazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0341] (4-(3-methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0342] (4-phenyl-3,6-dihydropyridin-1(2H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0343] N-(3-cyanophenyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;

[0344] (3,4-dihydroisoquinolin-2(1H)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0345] (5-fluoroisoindolin-2-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0346] 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;

[0347] (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;

[0348] (4-((5-methoxypyridin-2-yl)oxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0349] (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;

[0350] (4-(pyridin-3-yloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0351] 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;

[0352] (4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0353] 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;

[0354] (3-(4-fluorophenyl)azetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0355] N-isopropyl-N-((3-methylpyridin-2-yl)methyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;

[0356] (3-propylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0357] (1-phenyl-3-azabicyclo[3.1.0]hexan-3-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0358] N-(1-(4-methoxyphenyl)ethyl)-N-methyl-5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxamide;

[0359] (3-(4-fluorophenoxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0360] 4-phenyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperidine-4-carbonitrile;

[0361] (4-phenylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0362] 2-(4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile;

[0363] 4-(4-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)piperazin-1-yl)benzonitrile;

[0364] (4-(2-methoxyphenyl)piperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0365] 3-(1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile;

[0366] 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile;

[0367] ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

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

[0369] ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;

[0370] (5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone;

[0371] 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide;

[0372] 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide;

[0373] (S)-(3-phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0374] (3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0375] (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0376] (3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0377] (3-(Benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0378] (R)-(3-phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0379] N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide;

[0380] N-((1-cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide;

[0381] (R)-(5-(4-fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone;

[0382] (3H-spiro[isobenzofuran-1,3'-pyrrolidin]-1'-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0383] (S)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0384] (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone;

[0385] N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide;

[0386] 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile;

[0387] (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;

[0388] ((2S,6R)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0389] 2-(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;

[0390] ((2R,6S)-2,6-dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone; and

[0391] ((3R,5S)-3,5-dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone.

[0392] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is selected from:

[0393] ((4aR,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0394] ((4aS,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0395] ((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0396] ((4aS,7aS)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0397] (5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone;

[0398] (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone;

[0399] (4-oxa-7-azaspiro[2.5]octan-7-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0400] ((3R,5S)-3,5-dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone; and

[0401] ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone.

[0402] In an embodiment, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is selected from:

[0403] rac-((2R,6S)-2-ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0404] rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone;

[0405] (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

[0406] (5-(2-Bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone.

[0407] Another feature is any embodiment described in this specification, with the proviso that any specific example is individually disclaimed.Another feature is any embodiment described in this specification, with the proviso that any one or more compounds selected from the above list of examples of compounds of this specification are individually disclaimed.

[0408] Compounds disclosed herein may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or separated into pure stereoisomers, i.e., single enantiomers, diastereomers, or stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched) mixtures are included within the scope of the embodiments. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0409] Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to encompass all possible stereoisomers, diastereomers, conformers, rotational isomers, and tautomers of the described compound. For example, a compound containing one chiral carbon atom is intended to include both the (R) enantiomer and the (S) enantiomer, as well as mixtures of these enantiomers, including racemic mixtures; and a compound containing two chiral carbon atoms is intended to include all enantiomers and diastereomers, including (R,R), (S,S), (R,S), and (S,R).

[0410] In an embodiment, a pharmaceutical composition is provided, which comprises a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, 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), or (VII), or a pharmaceutically acceptable salt thereof. The invention relates to a 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, wherein the compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is present in the composition in an enantiomeric excess (%ee) of ≥90% and a diastereomeric excess (%de) of ≥90%.

[0411] 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 any given compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salt thereof may form more than one crystalline / polymorphic form, including hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates or other stoichiometric hydrates) and / or solvated forms. It should be understood that the present description includes any and all such solid forms of compounds having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (HID), (IV), (V), (VI) or (VII) and pharmaceutically acceptable salts thereof.

[0412] In further embodiments, compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, are provided and can be obtained by the methods described in the "Examples" section below.

[0413] This specification is intended to include all isotopes of atoms present in the compounds of the invention. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C. Isotopes of nitrogen include 15 N. Isotopes of fluorine include 18 F.

[0414] 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) may be formed by contacting the compound with a suitable inorganic or organic base under conditions known to the skilled person. Base addition salts may, for example, be alkali metal salts (e.g., sodium, potassium or lithium salts) or alkaline earth metal salts (e.g., calcium salts), which may be formed using alkali metal or alkaline earth metal hydroxides or alkoxides (e.g., ethanol or methanol salts). Base addition salts may also be formed using suitable basic organic amines (e.g., choline or meglumine salts).

[0415] 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 the skilled person. 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 can also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0416] Another suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) is a salt that is formed in a patient's body, for example, after administering a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) to a patient.

[0417] 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 prepared as co-crystal solid forms. It should 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 constitute one aspect of the present specification.

[0418] In another aspect, a pharmaceutical composition is provided 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.

[0419] The term "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective, and does not contain other components that are unacceptably toxic to the patient to whom the composition is to be administered. Such a composition can be sterile. The pharmaceutical composition according to this specification will include a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) for oral administration (for example, as a tablet, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granule, syrup or elixir) or a form that is suitable for parenteral administration (for example, 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 known in the art. Therefore, 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.

[0420] The compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (HID), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, will generally be administered via the oral route, but administration in the form of a pharmaceutical preparation comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, parenterally, intravenously, intramuscularly, subcutaneously or otherwise injectable, buccal, rectal, vaginally, transdermally and / or nasally, and / or via inhalation in a pharmaceutically acceptable dosage form is also possible. Depending on the disorder and patient to be treated and the route of administration, these compositions may be administered at varying doses.

[0421] Pharmaceutical formulations of the compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) described above can be prepared, for example, for parenteral, subcutaneous, intramuscular or intravenous administration.

[0422] Pharmaceutical formulations of the compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., (1985).

[0423] Pharmaceutical formulations suitable for oral administration may include one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with the following: binders; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifiers; and preservatives. Liquid compositions may be encapsulated in, for example, 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 will include a compound having 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, which is filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0424] Due to their 17BHSD13 inhibitory activity, compounds having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (HID), (IV), (V), (VI) or (VII) and pharmaceutically acceptable salts thereof are expected to be useful in therapy, e.g., treating a disease or medical condition mediated at least in part by 17BHSD13, including liver disease, e.g., NASH.

[0425] In one aspect of the present specification, 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 therapy.

[0426] In one aspect of the specification, a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating a liver disease. In an embodiment, the liver disease is selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD (e.g., NASH, liver fibrosis, cirrhosis, and isolated steatosis), liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV), and hepatocellular carcinoma (HCC).

[0427] The term "therapy" is intended to have its normal meaning: treating a disease so as to fully or partially relieve one, some or all of its symptoms, or so as to correct or compensate for an underlying pathology. The term "therapy" also includes "prophylaxis" unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

[0428] The term "prophylaxis" is intended to have its normal meaning and includes primary prevention, which prevents the development of a disease, and secondary prevention, where the disease has already developed and the patient is temporarily or permanently protected against an exacerbation or worsening of the disease or against the development of new symptoms associated with the disease.

[0429] The term "treatment" is used synonymously with "therapy". Similarly, the term "treat" may be viewed as "applying therapy", where "therapy" is as defined herein.

[0430] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in providing an inhibitory effect on 17βHSD13.

[0431] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease mediated by 17βHSD13, such as a liver disease (e.g., NASH).

[0432] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating fatty liver disease.

[0433] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating non-alcoholic fatty liver disease (NAFLD), such as isolated steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis or cirrhosis. In another embodiment, the liver disease is end-stage liver disease.

[0434] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as 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 insufficiency.

[0435] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating a liver disease, such as NASH, wherein the patient has a 27 kg / m 2 Up to 40kg / m 2 In another embodiment, the subject has a body mass index (BMI) of 30 kg / m 2 Up to 39.9kg / m 2 In other embodiments, the patient has a BMI of at least 40 kg / m 2 In other embodiments, the patient is overweight. In other embodiments, the patient is obese.

[0436] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as NASH, wherein the patient also suffers from or is susceptible to dyslipidemia.

[0437] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as NASH, wherein the patient also suffers from or is susceptible to insulin resistance.

[0438] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as NASH, wherein the patient also has or is susceptible to type 2 diabetes.

[0439] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as NASH, wherein the patient also suffers from or is susceptible to renal insufficiency.

[0440] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a 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 insufficiency.

[0441] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating a liver disease, such as NASH, wherein the patient also has or is susceptible to cirrhosis. In further embodiments, the patient (i) has or is susceptible to cirrhosis, 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 insufficiency.

[0442] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating NAFLD. In another embodiment, the NAFLD is Stage 1 NAFLD. In another embodiment, the NAFLD is Stage 2 NAFLD. In another embodiment, the NAFLD is Stage 3 NAFLD. In another embodiment, the NAFLD is Stage 4 NAFLD. See, for example, “The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases,” Hepatology, Vol. 67, No. 1, 2018.

[0443] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating NAFLD, such as NASH. In further embodiments, the patient is obese. In further embodiments, the patient has alcoholic liver disease. In further embodiments, the patient has a genetic risk factor for liver disease, such as the (rs738409C>G) variant in PNPLA3.

[0444] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating NASH. In further embodiments, the NASH is Stage 1 NASH. In further embodiments, the NASH is Stage 2 NASH. In further embodiments, the NASH is Stage 3 NASH. In further embodiments, the NASH is Stage 4 NASH. In further embodiments, the patient further suffers from or is susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0445] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating 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 insufficiency.

[0446] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating cirrhosis. 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 obesity, dyslipidemia, insulin resistance, type 2 diabetes, and renal insufficiency.

[0447] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof is provided for use in treating liver inflammation. In further embodiments, the inflammation is a chronic inflammation. In further embodiments, the chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease. In further embodiments, the chronic inflammation is rheumatoid arthritis.

[0448] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating hepatocellular carcinoma (HCC).

[0449] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating alcoholic steatohepatitis (ASH).

[0450] In an embodiment, a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, is provided for use in treating hepatitis C virus (HCV).

[0451] In one aspect of the present specification, there is provided a use of a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) as described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament, such as a medicament for treating a disease (e.g., NASH).

[0452] In one aspect of the specification, a method of treating a disease such as NASH in a patient is provided, the method comprising administering to the patient an effective amount of a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof.

[0453] Terms such as "treating" or "treatment" refer to (1) therapeutic measures that result in the diagnosis of a pathological condition or disorder being cured, slowed, relieved, and / or stopped from progressing and (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathological condition or disorder. Thus, those in need of treatment include those already suffering from the disorder; those prone to suffering from the disorder; and those in whom prevention of the disorder is desired.

[0454] The term "effective amount" means an amount of active ingredient sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., to provide a positive clinical response). The effective amount of the active ingredient used in the pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific active ingredient(s) utilized, the specific pharmaceutically acceptable excipient(s) utilized, and similar factors that are within the knowledge and expertise of the attending physician.

[0455] The term "patient" refers to any animal (eg, mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the term "patient" refers to a human subject.

[0456] In an embodiment, a method of treating a disease in a patient is provided, the method comprising administering to the patient an effective amount of a compound having 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 steatosis, NASH, liver fibrosis and cirrhosis.

[0457] In an embodiment, a method of treating a 17βHSD13-mediated disease such as NASH in a patient is provided, the method comprising administering to the patient an effective amount of a compound having Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof.

[0458] The compounds of the present disclosure can be used in the above methods as a single pharmacological agent or in combination with other pharmacological agents or technologies. Such combination therapies can be achieved by administering the single components of the treatment simultaneously, sequentially or separately. These combination therapies (and corresponding combination products) use the compounds of the present disclosure and one or more other pharmacological agents.

[0459] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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 transporter 2 (SGLT2) inhibitor. In a further embodiment, the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and remogliflozin.

[0460] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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.

[0461] In an embodiment, a combination for use in treating liver disease, such as NASH, is provided, 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 further embodiments, the GLP1 agonist is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide.

[0462] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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 a further embodiment, the DPP4 inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, alagliptin, teneligliptin, alogliptin, trelagliptin, aulogliptin, evogliptin, gogliptin and dutogliptin.

[0463] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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 PPAR alpha agonist. In a further embodiment, the PPAR agonist is a PPAR gamma agonist. In a further embodiment, the PPAR agonist is a PPAR alpha / gamma 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 further embodiments, the PPAR agonist stimulates hepatic expression of FGF21.

[0464] In an embodiment, a combination for use in treating liver disease, such as NASH, is provided, 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 pan-PPAR agonist. In a further embodiment, the pan-PPAR agonist is lanifibranor.

[0465] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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.

[0466] In an embodiment, a combination for use in treating a liver disease, such as NASH, is provided, 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 FXR agonist. In further embodiments, the FXR agonist is obeticholic acid.

[0467] Although compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (IIE), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (V), (VI) or (VII) are primarily of value as therapeutic agents for use in patients, they are also useful whenever inhibition of 17βHSD13 is desired. Therefore, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

[0468] In one aspect of the present specification, intermediates and methods for synthesizing compounds of formula (I) and pharmaceutically acceptable salts thereof are provided. Schemes P1-P10 disclose intermediates and methods for synthesizing compounds of formula (I), wherein X 1 , X 2 , X 3 , R 1 , R 2 and A is as defined herein for compounds of formula (I), LG is a leaving group (eg, Cl, Br or I), B 1 is boronic acid or a derivative thereof (e.g., boronic acid, boronic ester or trifluoroborate), unless otherwise indicated, R P It is C 1-4 Alkyl group.

[0469] Plan P1

[0470]

[0471] Compounds of formula (I) can 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 the presence of a coupling agent (e.g., DIC, EDC, COMU, TBTU, or HATU) in the presence of a base (e.g., DIPEA or 2,6-lutidine) in a solvent (e.g., DMF, MeCN, EtOAc, or a mixture thereof), optionally at a temperature in the range of 18 to 60°C. Optionally, the reaction can be carried out in the presence of HOBt. Compounds of formula (P1.2) can be formed by hydrolysis of an ester of formula (P1.1) by standard methods. For esters such as Me or Et, a base (e.g., LiOH or NaOH) can be used in a solvent (e.g., H2O, MeOH, THF, or a mixture thereof), optionally at a temperature in the range of 18 to 60°C. For acid-labile esters (e.g., t Bu), can be hydrolyzed using an acid such as TFA, either neat or in a solvent such as DCM or H2O, optionally at 18°C.

[0472] Compounds of formula (I) can also be formed by reacting an ester of formula (P1.1) (wherein R P is Me or Et) and reacts with an amine having formula (P1.3).

[0473] Plan P2

[0474]

[0475] Compounds of formula (P2.4) can be formed by reacting a compound of formula (P2.2) with a compound of formula (P2.3) (wherein R P is Me or Et). Compounds of formula (P2.2) can be formed from nitriles of formula (P2.1) by reaction with hydroxylamine (or a salt thereof, such as HCl) in a solvent such as H2O, MeOH or EtOH or a mixture thereof, optionally at a temperature in the range of 50 to 80°C. If a hydroxylammonium salt such as HCl is used, an additional base such as NaHCO3 may be added.

[0476] Plan P3

[0477]

[0478] The compound of formula (P3.3) can be formed by reacting a compound of formula (P3.1) and a compound of formula (P3.2) with EDC and a base (eg NaHCO3), optionally in DMF, optionally at a temperature of 100°C. Optionally, R P It's Me or Et.

[0479] Plan P4

[0480]

[0481] A compound having the formula (P4.4) (wherein R P is Me or Et) can be formed by reacting a compound of formula (P4.3) with a dehydrating agent (e.g. POCl 3， SOCl2 or EDC), either pure dehydrating agent or in a solvent such as toluene or DCM, optionally at a temperature ranging from 18 to 90°C, optionally in the presence of a base such as pyridine. Compounds of formula (P4.3) can be formed by reacting a hydrazide of formula (P4.1) with a compound of formula (P4.2) in a solvent such as dioxane, THF, DCM or a mixture thereof, optionally at a temperature of 0 to 18°C, optionally in the presence of a base such as TEA or DIPEA.

[0482] Plan P5

[0483]

[0484] Compounds of formula (5.1) can be reacted with compounds of formula (P5.2). The reaction can be carried out with a Pd reagent (e.g. XPhos PdG3) in the presence of H2O and a base (e.g. K3PO4) in a solvent (e.g. dioxane, THF or a mixture thereof) optionally at 60°C.

[0485] Plan P6

[0486]

[0487] A compound of formula (P6.3) can be formed by reacting a compound of formula (P6.2) with a compound of formula (P6.1). The reaction can be catalyzed by a Pd reagent (e.g., Pd-118) in the presence of a base (e.g., Cs2CO3, K2CO3, or Na2CO3) and H2O in a solvent (e.g., dioxane, THF, EtOH, DMF, or a mixture thereof) at a temperature of 60°C. Alternatively, a compound of formula (P6.3) can be formed by reacting a compound of formula (P6.4) with a compound of formula (P6.5) (wherein LG is optionally Br). The reaction can be catalyzed by a Pd reagent (e.g., Pd-118) in the presence of a base (e.g., K2CO3) and H2O in a solvent (e.g., 1,4-dioxane) at a temperature in the range of 50 to 80°C.

[0488] Solution P7

[0489]

[0490] Compounds of formula (P7.3) can be formed by reacting an alkyne of formula (P7.2) with ethyl (Z)-2-chloro-2-(hydroxyimino)acetate in the presence of a base (e.g., TEA) in a solvent (e.g., DCM), optionally at a temperature ranging from 18 to 45° C. Compounds of formula (P7.2) can be formed by reacting an aldehyde of formula (P7.1) with dimethyl (1-diazo-2-oxopropyl)phosphonate in the presence of a base (e.g., K2CO3) in a solvent (e.g., MeOH), optionally at room temperature.

[0491] 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 to 100° C. A diketone 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.

[0492] Solution P8

[0493]

[0494] A compound having the formula (P8.4) (wherein R P=Et) can be formed from a compound of formula (P8.2) by reacting with a compound of formula (P8.3) in the presence of a base (e.g., TEA) in a solvent (e.g., EtOH), optionally at room temperature. A compound of formula (P8.2) can be formed from an ester of formula (P8.1) by reacting with MeCN and a strong base (e.g., NaH) in a solvent (e.g., THF), optionally at a temperature in the range of 18°C ​​to 50°C.

[0495] Solution P9

[0496]

[0497] A compound having the formula (P9.4) (wherein R P is Me or t Bu) can be formed from a compound of formula (P9.2) by reacting with a compound of formula (P9.3) and OXONE (potassium peroxymonosulfate) in the presence of KCl in a solvent such as H2O or aqueous MeCN, optionally at a temperature in the range of 0 to 18°C. A compound of formula (P9.2) can be formed from an aldehyde of formula (P9.1) by reacting with hydroxylamine or a salt thereof such as HCl in a solvent such as H2O, MeOH or EtOH or a mixture thereof, optionally at a temperature in the range of 0 to 18°C. If a hydroxylammonium salt such as HCl is used, an additional base such as NaOH, NaOAc or Na2CO3 may be added.

[0498] Solution P10

[0499]

[0500] A compound having the formula (P10.4) (wherein R P is Me or Et) can be formed from a compound of formula (P10.2) by reacting with a compound of formula (P10.3) in a solvent such as toluene, optionally at a temperature in the range of 105 to 110°C. A compound of formula (P10.2) can 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 to 65°C.

[0501] It should be understood that the organic reactions described herein are performed according to laboratory practices known to those skilled in the art. It should be understood that some of the reactions described herein may optionally be performed in an order different from that shown herein. It should be understood that the chiral isomers of the compounds described herein may be separated at any stage of the synthetic process by using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatography methods described in the literature and known to those skilled in the art or as further described in the Examples.

[0502] It should be understood that additional and / or other protecting groups may be optionally required in some of the above steps, and it should be further understood that the deprotection step may optionally be performed using methods described in the literature and known to those skilled in the art. The protection and deprotection of functional groups are described in Protective Groups in Organic Synthesis, 3rd edition, TW Greene and PGM Wutz, Wiley-Interscience (1999), which is incorporated herein by reference.

[0503] Examples

[0504] The present description will now be illustrated by the following non-limiting examples, in which generally:

[0505] (i) unless otherwise stated, operations were performed at room temperature (rt) (i.e. in the range of 17° C. to 28° C.) and, when necessary, under an atmosphere of an inert gas such as N 2 ;

[0506] (ii) where the reaction is degassed or purged, this may be carried out, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 to 10 min) or by repeatedly evacuating the vessel and backfilling with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g));

[0507] (iii) when the reaction involves the use of a microwave reactor, one of the following microwave reactors is used: a BIOTAGE initiator, a PERSONAL CHEMISTRY EMRYS OPTIMIZER, a PERSONAL CHEMISTRY SMITH CREATOR, or a CEM detector;

[0508] (iv) Typically, the reaction process is followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), which is usually coupled to a mass spectrometer (LCMS).

[0509] (v) If necessary, the organic solution is dried over anhydrous MgSO4 or Na2SO4, or through a phase separator (using an ISOLUTE phase separator), and the work-up procedures are carried out using conventional phase separation techniques. When a drying agent such as MgSO4 or Na2SO4 is used to dry the organic layer, it should be understood that the layer is filtered before concentrating the organic layer.

[0510] (vi) by rotary evaporation in vacuum or evaporation in a GENEVAC HT-4 / EZ-2 or BIOTAGE V10;

[0511] (vii) Unless otherwise stated, flash column chromatography was performed as follows: 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 Silica HCD cartridge (20 μm, 10-100 g), INTERCHIMPURIFLASH cartridge (25 μm, 4-120 g), INTERCHIM PURIFLASH cartridge (50 μm, 25-330 g), GRACE GRACERESOLV silica fast cartridge (4-120 g) or AGELA fast column silica-CS cartridge (80-330 g), or on reverse phase silica using AGELATECHNOLOGIES C-18, spherical cartridge (20-35 μm, 100A, 80-330 g), manually or automatically using GRACEREVELERISX2 fast system or similar system;

[0512] (viii) Preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with MS and / or UV triggered fraction collection instruments, using isocratic or gradient mobile phases as described in the experimental section and using one of the following methods: Preparative Method A: The compound was purified by preparative HPLC on a WATERS SUNFIRE C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparative Method B: The compound was purified by preparative HPLC on an XBRIDGE C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase; Preparative Method C: The compound was purified by preparative HPLC on a KROMASIL C8 column (10 μm, 250×20 mm ID). ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation D: The compound was purified by preparative HPLC on a KROMASIL C8 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation E: The compound was purified by preparative HPLC on a WATERS SUNFIRE C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation F: The compound was purified by preparative HPLC on a Waters HSS C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation G: The compound was purified by preparative HPLC on a WATERS SUNFIRE C18 column (5 μm, 100×10 mm ID) was used as the mobile phase using a gradient of MeCN in H2O / FA ​​(0.1 M, pH 3); Preparation method H: The compound was purified by preparative HPLC on a WATERS XBRIDGE C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / NH3 (0.2%, pH 10) as the mobile phase; Preparation method I: The compound was purified by preparative HPLC on a WATERS XSELECT CSH fluorophenyl column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation method J: The compound was purified by preparative HPLC on an XBRIDGE C18 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; Preparation K: the compound was purified by preparative HPLC on an XBRIDGEPrep OBD C18 column (5 μm, 30×150 mm) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation L: the compound was purified by preparative HPLC on a YMC-ACTUS TRIART C18 column (5 μm, 30×250 mm) using a gradient of MeCN in H2O / NH3 (0.05%) as the mobile phase; Preparation M: the compound was purified by preparative HPLC on a WATERS XSELECT CSH fluorophenyl column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / TFA (0.05%) as the mobile phase; Preparation N: the compound was purified by preparative HPLC on a WATERS XSELECT CSH OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase; Preparation Method O: The compound was purified by preparative HPLC on a YMC-Actus TriartC18ExRS column (5 μm, 30×150 mm) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) + 0.1% NH4OH as the mobile phase; Preparation Method P: The compound was purified by preparative HPLC on an XBRIDGE C18 ODB column (5 μm, 250×19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) + 0.1% NH4OH as the mobile phase; Preparation Method Q: The compound was purified by preparative HPLC on a WATERS SUNFIRE C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation Method R: The compound was purified by preparative HPLC on an XBRIDGE SHIELDRP18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase; Preparation S: The compound was purified by preparative SFC on a Phenomenex Luna Hilic column (5 μm, 250×30 mm ID) using a gradient of MeOH / NH3 (20 mM) in CO2 as the mobile phase; Preparation T: The compound was purified by preparative HPLC on a WATERS XSELECT CSH OBD column (5 μm, 150×30 mm ID) using MeCN in H2O / FA ​​(0.Preparation U: The compound was purified by preparative SFC on a PHENOMENE Xluna Hilic column (5 μm, 250×30 mm ID) using a gradient of EtOH / FA (20 mM) in CO2 as the mobile phase; Preparation V: The compound was purified by preparative HPLC on a Waters Xselect CSHOBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1 M) as the mobile phase; Preparation X: The compound was purified by preparative HPLC on an XBridge. TM Purification was performed on a C18 ODB column (5 μm, 250×30 mm ID) using a gradient of MeCN in H 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH as the mobile phase; Preparation Method Y: Compounds were purified by preparative HPLC on XBridge TM Purification was performed on a C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in H 2 O / NH 4 HCO 3 (10 mM) + 0.1% NH 4 OH as the mobile phase; Preparation Method Z: Compounds were purified by preparative HPLC on XBridge TM Purification was performed on a C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in H 2 O / AcOH (0.1%) as the mobile phase. SFC preparation method: Preparative method SFC-A: Compounds were purified by preparative SFC (on a Waters TM Purification was performed on BEH (5 μm, 250×30 mm ID) using MeOH / H 2 O (NH 3 50 mM) (97 / 3) in CO 2 as mobile phase);

[0513] In some cases, the compound can be dissolved in a solvent (eg, DMSO) and filtered through a syringe filter prior to purification on preparative HPLC.

[0514] The relevant fractions were collected, combined and freeze-dried or evaporated to give the purified compound, or the relevant fractions were collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc and the organic phase was dried over Na2SO4 or by using a phase separator and then concentrated under reduced pressure to give the purified compound.

[0515] (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC instruments, respectively, and isocratic or gradient runs using the mobile phases described below;

[0516] (x) where present, the yield is not necessarily the maximum achievable and, if necessary, the reaction is repeated if a larger amount of the reaction product is desired;

[0517] (xi) Where certain compounds are obtained as acid addition salts (e.g., mono- or dihydrochloride salts), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the exact stoichiometry of the salt cannot usually be determined, for example, from elemental analysis data;

[0518] (xii) In general, the structure of the final product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; proton NMR chemical shift values ​​are measured using a BRUKER AVANCE III 300, 400, 500 and 600 spectrometer at 300, 400, 500 and 600 MHz, respectively. 1 H frequency is measured on the delta scale. Typically, these experiments are recorded at 25°C. Chemical shifts are given in parts per million with the solvent as an internal standard. Protons on heteroatoms such as NH and OH protons are reported only when detected in the NMR and may therefore be missing. In some cases, protons may be obscured or partially obscured by solvent peaks and will therefore be missing and not reported or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivative forms, such as dd, doublet, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, quintet. In some cases, the structure of the final product of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peaks of the major rotamers are reported. In some cases, the structure of the intermediate and / or final product of formula (I) may appear as a rotational isomer in the NMR spectrum, in which case the peaks of all rotational isomers are reported and only the total number of protons is reported. If known, the ratio of the major and minor rotational isomers is reported. Electrospray mass spectral data are obtained using a WATERS ACQUITY UPLC coupled to a WATERS single quadrupole mass spectrometer or similar device that collects positive and negative ion data, and generally only ions associated with the parent structure are reported; high-resolution electrospray mass spectral data are obtained using a WATERS XEVO qToF mass spectrometer or similar device coupled to a WATERS ACQUITY UPLC that collects positive and negative ion data, and generally only ions associated with the parent structure are reported;

[0519] (xiii) The intermediates are not necessarily completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC, analytical GCMS and / or NMR analysis and / or mass spectrometry;

[0520] (xiv) Unless otherwise stated, compounds containing asymmetric carbon and / or sulfur atoms were not resolved;

[0521] (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 chemical structure names using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the name and are assigned according to CIP rules. The "rac-" prefix indicates that the compound is racemic.

[0522] (xvi) In addition to the above, the following abbreviations and units are used:

[0523] AcOH Acetic acid

[0524] Aq water based

[0525] Boc tert-Butyloxycarbonyl

[0526] t-BuOH tert-Butanol

[0527] Brine saturated sodium chloride aqueous solution

[0528] Calcd

[0529] CBz benzyloxycarbonyl

[0530] COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbonium hexafluorophosphate (CAS Reg. No. 1075198-30-9)

[0531] 18-Crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane

[0532] DABAL-Me3 CAS Reg. No. 137203-34-0

[0533] DCM Dichloromethane

[0534] DEAD Diethyl azodicarboxylate

[0535] DIC Diisopropylmethanediimide

[0536] DIPEA N-ethyl-N-isopropyl-propan-2-amine

[0537] DMAP N,N-Dimethylpyridin-4-amine

[0538] DMF N,N-Dimethylformamide

[0539] DMSO Dimethyl sulfoxide

[0540] DPPA Diphenylphosphorylazide

[0541] EDC 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine

[0542] ESI Electrospray ionization

[0543] Et2O Ether

[0544] EtOAc Ethyl acetate

[0545] EtOH

[0546] eq equivalent

[0547] FA Formic acid

[0548] (g) Gas

[0549] GC Gas chromatography

[0550] HPLC High Performance Liquid Chromatography

[0551] HATU (1-(bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxohexafluorophosphate)

[0552] HOBt 1-Hydroxybenzotriazole; hydrate

[0553] HRMS High Resolution Mass Spectrometry

[0554] ID inner diameter

[0555] Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphine 2,4-disulfide

[0556] LiHMDS Lithium Bis(trimethylsilyl)amide

[0557] LC Liquid Chromatography

[0558] Me3Al trimethylaluminum

[0559] MeCN Acetonitrile

[0560] MeI Methyl iodide

[0561] MeMgBr Methylmagnesium bromide

[0562] MeOH Methanol

[0563] MS mass spectrometry

[0564] MTBE Methyl tert-butyl ether

[0565] m / z mass spectrum peak

[0566] NBS N-Bromosuccinimide

[0567] NIS 1-iodopyrrolidine-2,5-dione

[0568] NMR Nuclear Magnetic Resonance

[0569] PE Petroleum Ether

[0570] Pd-118[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0571] Pd-C Palladium Carbon

[0572] PPh3 Triphenylphosphine

[0573] sat SFC saturated supercritical fluid chromatography

[0574] TBTU 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[0575] TEA Triethylamine

[0576] TFA Trifluoroacetic acid

[0577] THF Tetrahydrofuran

[0578] TLC Thin layer chromatography

[0579] UPLC Ultra-Performance Liquid Chromatography

[0580] UV

[0581] Xphos Pd G3(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-diphenyl)[2-(2'-amino-1,1'-diphenyl)]methanesulfonate palladium(II)

[0582] Intermediate 1: 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester

[0583]

[0584] Under N2(g) atmosphere, EDC (43.5 g, 227.07 mmol) and HOBt (15.34 g, 113.53 mmol) were added to (Z)-2-amino-2-(hydroxyimino)ethyl acetate (15 g, 113.53 mmol), 2,4,5-trifluoro-3-hydroxybenzoic acid (21.81 g, 113.53 mmol) and NaHCO3 (28.6 g, 340.60 mmol) in DMF (150 mL). 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 Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography on a C18 column (gradient 50-60% MeCN(FA) in water) to give the title compound as a white solid (7.0 g, 21%); MS (ESI) m / z [M+H] + 289; 1 HNMR (300MHz, DMSO-d6) δ1.36(t,3H),4.45(m,2H),7.28–7.81(m,1H),11.70(s,1H).

[0585] Alternative synthesis of intermediate 1: SOCl2 (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 for 4 hours. The temperature was adjusted to 85-95 ° C and the mixture was stirred for 20 h. The mixture was concentrated to about 4 L at less than 50 ° C, and then toluene (14.5 L) was added. This process of concentration and addition of toluene was repeated twice, and then toluene (14.5 L) was added to the resulting mixture and concentrated to about 3 L at less than 50 ° C to give a solution of 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 mmol, 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 at a temperature of 140° C. with a residence time of 45 min in the process (see Figure 1). After heating, the reaction mixture was quenched in the process with a mixture of EtOH (1.4 L) and water (1.4 L) preheated to a temperature of 20-30 ° C. At the end of the mobile reaction, the resulting mixture was adjusted to pH 2-3 with 2M HCl (13.72 L) at 5-15 ° C for 6 h. 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 organics were then concentrated under vacuum at 35-45 ° C, and EtOH (14 L) was then added. The process of concentrating and adding EtOH was repeated, and the mixture was then concentrated under vacuum at 35-45 ° C. The mixture was then treated with water (12.6 L) at 20-30 ° C for 2 hours, and then stirred at 20-30 ° C for 16 h. The resulting mixture was filtered and rinsed with water (2.8 L) and n-heptane (4.2 L) and the filter cake was dried at 30-40 °C for 16 h to give 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 2 stages).

[0586] Intermediate 2: 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid

[0587]

[0588] LiOH (0.482 g, 20.13 mmol) dissolved in water (10 mL) was added to 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (1.45 g, 5.03 mmol) in THF (10 mL) at 20 ° C. The solution was stirred at room temperature for 2 h and then at 60 ° C for 1 h. THF was evaporated and the aqueous phase was cooled to 0 ° C, acidified with 1M HCl, and then freeze-dried overnight. The white solid was dissolved in EtOAc and washed with a small amount of 1M HCl. The organic layer was passed through a phase separator and concentrated to give the title compound (1.08 g, 83%) as an off-white solid; MSm / z(ESI)[MH] - 259.0; 1 HNMR(500MHz,DMSO-d6)δ6.93–7.21(1H,m),10.60(1H,s).

[0589] Intermediate 3: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

[0590]

[0591] 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid intermediate 23 (22 mg, 0.08 mmol), NaHCO3 (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) and stirred for 5 min in a vial. Then a solution of (R)-3-phenylpyrrolidine HCl (14 mg, 0.08 mmol) in DMF (0.4 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl (aq, 2 mL) and the mixture was extracted with DCM (× 3). The combined organic layer was washed with 1M KHSO4 and brine, passed through a phase separator and concentrated. The crude product was purified by flash chromatography on silica (gradient: 10-50% EtOAc in heptane) to give the title compound as a white solid (17 mg, 53%); MS (ESI) m / z [M+H] + 418.1.

[0592] Intermediate 4: (S)-N-Benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycine ethyl ester

[0593]

[0594] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (600 g, 3.0 mol) and benzylglycine ethyl ester (600 g, 3.0 mol) in 5 L DCM was added TEA (597 g, 6.0 mol) and TBTU (1043 g, 3.3 mol). The solution was stirred at room temperature overnight and then diluted with 10% HCl (1 L). The organic layer was separated and washed with saturated NaHCO3 (1 L) and brine (1 L), dried over MgSO4. The DCM was removed under vacuum and the crude product was purified by silica column chromatography (gradient: 0-10% EtOAc in PE) to give the title compound as a yellow liquid (1005 g, 90%); MS (ESI) m / z [M+Na] + 401.1.

[0595] Intermediate 5: (S)-N-Benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycine ethyl ester

[0596]

[0597] The reaction was carried out in three parallel reactions. To a solution of (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butanoyl)glycine ethyl ester intermediate 4 (357 g, 0.94 mol) in 2L anhydrous THF was added dropwise BH3 solution (10 M, 240 mL) at 0°C under N2(g) atmosphere within 2h. 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 organic layers were combined, dried over MgSO4, and evaporated under vacuum. The crude product was purified by silica column chromatography (gradient: 0-5% EtOAc in PE) to give the title compound (110 g, 32%) as a yellow liquid; MS (ESI) m / z[M+H] + 365.1.

[0598] Intermediate 6: (S)-4-Benzyl-6-ethylpiperazin-2-one

[0599]

[0600] To a solution of (S)-N-benzyl-N-(2-((tert-butoxycarbonyl)amino)butyl)glycine ethyl ester intermediate 5 (300 g, 0.82 mol) dissolved in anhydrous 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 and saturated Na2CO3 (500 mL) was added, and the solution was stirred for another 10 h. The mixture was extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and evaporated under vacuum to give the title compound (144 g, 80%) as a light yellow solid; MS (ESI) m / z [M+H] + 218.9.

[0601] Intermediate 7: (S)-6-Ethylpiperazin-2-one

[0602]

[0603] 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 as a white solid (42 g, 82%); MS (ESI) m / z [M+H] + 129.1.

[0604] Intermediate 8: 4-(((2-hydroxyethyl)amino)methyl)tetrahydro-2H-pyran-4-ol

[0605]

[0606] A solution of 1,6-dioxaspiro[2.5]octane (100 g, 0.877 mol) and 2-aminoethan-1-ol (64 g 1.05 mol) in anhydrous 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.

[0607] Intermediate 9: Benzyl (2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)carbamate

[0608]

[0609] 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 anhydrous DCM (2 L) was added benzyl chloroformate (183 g, 1.07 mol) dropwise at 0°C. After 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] + 332.

[0610] Intermediate 10: Benzyl 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylate

[0611]

[0612] Crude (2-hydroxyethyl)((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)benzylcarbamate intermediate 9 (140 g, 0.45 mol) and PPh3 (140 g, 0.53 mol) were dissolved in anhydrous 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 anhydrous 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%); 1HNMR (CDCl3, 400MHz) 7.29-7.33 (m, 5H); 5.11-5.12 (m, 2H); 4.08-4.16 (m, 6H), 3.47 (brs, 2H); 3.33 (brs, 2H); 2.01-2.02 (d, 2H); 1.71-1.74 (m, 2H).

[0613] Intermediate 11: 1,9-dioxa-4-azaspiro[5.5]undecane

[0614]

[0615] 1,9-dioxa-4-azaspiro[5.5]undecane-4-carboxylic acid benzyl ester intermediate 10 (60 g, 210 mmol) and Pd / C (10 g) in THF (1 L) were stirred at 25 ° C under H2(g) (40 psi) 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 as HCl salt (22.5 g, 58%); MS (ESI) m / z [M+H] + 158.

[0616] Intermediate 12: tert-Butyl 4-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate

[0617]

[0618] 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 Et2O (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a yellow liquid. The crude gum was triturated with Et2O 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.

[0619] Intermediate 13: 1-(2-((5-bromopyridin-2-yl)oxy)ethyl)piperazine

[0620]

[0621] 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. Et2O (50 mL) was added to the reaction mixture and the precipitate was collected by filtration, washed with Et2O and dried under vacuum to give the title compound as a white solid (15 g, 97%); MS (ESI) m / z [M+H] + 287.9.

[0622] Intermediate 14: 2,4,5-trifluoro-N,3-dimethoxy-N-methylbenzamide

[0623]

[0624] DIPEA (2.54 mL, 14.55 mmol) and N, O-dimethylhydroxylamine HCl (0.6 g, 6.15 mmol) were added 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). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1M HCl (aq), 1M 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 in heptane) to give the title compound (1.03 g, 85%) as a light yellow oil; MS (ESI) m / z [M+H] + 250.1.

[0625] Intermediate 15: 1-(2,4,5-trifluoro-3-methoxyphenyl)ethan-1-one

[0626]

[0627] MeMgBr (3.4M, 5.31mL, 18.06mmol) in THF was added dropwise to 2,4,5-trifluoro-N,3-dimethoxy-N-methylbenzamide intermediate 14 (0.9g, 3.61mmol) in THF (12mL) at 0°C and under N2(g) atmosphere. The solution was stirred at room temperature for 1h. The reaction was quenched when poured into an ice-cooled mixture of 1M HCl (aq, 15mL) and THF (10mL). 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 (0.736g, 100%) as a light yellow oil;1 HNMR(500MHz, CDCl3)δ2.63(3H,d),4.07(3H,t),7.38–7.47(1H,m).

[0628] Intermediate 16: Ethyl 2,4-dioxo-4-(2,4,5-trifluoro-3-methoxyphenyl)butanoate

[0629]

[0630] LiHMDS (1M, 4mL, 4.00mmol) in toluene was added to 1-(2,4,5-trifluoro-3-methoxyphenyl)ethan-1-one intermediate 15 (0.736g, 3.61mmol) in THF (10mL) and cooled to -20°C under N2(g) atmosphere. The mixture was stirred at -20°C for 40min. Diethyl oxalate (0.5mL, 3.68mmol) was added and the solution was stirred at room temperature for 40min. The reaction was quenched by adding 1M HCl (aq, 15mL) and then EtOAc. The phases were separated, 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) in heptane) to give the title compound (0.924g, 84%) as a beige solid; MS (ESI) m / z[M+H] + 305.0.

[0631] Intermediate 17: Ethyl 5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazole-3-carboxylate

[0632]

[0633] 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 and diluted with EtOAc and washed once with 1M HCl (aq) and once with water. The phases were separated using a phase separator and the organic phase was concentrated. The crude product was purified by flash chromatography on silica (gradient: 20-40% EtOAc in heptane) to give the title compound (0.585 g, 64%) as a white solid; MS (ESI) m / z [M+H] + 302.0.

[0634] Intermediate 18: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone

[0635]

[0636] (2R,6S)-2,6-dimethylmorpholine (0.102 g, 0.89 mmol) was dissolved in dry toluene (1 mL) and Me3Al (2M, 0.830 mL, 1.66 mmol) in toluene was added dropwise at room temperature under N2(g) atmosphere. The resulting clear solution was stirred at room temperature for 45 min. The above solution was added dropwise 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) at room temperature under N2(g) atmosphere. The solution was heated to 60°C for 20 h. Tartaric acid (30%, aq, 5 mL) was added dropwise until 2 clear phases appeared. The mixture was extracted with EtOAc. The phases were separated. The aqueous phase was extracted again with EtOAc. The organic phases were combined and concentrated. The residue was purified by preparative HPLC, PrepMethod D (gradient: 15-65%) to give the title compound (143 mg, 58%) as a yellow oil which became solid upon standing; MS (ESI) m / z [M+H] + 371.2.

[0637] Intermediate 19: Methyl 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazino)-2-oxoacetate

[0638]

[0639] 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) at 5 °C under N2(g) atmosphere. The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was removed under reduced pressure to provide the title compound (10.20 g, 98%) as a white solid; MS (ESI) m / z [M+H] + 257.

[0640] Intermediate 20: 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester

[0641]

[0642] A mixture of methyl 2-(2-(4-fluoro-3-hydroxybenzoyl)hydrazine)-2-oxoacetate 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.

[0643] Intermediate 21: 1,2,4-Trifluoro-5-iodo-3-methoxybenzene

[0644]

[0645] 2,4,5-trifluoro-3-methoxybenzoic acid (0.5 g, 2.43 mmol), K3PO4 (0.515 g, 2.43 mmol) and iodine (2.463 g, 9.70 mmol) and a stirring bar were placed in a dried 20 mL microwave vial. The vial was capped, evacuated and backfilled with N2(g). Anhydrous MeCN (8 mL) was added and the reaction mixture was heated at 120 ° C for 23 h. The reaction mixture was allowed to reach room temperature and 15% Na2SO3(aq) was added until the dark color disappeared. A second batch was prepared as described above and the reaction mixtures were combined and extracted with DCM (× 3). The combined organic layers were washed with 8% Na2CO3(aq), passed through a phase separator and concentrated. The residue was purified by normal phase flash chromatography on silica gel (gradient: 5-17% MTBE in pentane) to give the title compound (0.841 g, 60%) as an almost colorless oil; MS (EI) m / z[M] + 288.0.

[0646] Intermediate 22 tert-Butyl 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate

[0647]

[0648] 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), 2MKCO(aq) (2.12 ml, 4.24 mmol) and a stir bar. The vial was capped, evacuated and backfilled with N(g) (x3) and 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: 0-30% EtOAc in heptane). Combine and concentrate the fractions containing the title compound, dissolve the residue in MTBE (about 10 mL) and treat with SILIAMET S THIOL (1 g, loading: 1.4 mmol / g) at 40° C. for 30 min. Filter the mixture and wash the solid with MTBE. Concentrate the combined filtrate and purify the residue by preparative HPLC, Preparation Method J (gradient: 50-100%) to give the title compound (176 mg, 36%); 1 HNMR(500MHz, CDCl3) δ1.59(9H,s),4.08(3H,d),7.13(1H,ddd),7.34(1H,dd),7.69(1H,dd).

[0649] Intermediate 23: 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid

[0650]

[0651] TFA (0.5 mL) was added to a solution of tert-butyl 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylate intermediate 22 (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.

[0652] Intermediate 24: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophen-2-yl)methanone

[0653]

[0654] HATU (206 mg, 0.54 mmol) was added to a stirred solution of 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) in a mixture of MeCN (3 mL) and EtOAc (3 mL), 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 successively with saturated Na2CO3(aq) and water. The organic layer was passed through a phase separator and concentrated. The residue was purified by preparative HPLC, Preparation Method J (gradient: 40-85%). The fractions containing the title compound were combined and concentrated to near dryness and then partitioned between DCM and water using a phase separator. The organic layer was concentrated to give the title compound as a solid (145 mg, 83%); MS m / z (ESI) [M+H] + 386.2.

[0655] Intermediate 25: tert-Butyl (1-cyclohexyl-1H-pyrazol-5-yl)carbamate

[0656]

[0657] DPPA (2267 mg, 8.24 mmol) followed by TEA (2296 μl, 16.47 mmol) was slowly added to a stirred solution of 1-cyclohexyl-1H-pyrazole-5-carboxylic acid (800 mg, 4.12 mmol) in t-BuOH (10 mL) at 15 ° C. The resulting solution was stirred at 80 ° C for 16 h under an N2(g) atmosphere. 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 in water) and then purified by preparative HPLC, preparation 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.

[0658] Intermediate 26: tert-butyl (1-cyclohexyl-1H-pyrazol-5-yl)(methyl)carbamate

[0659]

[0660] 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 2M NH4Cl (aq, 30 mL, 60 mmol) at 10 ° C. The reaction mixture was concentrated and diluted with EtOAc (50 mL), then washed with saturated 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 HNMR (300MHz, DMSO-d6) δ1.11–1.45(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).

[0661] Intermediate 27: 1-cyclohexyl-N-methyl-1H-pyrazol-5-amine

[0662]

[0663] 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 h. The solvent was removed under reduced pressure to afford the title compound as a yellow oil (0.250 g, 95%); MS m / z (ESI) [M+H] + 180.

[0664] Intermediate 28: tert-Butyl 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate

[0665]

[0666] Tert-butyl propiolate (373 mg, 2.96 mmol) was added to a mixture of 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 H2O (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 diatomaceous earth. The process was repeated 17 times, using a total of 21.4 mmol 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 in H2O) to give the title compound (0.397 g, 6%) as a light brown solid; MS m / z (ESI) [M+H] + 294.

[0667] Intermediate 29: 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylic acid

[0668]

[0669] 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 afford the title compound as a beige solid (0.325 g, 99%); MS m / z (ESI) [M+H] + 238.

[0670] Intermediate 30: N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-methoxyphenyl)-N-methylisoxazole-5-carboxamide

[0671]

[0672] DIC (215 μl, 1.38 mmol) was slowly 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-pyrazole-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 and washed with saturated brine (10×20 mL), dried over Na2SO4, 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 in water) to give the title compound (0.109 g, 40%) as a colorless oil which solidified upon standing; MS m / z (ESI) [M+H] + 399.

[0673] Intermediate 31: (3-(4-fluoro-3-methoxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

[0674]

[0675] 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 saturated NaHCO3 (aq, 20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated brine (5×20 mL) and water (20 mL) in sequence. The organic layer was dried over Na2SO4, filtered and 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.

[0676] Intermediate 32: Ethyl 4-(4-fluoro-3-hydroxyphenyl)-2,4-dioxobutanoate

[0677]

[0678] LiHMDS (1M, 14.27ml, 14.27mmol) in THF was added dropwise to 1-(4-fluoro-3-hydroxyphenyl)ethan-1-one (1.0g, 6.49mmol) in THF (15mL) at -20°C and the reaction mixture was stirred at -20°C for 1h. Diethyl oxalate (2.84g, 19.46mmol) was added and the reaction mixture was stirred at room temperature for 2h. The reaction was quenched by adding 2M HCl (10mL). The reaction mixture was diluted with EtOAc (150ml) and washed with 2M HCl (2×50ml). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (1.50g, 91%) as a solid; 1 HNMR (300MHz, CDCl3) δ15.17(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).

[0679] Intermediate 33: Ethyl 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

[0680]

[0681] 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 saturated NaHCO3 (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O (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.

[0682] Intermediate 34: 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid

[0683]

[0684] A solution of NaOH (191 mg, 4.78 mmol) in water (2 mL) was added to 5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid ethyl ester intermediate 33 (400 mg, 1.59 mmol) in EtOH (2 mL). The reaction mixture was vigorously stirred at 50 ° C for 4 h. The pH of the reaction mixture was adjusted to 2 using 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 in water containing 0.1% FA) to give the title compound (0.280 g, 79%) as an off-white solid; 1 HNMR (300MHz, DMSO-d6) δ7.23–7.35(m,2H),7.39(ddd,1H),7.48(dd,1H),10.44(s,1H).

[0685] Intermediate 35: 3-ethynyl-2,5,6-trifluorophenol

[0686]

[0687] 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) [MH] - 171.

[0688] Intermediate 36: Ethyl 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate

[0689]

[0690] TEA (1215 μl, 8.72 mmol) was added to 3-ethynyl-2,5,6-trifluorophenol intermediate 35 (300 mg, 1.74 mmol) and (Z)-2-chloro-2-(hydroxyimino)ethyl 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 Na2SO4, 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 yellow solid; 1 HNMR (300MHz, DMSO-d6) δ1.13–1.30(m,3H),4.23–4.40(m,2H),7.27(d,1H),7.57(m,1H),11.48(s,1H).;

[0691] Intermediate 37: 5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid

[0692]

[0693] 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 using 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) [MH] - 258.

[0694] Intermediate 38: Ethyl 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate

[0695]

[0696] 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)-ethyl 2-amino-2-(hydroxyimino)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 in water) to give the title compound as a white solid (0.940 g, 41%); MS m / z (ESI) [M+H] + 304.

[0697] Intermediate 39: Ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

[0698]

[0699] 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 Na SO, filtered and evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 40-50% EtOAc in PE) to give the title compound (1.200 g, 63%) as a white solid; MS m / z (ESI) [M+H] + 253.

[0700] Intermediate 40: 5-(4-Fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid

[0701]

[0702] A mixture of ethyl 5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate intermediate 39 (470 mg, 1.86 mmol) and 2M LiOH (aq, 9.32 mL, 18.6 mmol) in EtOH (10 mL) was 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 2M HCl. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide the title compound (0.400 g, 96%); MS m / z (ESI) [M+H] + 225.

[0703] Intermediate 41: 2-(4-Fluoro-3-hydroxyphenyl)oxazole-5-carboxylic acid

[0704]

[0705] 2-bromooxazole-5-formic acid methyl ester (470mg, 2.28mmol), (4-fluoro-3-hydroxyphenyl) boronic acid (391mg, 2.51mmol), K3PO4 hydrate (1576mg, 6.84mmol) and XPhosPdG3 (97mg, 0.11mmol) are added to a vial and the reaction mixture is rinsed with N2(g). THF (10mL) and water (10mL) are added, and the reaction mixture is rinsed with N2(g) again. The reaction mixture is heated at 60°C overnight in a preheated heating block. The reaction mixture is brought to room temperature. Starting from 2-bromooxazole-5-formic acid methyl ester (50mg, 0.24mmol), another batch is prepared as described above. The combined reaction mixture is diluted with EtOAc and saturated NH4Cl(aq). The water layer is extracted with EtOAc (×3). The combined organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a residue. The aqueous layer was then acidified to pH about 1 using 2M HCl and extracted with EtOAc (× 4), and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a second residue. The residues were combined and purified by normal phase flash chromatography on silica (gradient: 0-10% MeOH in EtOAc). The fractions containing the product 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 (× 3). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound (370 mg, 73%); MS m / z (ESI) [M+H] + 224.

[0706] Intermediate 42: 3-(4-Fluoro-3-hydroxyphenyl)-3-oxopropionitrile

[0707]

[0708] 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. H2O was added, the mixture was acidified with 3.8 M HCl and extracted with EtOAc. The organic layer was concentrated, and the residue was purified by silica normal phase flash chromatography (gradient: 0-100% EtOAc in heptane) to give the title compound (0.075 g, 71%) as a white solid; MS (ESI) m / z [MH] - 311.

[0709] Intermediate 43: 4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid ethyl ester

[0710]

[0711] TEA (0.117 mL, 0.84 mmol) was added to a stirred suspension of 3-(4-fluoro-3-hydroxyphenyl)-3-oxopropionitrile 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 min. (Z)-2-chloro-2-(hydroxyimino)acetic acid ethyl ester (0.063 g, 0.42 mmol) was added and the reaction 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: 0-50% EtOAc in heptane) to give the title compound (0.056 g, 48%) as a white solid; MS (ESI) m / z [MH] - 275.

[0712] Intermediate 44: 4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid ethyl ester

[0713]

[0714] 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. H2O (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 in heptane). The impure product was combined with crude product from another batch prepared as described 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 as a white solid (0.900 g, 12%); MS (ESI) m / z [MH] - 311; 1 HNMR(500MHz,CD3OD)δ7.37(ddd,1H),4.53(q,2H),1.47(t,3H).

[0715] Intermediate 45: N-methyl-1-phenyl-1H-tetrazolyl-5-amine

[0716]

[0717] A solution of 5-chloro-1-phenyl-1H-tetrazole (2 g, 11.07 mmol) in methylamine (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 in PE) to give the title compound (1.2 g, 61%) as a white solid; MS (ESI) m / z [M+H] + =176.0

[0718] Intermediate 46: (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline tert-butyl ester

[0719]

[0720] DIPEA (771 μL, 4.41 mmol) was slowly added to 5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carboxylic acid intermediate 23 (424 mg, 1.47 mmol), tert-butyl proline ester (252 mg, 1.47 mmol) and HATU (1398 mg, 3.68 mmol) in DMF (10 mL) cooled to 10° C. under N2 atmosphere. 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 x 100 mL), saturated NaHCO3 (1 x 100 mL) and water (1 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (0.255 g, 39%) as a pale yellow solid; MS (ESI) m / z [M+H] + =442.0

[0721] Intermediate 47: (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline

[0722]

[0723] A solution of HCl (4M in dioxane, 60.8 μL, 2 mmol) in 1,4-dioxane (0.5 mL) was added dropwise to a stirred solution of (5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)proline tert-butyl ester 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

[0724] Intermediate 48: N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-methoxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

[0725]

[0726] 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) at 20 °C under N2 atmosphere. 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 Na2SO4, 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

[0727] Intermediate 49: (Z)-tert-butyl 4-((((1-amino-2-methylpropylidene)amino)oxy)carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0728]

[0729] TBTU (524mg, 1.63mmol) was added to a solution of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (309mg, 1.36mmol) and DIPEA (0.521mL, 2.99mmol) in DCM (6mL) at room temperature. The mixture was stirred for about 10min, followed by addition of a solution / mixture of (Z)-N'-hydroxyisobutyrimide (176mg, 1.72mmol) in DCM (2mL). The reaction mixture was stirred at room temperature for 3h, then washed with 8% NaHCO3 (aq, 3x 5mL) using a phase separator. The organic layer was concentrated, and the residue was purified by flash chromatography on silica (gradient: 0-75% EtOAc in heptane) to give the title compound (141mg, 33%) as a white solid; MS (ESI) m / z [M+H] + =312.4

[0730] Intermediate 50: tert-Butyl 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0731]

[0732] A solution of sodium acetate (0.784 mL, 2.15 mmol) in water (0.784 mL) was added to a mixture of (Z)-tert-butyl 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, Preparation Method J (Gradient: 40-80%) to give the title compound (339 mg, 59%); MS m / z (ESI) [M-tBu] + =238.2

[0733] Intermediate 51: 3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazole

[0734]

[0735] 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 intermediate 50 (325 mg, 1.11 mmol) in DCM (3 mL) at room temperature and the solution was stirred at room temperature for 45 min. 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 crude title compound (204 mg, 95%) as a light brown oil; MS (ESI) m / z [M+H] + =194.2

[0736] Intermediate 52: 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylic acid methyl ester

[0737]

[0738] A mixture of 2,4,5-trifluoro-3-hydroxybenzonitrile (249 mg, 1.44 mmol), hydroxylammonium chloride (120 mg, 1.73 mmol) and NaHCO3 (193 mg, 2.30 mmol) in MeOH (2.5 mL) was stirred for 23 h at 50 ° C. The reaction mixture was concentrated and the residue was suspended in pyridine and cooled to 0 ° C. 2-chloro-2-oxoacetic acid methyl ester (0.199 mL, 2.16 mmol) was added, and the mixture was stirred at room temperature for 20 min, and then stirred at 50 ° C for 1.5 h. The reaction mixture was cooled to room temperature and poured on a mixture of ice and 4MHCl (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, Preparation Method J, (gradient: 20-65%) to give the title compound as a white solid (153 mg, 39%); MS m / z (ESI) [MH] - 273.0.

[0739] Intermediate 53: Ethyl 5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate

[0740]

[0741] Oxalyl chloride (4.09mL, 47.7mmol) and catalytic amount of DMF (0.154mL, 1.99mmol) are added to a stirred suspension of 3,4-difluoro-5-hydroxybenzoic acid (3.46g, 19.9mmol) in DCM (50mL) at room temperature, and the resulting mixture is stirred at room temperature for 20h. The reaction mixture is concentrated and co-evaporated twice from toluene. The residue is dissolved in THF (20mL) at room temperature and added dropwise to a stirred solution of (Z)-2-amino-2-(hydroxyimino)ethyl acetate (2.63g, 19.9mmol) in pyridine (40mL, 494mmol). The resulting mixture is heated to 70 ° C for 5 days, cooled to room temperature and poured on a stirred mixture (400mL) of 3.8MHCl (150mL) and ice. The mixture is stirred at room temperature for 1h. The solid is filtered out and washed with H o to obtain a crude product as a brown solid. The crude product was dissolved in DCM (about 50 mL) and loaded onto a silica plug (14 g). The product was eluted with DCM (40 mL) and heptane / EtOAc (1: 1, 100 mL). The impure product was combined with another batch of crude product prepared from 3,4-difluoro-5-hydroxybenzoic acid (1.00 g, 5.74 mmol) as described above, 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 [MH]- 269.

[0742] Intermediate 54: 2,4,5-Trifluoro-3-methoxybenzothioamide

[0743]

[0744] 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 in heptane) to give the title compound (1.225 g, 76%) as a yellow solid; MS m / z (ESI) [MH] - 220.1.

[0745] Intermediate 55: Ethyl 2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate

[0746]

[0747] A solution of 2,4,5-trifluoro-3-methoxybenzenethioamide 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 silica straight phase flash chromatography (0-30% EtOAc in heptane) to give an orange solid, which was further purified by trituration with heptane to give the title compound as a light orange solid (282 mg, 18%); MS m / z (ESI) [M+H] + 318.1.

[0748] Intermediate 56: ((2R,6S)-2,6-dimethylmorpholino)(2-(2,4,5-trifluoro-3-methoxyphenyl)thiazol-5-yl)methanone

[0749]

[0750] Me3Al (2M in toluene) (0.989ml, 1.98mmol) was added dropwise to a solution of (2R, 6S)-2,6-dimethylmorpholine (0.140mL, 1.11mmol) in anhydrous toluene (1.1mL) at room temperature under N2(g) atmosphere. The reaction mixture was stirred at room temperature for 1h under N2(g) atmosphere and then added dropwise to a stirred slurry of ethyl 2-(2,4,5-trifluoro-3-methoxyphenyl)thiazole-5-carboxylate intermediate 55 (251mg, 0.79mmol) in toluene (1.6mL) at room temperature. The resulting solution was heated at 60°C for 9h and then cooled to 0°C. Tartaric acid (30%, aq, 10mL) was added dropwise and the mixture was extracted with EtOAc (×2). 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.

[0751] Example 1: (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(3-phenylpyrrolidin-1-yl)methanone

[0752]

[0753] DIPEA (0.440 mL, 2.52 mmol) was added dropwise to 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylic acid methyl ester intermediate 20 (100 mg, 0.42 mmol) and (R)-3-phenylpyrrolidine HCl (463 mg, 2.52 mmol) in DMF (4 mL) at 25 ° C and under N2 (g) atmosphere, and the reaction mixture was stirred at 80 ° C for 16 h. The reaction was quenched with water (100 mL), extracted with EtOAc (3×100 mL), and the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, preparation method E, (gradient: 42-52%) to give the title compound (61 mg, 41%) as a white solid; HRMS (ESI) m / z[M+H] + C 19 H 17 Calculated value for FN3O3: 354.1248, found value: 354.1254; 1HNMR (300 MHz, DMSO-d6) δ1.97–2.18 (1H, m), 2.22–2.45 (overlapping with solvent, m), 3.41–3.72 (overlapping with solvent, m), 3.72–4.15 (2H, m), 4.17–4.56 (1H, m), 7.13–7.56 (7H, m), 7.59–7.72 (1H, m), 10.64 (1H, s).

[0754] Example 2: (3-phenoxyazetidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0755]

[0756] 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 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 in 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 for F3N3O4: 392.0852, found value: 392.0840; 1 HNMR(400MHz,DMSO-d6)δ11.71(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).

[0757] Example 3: ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone

[0758]

[0759] BBr3 (1M, 1.06mL, 1.06mmol) 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 (136mg, 0.35mmol) in DCM (5mL) at 0°C. The reaction mixture was stirred at room temperature for 1.5h. The reaction mixture was diluted with DCM and water was carefully added. The layers were separated and the aqueous layer was acidified with 1M 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, Preparation Method J, (gradient: 30-70%) to give the title compound (110mg, 84%) as a white solid; HRMS (ESI) m / z[M+H] + C 17 H 17 F3NO3S:372.0876, found value:372.0892; 1 H NMR (500 MHz, DMSO-d6) δ 1.11 (6H, d), 2.66 (overlap with solvent, 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).

[0760] Example 4: (3-(2-methoxyphenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0761]

[0762] (2-Methoxyphenyl)pyrrolidine HCl (0.102 g, 0.48 mmol) was suspended in EtOAc and washed with 10% Na2CO3. The organic layer was concentrated, toluene (1 mL) and Me3Al (2M, 0.599 mL, 1.20 mmol) in toluene were added to the residue under N2(g) atmosphere, and the resulting mixture was stirred at room temperature for 1 h. The mixture was added to a stirred slurry of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester 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 for F3N3O4: 420.1166, found: 420.1164; 1 HNMR(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).

[0763] Example 5: N-(1-cyclohexyl-1H-pyrazol-5-yl)-3-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-5-carboxamide

[0764]

[0765] BBr3 (1M, 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 and under N2 (g) atmosphere. The resulting solution was stirred at 15 ° C for 2 h. Additional BBr3 solution (1M, 20 mL, 20.00 mmol) in DCM was slowly added to the above solution, cooled to 0 ° C, and under N2 (g) atmosphere. The resulting solution was stirred at 15 ° C for 2 h. The reaction mixture was poured into 2M NaOH (aq, 50 mL) and extracted with EtOAc (3×75 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:2) and then further purified by preparative HPLC, Preparation Method N, (gradient: 45-55%) to give the title compound as a white solid (0.014 g, 16%); HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated value for FN4O3: 385.1670, found value: 385.1674; 1 H NMR(300MHz,DMSO-d6)δ1.06–1.92(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).

[0766] Example 6: (3-(4-fluoro-3-hydroxyphenyl)isoxazol-5-yl)(3-phenylpyrrolidin-1-yl)methanone

[0767]

[0768] BBr3 (1 M, 5 mL, 5 mmol) in DCM was slowly added 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 over 5 min and under N2(g) atmosphere. The resulting solution was stirred at 15 °C for 3 h under 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 organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC, Preparation Method N, (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 for FN2O3: 353.1296, found value: 353.1304; 1 HNMR (300MHz, DMSO-d6) δ1.94–2.2(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).

[0769] Example 7: N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)-N-methylisoxazole-3-carboxamide

[0770]

[0771] (COCl)2 (50.8 mg, 0.40 mmol) was slowly added 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 and under N2 (g) atmosphere. The resulting solution was stirred at 28 ° C for 0.5 h. 1-cyclohexyl-N-methyl-1H-pyrazole-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 reverse phase HPLC, Preparation Method O, (gradient: 28-61%) to give the title compound as a white solid (1.1 mg, 1%); HRMS (ESI) m / z [M+H] +C 20 H 22 Calculated value for FN4O3: 385.1670, found 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 (overlapping with solvent, s), 6.17 (1H, d), 7.00 (1H, s), 7.23–7.34 (3H, m), 7.37 (1H, s).

[0772] Example 8: (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

[0773]

[0774] 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 for 2 h under 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 further purified by preparative HPLC, Preparation Method P, (gradient: 60-85%) to give the title compound as a white solid (0.025 g, 19%); HRMS (ESI) m / z [M+H] + C 20 H 15 Calculated for ClF3N2O3: 423.0718, found: 423.0718; 1 H NMR (400MHz, DMSO-d6, 80℃) δ2.01(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).

[0775] Example 9: 4-(3-(3-phenylpyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

[0776]

[0777] Me3Al (2M, 0.5mL, 1.00mmol) in toluene was added to a solution of 3-phenylpyrrolidine (73mg, 0.49mmol) in toluene (0.5mL) at 25°C and stirred for 40min. 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 (100mg, 0.33mmol) in toluene (0.5mL) and under N2(g) atmosphere, and the mixture was stirred at 60°C for 3h. The reaction mixture was diluted with water (75mL) and filtered through a celite pad. The aqueous layer was extracted with EtOAc (3×20mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC, Preparation Method Q, (gradient: 50-62%) to give the title compound as a white solid (34 mg, 25%); HRMS (ESI) m / z [M+H] + C 19 H 16 Calculated for F3N4O3: 405.1168, found: 405.1166; 1 H NMR (300MHz, DMSO-d6) δ2.00–2.18(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).

[0778] Example 10: 4-(3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)-6-(trifluoromethyl)pyridin-2(1H)-one

[0779]

[0780] DABAL-Me3 (127 mg, 0.49 mmol) was added in batches 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 h under N2 (g) atmosphere. A solution of 5-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 38 (100 mg, 0.33 mmol) in THF (1 mL) was added to the mixture in batches at 50 ° C under N2 (g) atmosphere. The resulting solution was stirred at 80 ° C for 2 h. 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 for F3N5O4: 450.1384, found: 450.1380; 1 HNMR(300MHz,DMSO-d6)δ2.94–3.11(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).

[0781] Example 11: (R)-(5-(4-fluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

[0782]

[0783] Under N2(g) atmosphere, (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). 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 in 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 17Calculated value for FN3O3: 354.1248, found value: 354.1256; 1 HNMR(400MHz,CD3OD)δ2.10–2.24(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).

[0784] Example 12: N-(1-cyclohexyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

[0785]

[0786] 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-Lutidine (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), washed with saturated NaHCO3 (10 mL) and brine (3×10 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse phase HPLC, Preparation 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 for FN4O3: 371.1514, found value: 371.1516; 1 H NMR (600MHz, DMSO-d6) δ1.13–1.22(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).

[0787] Example 13: 5-(4-Fluoro-3-hydroxyphenyl)-3-(3-phenylpyrrolidine-1-carbonyl)isoxazole-4-carbonitrile

[0788]

[0789] Under N2(g) atmosphere, Me3Al (2M, 0.185mL, 0.37mmol) in toluene was added to a stirred solution of 3-phenylpyrrolidine (0.054g, 0.37mmol) in toluene (0.3mL) and the resulting mixture was stirred at room temperature for 1h. The mixture was added to 4-cyano-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxylic acid ethyl ester intermediate 43 (0.034g, 0.12mmol) and the resulting mixture was heated to 60°C for 22h and then cooled to room temperature. Tartaric acid (30%, aq, 2mL) was added, and the mixture was extracted with EtOAc (5mL). The organic layer was concentrated, and the residue was purified by silica normal phase flash chromatography (gradient: 0-100% EtOAc in heptane) to give the title compound (22mg, 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 (500 MHz, 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.

[0790] The following examples 14-29 were prepared from ethyl 4-cyano-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxylate intermediate 44 using the appropriate commercially available amines in analogy to Example 13. The HCl- and AcOH-salts of the amines were dissolved in MeOH, passed through a 5 g ISOLUTE NH2 ion exchange column and concentrated before use. The crude product was purified as specified.

[0791] Example 14: 3-(4-(3-(4-fluorophenoxy)propyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0792]

[0793] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (24 mg, 37%); HRMS (ESI) m / z [M+H] + ; C 24 H 21 Calculated value for F4N4O4: 505.1494, found value: 505.1486; 1 HNMR (500MHz, CD3OD) δ2.04(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).

[0794] Example 15: 3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0795]

[0796] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (9 mg, 16%); HRMS (ESI) m / z [M+H] + ; C 20 H 15 Calculated for F3N5O3: 430.1122, found: 430.1126; 1 HNMR(500MHz,CD3OD)δ3.68(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).

[0797] Example 16: 3-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0798]

[0799] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (25 mg, 43%); HRMS (ESI) m / z [M+H] + ; C 22 H 18 Calculated value for F3N4O4: 459.1274, found value: 459.1258;1 HNMR (500MHz, CD3OD) δ3.27(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).

[0800] 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

[0801]

[0802] The crude product was purified by preparative HPLC, Prep Method C (Gradient: 20-80%) to give the title compound as an off-white solid (20 mg, 29%); HRMS (ESI) m / z [M+H] + ; C 21 H 13 Calculated for F6N8O3: 539.1008, found: 539.1016; 1 HNMR(500MHz,CD3OD)δ3.85(dt,4H),4.01(dt,4H),7.36(ddd,1H),7.56(d,1H),8.11(d,1H).

[0803] Example 18: 3-(5-Fluoroisoindoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0804]

[0805] The crude product was purified by preparative HPLC, Prep Method C (Gradient: 20-80%) to give the title compound as an off-white solid (12 mg, 27%); 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 HNMR (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.

[0806] Example 19: N-(tert-butyl)-4-cyano-N-(pyridin-2-ylmethyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-3-carboxamide

[0807]

[0808] 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 for F3N4O3: 431.1326, found: 431.1334; 1 HNMR (600MHz, DMSO-d6) δ1.39(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).

[0809] 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

[0810]

[0811] The crude product was purified by preparative HPLC, Preparation 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 HNMR (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.

[0812] Example 21: (S)-3-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0813]

[0814] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (18 mg, 36%); 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: 1 H 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.

[0815] Example 22: 3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0816]

[0817] The crude product was purified by preparative HPLC, Preparative Method C (gradient: 20-80%) to give the title compound as an off-white solid (5 mg, 9%); HRMS (ESI) m / z [M+H] + ; C 17 H 15 Calculated for F3N3O4: 382.1008, found: 382.1008; 1 HNMR(500MHz,CD3OD)δ1.16(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).

[0818] Example 23: 3-(4-(Benzo[d]oxazol-2-yl)piperazine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0819]

[0820] The crude product was purified by preparative HPLC, Prep Method C (Gradient: 20-80%) to give the title compound as an off-white solid (23 mg, 38%); HRMS (ESI) m / z [M+H] + ; C 22 H 15 Calculated value for F3N5O4: 470.1070, found value: 470.1048; 1 HNMR(500MHz,CD3OD)δ3.84(dt,4H),4.00(q,4H),7.08(td,1H),7.19(td,1H),7.29–7.4(m,3H).

[0821] 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

[0822]

[0823] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (5 mg, 7%); HRMS (ESI) m / z [M+H] + ; C 25 H 18 Calculated value for F4N5O4: 528.1290, found value: 528.1276; 1 HNMR (500 MHz, CD3OD) δ1.9–2.16 (m, 4H), 3.10 (td, 1H), 3.38–3.49 (m, 1H), 4.3–4.46 (m, 2H), 4.80–4.87 (m, 1H, OH obscured by the solvent), 6.97 (s, 1H), 7.04–7.14 (m, 2H), 7.29–7.38 (m, 1H), 7.46–7.53 (m, 2H).

[0824] Example 25: 3-(4-((5-methoxypyridin-2-yl)oxy)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0825]

[0826] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (32 mg, 53%); HRMS (ESI) m / z [M+H] + ; C 22 H18 Calculated value for F3N4O5: 475.1224, found value: 475.1216; 1 HNMR(500MHz,CD3OD)δ1.82–1.94(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).

[0827] Example 26: 3-(4-Hydroxy-4-(trifluoromethyl)piperidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0828]

[0829] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (9 mg, 16%); HRMS (ESI) m / z [M+H] + ; C 17 H 12 Calculated value for F6N3O4: 436.0726, found value: 436.0732; 1 HNMR (500MHz, CD3OD) δ1.79–1.93(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).

[0830] Example 27: 3-(3-Cyclopropyl-3-fluoroazetidine-1-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0831]

[0832] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (10 mg, 23%); HRMS (ESI) m / z [M+H] + ; C 17 H 12 Calculated value for F4N3O3: 382.0810, found value: 382.0816; 1HNMR(500MHz,CD3OD)δ0.49–0.58(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).

[0833] Example 28: 5-(2,4,5-trifluoro-3-hydroxyphenyl)-3-(3-(trifluoromethyl)azetidine-1-carbonyl)isoxazole-4-carbonitrile

[0834]

[0835] The crude product was purified by preparative HPLC, Preparation Method U to give the title compound as an off-white solid (10 mg, 24%); HRMS (ESI) m / z [M+H] + ; C 15 Calculated for H8F6N3O3: 392.0464, found: 392.0450; 1 HNMR (500MHz, CD3OD)δ 1 H NMR δ3.65(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).

[0836] Example 29: 3-(7-Cyano-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazole-4-carbonitrile

[0837]

[0838] The crude product was purified by preparative HPLC, Preparative Method C (Gradient: 20-80%) to give the title compound as an off-white solid (17 mg, 34%); HRMS (ESI) m / z [M+H] + ; C 21 H 12 Calculated for F3N4O3: 425.0856, found: 425.0828; mixture of rotamers, major:minor ratio 1.5:1: 1 HNMR (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.

[0839] 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

[0840]

[0841] 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 crude residue was purified by preparative HPLC, Preparative 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.

[0842] Example 31: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile

[0843]

[0844] 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (38 mg, 0.15 mmol), HATU (111 mg, 0.29 mmol) and DMF (0.5 mL) were mixed in a vial. 1,2,3,4-tetrahydroisoquinoline-6-carbonitrile HCl (28 mg, 0.15 mmol) dissolved in DMF (0.5 mL) was added, followed by DIPEA (153 μL, 0.88 mmol). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DMSO and purified by preparative HPLC, preparation method A (gradient: 5-95%) to give the title compound (15 mg, 26%); HRMS (ESI) m / z [M+H]+ C 19 H 12 Calculated for F3N4O3: 401.0856, found: 401.0834; mixture of rotamers, major:minor ratio: 1:0.6: 1 HNMR (600MHz, DMSO-d6) δ2.97 (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.

[0845] Example 32: (2,2,6,6-Tetramethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0846]

[0847] 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 h. The reaction mixture was diluted with DMSO and purified by preparative HPLC, preparation 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 for F3N3O4: 386.1322, found value: 386.1324; 1 HNMR (600MHz, DMSO-d6) δ1.09(6H,s),1.17(6H,s),3.32(2H,s),3.49(2H,s),6.99–7.12(1H,m).

[0848] Example 33: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophen-2-yl)methanone

[0849]

[0850] BBr3 (1M, 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)thiophene-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 added carefully. The organic phase was separated. 1M KHSO4 was added to the aqueous phase and extracted with EtOAc (×3). The combined organic layers were dried using a phase separator and concentrated to give a white solid. The residue was purified by preparative HPLC, Preparation Method C (Gradient: 25-65%) to give the title compound (12 mg, 73%); HRMS (ESI) m / z [M+H] + C 21 H 17 F3NO2S: 404.0926, found: 404.0924; mixture of rotamers: 1 HNMR (500 MHz, DMSO-d6) δ1.95–2.21 (1H, m), 2.23–2.44 (1H, m), 3.42–3.64 (2H, m, overlaps 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.

[0851] General Preparation A

[0852] The appropriate amine (0.08 mmol, 2 eq) was added to a solution of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 (0.08-0.2 M, 0.04 mmol, 1 eq) and HATU (0.15-0.4 M, 0.08 mmol, 2 eq) in DMF. DIPEA (0.23 mmol, 6 eq) was added and the reaction 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; Preparation F, G, H or I (gradient 2-94%).

[0853] Table 1:

[0854] Examples 34-76 were prepared as described in General Preparation A using the appropriate amines described in the table below. If not otherwise stated, the amines were commercially available.

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865] General Preparation B

[0866] 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid intermediate 2 in DMF (0.4M, 0.06mmol, 1 eq) followed by DIPEA (0.35mmol, 6 eq) and HATU in DMF (0.47M, 0.12mmol, 2 eq) were added to a vial containing the appropriate amine (0.12mmol, 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 (0.3mL) and purified by preparative HPLC using one of the following methods; Preparation Method F, G, H or I (gradient 2-94%).

[0867] Table 2

[0868] Examples 77-84 were synthesized and purified as described in General Preparation B using the appropriate amine as the free base or as the corresponding HCl salt. If not otherwise stated, the amines were commercially available.

[0869]

[0870]

[0871]

[0872] Example 85: 3-(1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)azetidin-3-yl)benzonitrile

[0873]

[0874] 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-(azetidine-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 filtered and purified by preparative HPLC, preparation method D (gradient 20-60%). Pure fractions were combined and MeCN was evaporated. The remaining aqueous phase was extracted with EtOAc (× 2). The combined organic layers were concentrated to give a yellow oil, which was purified by preparative HPLC, preparation method D (gradient 30-80%). The relevant fractions were combined and evaporated. The residue was dissolved in MeCN and purified by preparative HPLC, Preparation Method J (gradient 15-55%). The pure fractions were combined and evaporated by freeze drying overnight. The residue was dissolved in EtOAc and washed with 1M KHSO4. The aqueous phase was extracted with EtOAc (×2). The organic layers were combined and evaporated. The residue was dissolved in MeCN / water and freeze dried 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 for F3N4O3: 401.0856, found value: 401.0846; 1 HNMR (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).

[0875] Example 86: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

[0876]

[0877] 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, Preparation Method D (gradient 15-55%). The pure fractions were combined and MeCN was evaporated. The remaining aqueous phase was extracted with EtOAc (×2). The combined organic layers were concentrated to give a beige oil. The oil was dissolved in MeCN and water was added. The compound was freeze-dried overnight to give a solid. Water was added to give a slurry, which was sonicated for 5 min. The slurry was freeze-dried overnight to give the title compound as a beige solid (76 mg, 62%); HRMS (ESI) m / z [M+H] + C 19 H 12 Calculated for F3N4O3: 401.0856, found: 401.0838; mixture of rotamers: major:minor ratio: 1:0.6; 1 HNMR (500MHz, DMSO-d6) δ3.01 (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.

[0878] Example 87: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0879]

[0880] (2R, 6S) -2,6- dimethylmorpholine (0.520g, 4.51mmol) was suspended in dry toluene (12mL) and Me3Al (2M, 4.34mL, 8.68mmol) in toluene was added under N2(g) atmosphere, and the resulting mixture was stirred at room temperature for 1h. The above mixture was added to a stirred slurry of 5- (2,4,5-trifluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (1g, 3.47mmol) in toluene (12mL). The resulting solution was heated to 60°C for 20h. The mixture was cooled to room temperature, tartaric acid (30%, aq, 100mL) 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 for F3N3O4: 358.1008, found value: 358.0978; 1 HNMR(500MHz,CD3OD)δ1.14(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).

[0881] Example 88: ((2R,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0882]

[0883] 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 analogy to Example 87. The crude product was purified by preparative HPLC, Preparation Method D (gradient 20-80%) to give the title compound (59 mg, 48%); HRMS (ESI) m / z [M+H] + C 15 H 15 Calculated for F3N3O4: 358.1008, found: 358.1008; 1HNMR(500MHz,CD3OD)δ1.20(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).

[0884] Example 89: ((2R,6S)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

[0885]

[0886] The title compound was prepared analogously to Example 33 from ((2R,6S)-2,6-dimethylmorpholino)(5-(2,4,5-trifluoro-3-methoxyphenyl)isoxazol-3-yl)methanone intermediate 18 but using 6 equivalents of BBr3 in DCM (1M). The crude product was purified by preparative HPLC, Preparation Method D (gradient 15-55%) to give the title compound (74 mg, 57%); HRMS (ESI) m / z [M+H] + C 16 H 16 Calculated for F3N2O4: 357.1056, found: 357.1066; 1 H NMR (500 MHz, DMSO-d6) δ 1.05 (3H, d), 1.16 (3H, d), 2.55 (1H, dd, overlaps 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).

[0887] The following compounds, Examples 90-111, were also prepared by methods similar to those described above.

[0888] Example 90: (5-(4-Fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)(5-oxa-8-azaspiro[3.5]nonan-8-yl)methanone

[0889]

[0890] 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, Preparation 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 for FN3O4: 334.1198, found value: 334.1176; 1 HNMR(300MHz,DMSO-d6)δppm 1.54-1.85(2H,m)1.87-2.12(4H,m)3.58-3.67(3H,m)3.71(1H,s)3.91

[0891] -4.02(2H,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).

[0892] Example 91: 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,3,4-oxadiazole-2-carboxamide

[0893]

[0894] Me3Al (1M in heptane, 2.52mL, 2.52mmol) was added dropwise to a mixture of 5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazole-2-formic acid methyl ester intermediate 20 (200mg, 0.84mmol) and N-methyl-1-phenyl-1H-tetrazol-5-amine intermediate 45 (441mg, 2.52mmol) in DCM (2mL) and THF (10mL) at 25°C under N2(g) atmosphere. The resulting mixture was stirred at 25°C for 3 days. The reaction mixture was poured into 0.1M HCl (100mL) and extracted with EtOAc (3×50mL). The organic layer was dried over Na2SO4, filtered and evaporated. The solid was purified by preparative HPLC, Prep Method V (Gradient: 50-65%) to give the title compound as a white solid (112 mg, 35%); HRMS (ESI) m / z [M+H] + C 17 H 13 Calculated value for FN7O3: 382.1058, found value: 382.1036;1 HNMR(300MHz,DMSO-d6)δppm 3.35(3H,s)7.32-7.45(2H,m)7.47-7.64(6H,m)10.65(1H,s).

[0895] Example 92: 5-(4-Fluoro-3-hydroxyphenyl)-N-methyl-N-(1-phenyl-1H-tetrazol-5-yl)-1,2,4-oxadiazole-3-carboxamide

[0896]

[0897] Me3Al (2M in hexanes, 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 2M HCl (10 mL) and extracted with EtOAc (3×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude orange oil was purified by flash chromatography on silica (gradient: 40-50% EtOAc in 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 for FN7O3: 382.1058, found value: 382.1058; 1 HNMR(400MHz,CD3OD)δ3.45(3H,s),7.22-7.30(1H,m),7.44–7.57(2H,m),7.62(5H,s).

[0898] Example 93: (S)-(3-Phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0899]

[0900] (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 MgSO4, filtered and evaporated. The solid was purified by preparative HPLC, preparation 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 for F3N3O4: 406.1008, found: 406.1008; 1 HNMR(300MHz, DMSO-d6)δppm2.09-2.37(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).

[0901] Example 94: (3-(Benzyloxy)piperidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0902]

[0903] 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 MgSO4, filtered and evaporated. The solid was purified by preparative HPLC, preparation 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 19Calculated value for F3N3O4: 434.1322, found value: 434.1314; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0904] Example 95: (R)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0905]

[0906] 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 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 in water) to give the title compound as a yellow solid (0.076 g, 13%); HRMS (ESI) m / z [M+H] + C 19 H 14 Calculated for ClF3N3O3: 424.0670, found: 424.0668; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0907] Example 96: (3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0908]

[0909] Me3Al (2M 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) at 25 ° C under N2 (g) atmosphere. The resulting solution was stirred at 60 ° C for 3 h. The reaction mixture was acidified with 2M HCl and then concentrated. The residue was diluted with EtOAc and washed with water and saturated NaHCO3 in sequence. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, preparation 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 for F3N3O3: 390.1060, found value: 390.1070; 1 H NMR(400MHz,DMSO-d6)δppm 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).

[0910] Example 97: (3-(Benzyloxy)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0911]

[0912] Me3Al (2M 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) at 25 ° C under N2 (g) atmosphere. The resulting solution was stirred at 25 ° C for 2 h. The reaction mixture was acidified with 2M HCl and then concentrated. The residue was diluted with EtOAc and washed with water in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product, which was purified by preparative HPLC, preparation 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 for F3N3O4: 420.1166, found: 420.1168; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0913] Example 98: (R)-(3-phenoxypyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0914]

[0915] (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 N2(g) atmosphere. The resulting mixture was stirred at 25°C for 3 h. The reaction mixture was concentrated, diluted with DCM (50 mL), and washed sequentially 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, preparation method N (gradient: 50-65%) to give the crude compound. The crude product was diluted with DCM (100 mL) and washed successively with saturated NaHCO (3×100 mL) and water (3×100 mL). The organic layer was dried over NaSO, filtered and evaporated. Since the residue still contained impurities, it was diluted with DCM again and washed with saturated NaHCO and water as described above, dried over NaSO, filtered and evaporated to give the title compound as a white solid (0.031 g, 34%); HRMS (ESI) m / z [M+H] + C 19 H 15 Calculated value for F3N3O4: 406.1008, found value: 406.1040; 1 H NMR(400MHz,DMSO-d6)δppm 2.12-2.32(2H,m)3.59-3.71(1H,m)3.72-4.10(3H,m)5.15(1H,brs)6.90-7.06(3H,m)7.24-7.39(2H,m)7.57-7.77(1H,m)11.52(1H,br s).

[0916] Example 99: N-(1-cyclohexyl-1H-pyrazol-5-yl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide

[0917]

[0918] 1-Cyclohexyl-1H-pyrazole-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 saturated 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 in water) to give the title compound as a white solid (0.072 g, 26%); HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated value for FN4O3: 371.1514, found value: 371.1514; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0919] Example 100: N-((1-cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(4-fluoro-3-hydroxyphenyl)oxazole-5-carboxamide

[0920]

[0921] 2,6-Lutidine (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)methylamine (40.2 mg, 0.22 mmol) and HATU (94 mg, 0.25 mmol) in DMF (2.11 mL). The reaction was left overnight at room temperature. The reaction was diluted with EtOAc (20 mL), washed with saturated NaHCO3 (10 mL) and brine (3×10 mL). The organic layer was dried over MgSO4, 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 for FN4O3: 385.1670, found value: 385.1660; 1 HNMR(600MHz,DMSO-d6)δ9.18(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).

[0922] Example 101: (R)-(5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)(3-phenylpyrrolidin-1-yl)methanone

[0923]

[0924] (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 vigorously 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 in water) and then by preparative HPLC, Preparation Method Y (gradient: 32-62%) to give the title compound (0.037 g, 15%) as a white solid; HRMS (ESI) m / z [M+H] + C20 H 18 Calculated value for FN2O3: 353.1296, found value: 353.1304; 1 HNMR(300MHz,DMSO-d6)δppm1.96-2.18(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).

[0925] Example 102: (3H-Spiro[isobenzofuran-1,3'-pyrrolidino]-1'-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0926]

[0927] 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) at 0 °C under N2(g) atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with saturated NaHCO3 (25 mL) and quenched 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 in water) to give the title compound (9 mg, 7%) as a white solid; HRMS (ESI) m / z[M+H] + C 20 H 15 Calculated for F3N3O4: 418.1008, found: 418.1014; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0928] Example 103: (S)-(3-(4-chlorophenyl)pyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0929]

[0930] (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 Na2SO4, filtered and evaporated. The yellow oil was purified by preparative HPLC, preparation 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 for ClF3N3O3: 424.0670, found: 424.0676; 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0931] Example 104: (R)-(3-phenylpyrrolidin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)isoxazol-3-yl)methanone

[0932]

[0933] 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 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) followed by preparative HPLC, Prep Method N (gradient: 45-55%) to give the title compound as a white solid (0.018 g, 15%); HRMS (ESI) m / z [M+H] + C 20 H 16 Calculated for F3N2O3: 389.1108, found: 389.1094; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0934] Example 105: N,N-dimethyl-1-(5-(2,4,5-trifluoro-3-hydroxyphenyl)thiophene-2-carbonyl)pyrrolidine-2-carboxamide

[0935]

[0936] 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) at 0°C under N2(g) atmosphere. The resulting mixture was stirred at 20°C for 8 h. The reaction mixture was quenched with MeOH (2 mL). The residue was purified by preparative TLC (MeOH:DCM, 1:10) and then by preparative HPLC, Preparation 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 HNMR (300 MHz, DMSO-d6) δppm 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.

[0937] Example 106: 2-(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carbonyl)isoindoline-5-carbonitrile

[0938]

[0939] 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 at room temperature overnight. The reaction mixture was diluted with DMSO and purified by preparative HPLC, preparation 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 18H 10 Calculated value for F3N4O3: 387.0700, found value: 387.0686; 1 HNMR (500MHz, DMSO-d6) δ4.99(2H,d),5.22(2H,d),7.56–7.7(2H,m),7.77–7.84(1H,m),7.91(1H,d).

[0940] 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

[0941]

[0942] Me3Al (2M in toluene, 0.985mL, 1.97mmol) was added to 3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-oxadiazole intermediate 51 (198mg, 1.02mmol) in toluene (2mL) under N2(g) atmosphere. The resulting mixture was stirred at room temperature for 45min. The mixture was added to a stirred slurry of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (227mg, 0.79mmol) in toluene (2mL). The resulting mixture was heated to 60°C for 5h and then cooled to room temperature. Tartaric acid (30%, aq, 12mL) was added and the mixture was extracted with EtOAc (×2). 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 as an off-white solid (209 mg, 61%); HRMS (ESI) m / z [M+H] + C 19 H 17 Calculated for F3N5O4: 436.1228, found: 436.1210; mixture of rotamers: 1 HNMR (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.

[0943] Example 108: ((2S,6R)-2,6-Dimethylmorpholino)(5-(2,4,5-trifluoro-3-hydroxy-6-iodophenyl)-1,2,4-oxadiazol-3-yl)methanone

[0944]

[0945] A mixture of ((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) was 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, Preparation Method C (Gradient: 20-80%) to give the title compound (27 mg, 68%) as a tan solid; HRMS (ESI) m / z [M+H] + C 15 H 14 Calculated value for F3IN3O4: 483.9976, found value: 483.9962; 1 HNMR (500MHz, CDCl3) δ1.22(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).

[0946] 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

[0947]

[0948] 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 rt for 20 h. The mixture was concentrated and the residue was purified by preparative HPLC, Preparative 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 for F3IN4O3: 526.9822, found value: 526.9808; 1HNMR(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).

[0949] Example 110: ((2R,6S)-2,6-Dimethylmorpholino)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

[0950]

[0951] Me3Al (2M 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 N2(g) atmosphere and at room temperature. The reaction mixture was stirred at room temperature for 1 h under N2(g) atmosphere and then added dropwise to a stirred mixture of 3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylic acid methyl ester intermediate 52 (80 mg, 0.29 mmol) in toluene (0.75 mL) 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 H2O (×2), passed through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC, Preparation Method D, (gradient: 25-65%) to give the title compound as a white solid (52 mg, 49%); HRMS (ESI) m / z [M+H] + C 15 H 15 Calculated value for F3N3O4: 358.1008, found value: 358.1022; 1 HNMR(500MHz,DMSO-d6)δ1.08(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).

[0952] Example 111: ((3R,5S)-3,5-dimethylpiperidin-1-yl)(3-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methanone

[0953]

[0954] 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) similar to the preparation of Example 110. The crude product was purified by preparative HPLC, Preparation Method D, (gradient: 35-75%) to give the title compound as a white solid (67 mg, 65%); HRMS (ESI) m / z [M+H] + C 16 H 17 Calculated value for F3N3O3: 356.1216, found value: 356.1224; 1 HNMR(500MHz,DMSO-d6)δ0.83(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).

[0955] 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

[0956]

[0957] (4aR,7aS)-octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol) was dissolved in MeOH and passed through an IsoluteNH2 column (1 g). The compound was eluted with MeOH. The MeOH was evaporated and the residue was dissolved in dry toluene (0.5 mL). Me3Al (2M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N2(g) atmosphere. The solution was stirred at room temperature for 45 min under nitrogen and then added dropwise to a stirred solution of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 mL) at room temperature. The solution was heated to 60°C for 20 h. 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 phases were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, Preparation 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.

[0958] 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

[0959]

[0960] (4aS,7aR)-octahydrocyclopenta[b][1,4]oxazine HCl (0.052 g, 0.32 mmol) was dissolved in MeOH and passed through an IsoluteNH2 ion exchange column (1 g). The compound was eluted with MeOH. The MeOH was evaporated and the residue was dissolved in dry toluene (0.5 mL). Me3Al (2M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N2(g) atmosphere. The solution was stirred at room temperature for 45 min under N2(g) atmosphere 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. The solution was heated to 60°C for 20 h. 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 phases were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, Preparation 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.

[0961] 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

[0962]

[0963] (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine (0.040 g, 0.32 mmol) was dissolved in dry toluene (0.5 mL). Me3Al (2M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N2(g) atmosphere. The resulting solution was stirred at room temperature for 45 min under N2(g) atmosphere 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). The solution was heated to 60°C for 20 h. Tartaric acid (30%, aq, 5 mL) was added dropwise and the mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, Preparative Method C (gradient: 30-100%) to give the title compound as a white solid (0.023 g, 26%); HRMS (ESI) m / z [M+H] + C 16 H 15 Calculated for F3N3O4: 370.1014, found: 370.1024; mixture of rotamers, 1 HNMR (500MHz, DMSO-d6) δ1.03–2.01 (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.

[0964] 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

[0965]

[0966] 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, Preparation Method D (Gradient: 30-100%) to give the title compound (0.039 g, 34%) as a light yellow solid. HRMS (ESI) m / z [M+H] + C 16 H 15 Calculated for F3N3O4: 370.1014, found: 370.0981; mixture of rotamers, 1 HNMR (500MHz, 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.

[0967] Example 116: (5-(3,4-difluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone

[0968]

[0969] Me3Al (2M 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 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 and 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, Preparation Method C, (gradient: 50-80%) to give the product as an off-white solid (65 mg, 52%); HRMS (ESI) m / z [M+H] + ; C 15 H 16 Calculated value for F2N3O4: 340.1104, found value: 340.1124; 1 HNMR(500MHz,DMSO-d6)δ1.04(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).

[0970] Example 117: (5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)(2,2,6-trimethylmorpholino)methanone

[0971]

[0972] 2,2,6-trimethylmorpholine (0.041 g, 0.32 mmol) was dissolved in dry toluene (0.5 mL). Me3Al (2M in toluene, 0.304 mL, 0.61 mmol) was added dropwise at room temperature under N2(g) atmosphere. The resulting solution was stirred at room temperature for 45 min under N2(g) atmosphere and then added dropwise to a stirred solution of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (0.07 g, 0.24 mmol) in toluene (0.6 mL) at room temperature. The solution was heated to 60°C for 20 h. Tartaric acid (30%, aq, 5 mL) was added dropwise. The mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative HPLC, Preparative Method D (gradient: 35-85%) to give the title compound as a white solid (0.034 g, 38%); HRMS (ESI) m / z [M+H] + C 16 H 17 Calculated for F3N3O4: 372.1166, found: 372.1158; mixture of rotamers: 1 HNMR (500MHz, 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.

[0973] 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

[0974]

[0975] 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 was diluted with DMSO and purified by preparative HPLC, preparation 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 for F3N3O4: 356.0852, found value: 356.0854; 1 HNMR(500MHz,DMSO-d6)δ0.56–0.61(1H,m),0.64–0.68(1H,m),0.68–0.74(1H,m),0.74–0.79(1H,m),3.5 0(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).

[0976] Example 119: ((3R,5S)-3,5-dimethylpiperazin-1-yl)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0977]

[0978] Tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (0.145 g, 0.68 mmol) was dissolved in dry toluene (1 mL). Me3Al (2M in toluene, 0.651 mL, 1.30 mmol) was added dropwise at room temperature under N2(g) atmosphere. The resulting solution was stirred at room temperature for 45 min under nitrogen 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). The solution was heated to 60°C for 20 h. Tartaric acid (30%, aq, 5 mL) was added dropwise. The aqueous phase was washed with EtOAc. The aqueous phase was purified by preparative HPLC, Preparative Method D (gradient: 5-45%) to give the title compound as a white solid (0.126 g, 68%); HRMS (ESI) m / z [M+H]+ C 15 H 16 Calculated for F3N4O3: 357.1168, found: 357.1158; 1 HNMR (500MHz, DMSO-d6) δ1.03(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).

[0979] Example 120: ((2R,6S)-2,6-Dimethylmorpholino)(2-(2,4,5-trifluoro-3-hydroxyphenyl)thiazol-5-yl)methanone

[0980]

[0981] BBr3 (1 M in DCM, 1.025 mL, 1.02 mmol) was added dropwise to a solution of ((2S,6R)-2,6-dimethylmorpholine)(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. Additional 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 by 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, Preparation 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 F3N2O3S: 373.0834, found: 373.0821; 1 H NMR (500 MHz, DMSO, 25°C) δ 0.72–1.35 (6H, m), 2.46–3.14 (overlapping with solvent, 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).

[0982] Example 121: rac-((2R,6S)-2-ethyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0983]

[0984] 2MAlMe3 in toluene (2.17mL, 4.34mmol) was added dropwise to a solution of rac-(2R, 6S)-2-ethyl-6-methylmorpholine (314mg, 2.43mmol) in anhydrous toluene (2.5mL) at room temperature under N2. The resulting solution was stirred for 1h under N2 and then added dropwise to a stirred mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (500mg, 1.74mmol) in anhydrous toluene (3.5mL) at room temperature. The resulting solution was stirred at 60°C for 7.5h. The reaction was cooled to room temperature overnight and then further cooled to 0°C. 30% tartaric acid (aq, 25mL) was added dropwise and the resulting mixture was extracted with EtOAc (x2). The organic layers were combined, washed with H2O, passed through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC, Preparation Method D, (gradient: 0-75%, then 100%) to give the title compound as a white solid (62 mg, 10%); HRMS (ESI) m / z [M+H] + Calculated for C16H17F3 N3 O4: 372.1171, found: 372.1156;

[0985] 1 H NMR (500 MHz, DMSO, 25°C, 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).

[0986] Example 122rac-((2R,6S)-2-isopropyl-6-methylmorpholino)(5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methanone

[0987]

[0988] 2MAlMe3 in toluene (2.17mL, 4.34mmol) was added dropwise to a solution of rac-(2R, 6S)-2-isopropyl-6-methylmorpholine (348mg, 2.43mmol) in anhydrous toluene (2.5mL) at room temperature under N2. The resulting solution was stirred at room temperature for 1h under N2 and then added dropwise to a stirred mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylic acid ethyl ester intermediate 1 (500mg, 1.74mmol) in anhydrous toluene (3.5mL) at room temperature. The resulting solution was stirred at 60°C for 7.5h. The reaction was cooled to room temperature overnight and then further cooled to 0°C. 30% tartaric acid (aq, 25mL) was added dropwise and the mixture was extracted with EtOAc (x2). The organic layers were combined, washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, Preparation 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 C17H19F3 N3 O4: 386.1328, found: 386.1328; 1 H NMR (500 MHz, DMSO, 25 °C, 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,dd),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).

[0989] 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

[0990]

[0991] 2M AlMe3 (1.09ml, 2.17mmol) was added dropwise to a solution of rac-(R)-6-methyl-5-oxa-8-azaspiro[3.5]nonane (172mg, 1.21mmol) in anhydrous toluene at room temperature under N2. The resulting solution was stirred at room temperature for 1h under N2 and then added dropwise to a stirred mixture of 5-(2,4,5-trifluoro-3-hydroxyphenyl)-1,2,4-oxadiazole-3-ethyl carboxylate intermediate 1 (0.25g, 0.87mmol) in anhydrous toluene (1.75ml) at room temperature. The resulting solution was heated at 60°C for 4h. The heating was turned off and the reaction was cooled to room temperature overnight, and then further cooled to 0°C. 30% tartaric acid (aq, 13mL) 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, Preparation Method J (gradient: 35-75%). The fractions containing the product were acidified to pH 5 using 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, Preparation Method D (gradient: 35-75%) to give the title compound (208 mg, 63%) as a white solid; HRMS (ESI) m / z [M+H] + Calculated for C17 H17 F3 N3 O4: 384.1171, found: 384.1185; 1 H NMR (500 MHz, DMSO, 25°C, 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).

[0992] Example 124 (5-(2-bromo-3,4,6-trifluoro-5-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)((2R,6S)-2,6-dimethylmorpholino)methanone

[0993]

[0994] 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 (5x50 mL). A small aliquot of 30% NaCl(aq) (typically 1-3 mL) was added to accelerate phase separation. The organic layer was washed with 30% NaCl(aq), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.91 g, 100%) as a light yellow solid foam.

[0995] A small portion of the title compound (200 mg) was further purified by preparative HPLC, Preparation Method D, gradient (30-70%) to give the title compound as a white solid (133 mg); HRMS (ESI) m / z [M+H] + Calculated for C15 H14BrF3 N3O4: 436.0120, found: 436.0116; 1 HNMR (500MHz, DMSO, 25℃) δ1.06(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).

[0996] In vitro 17bHSD13 enzyme assay

[0997] Compounds (0.2 μl) at 10 concentrations in DMSO were added to a GREINERPP 384-well plate (781280) using an ECHO dispenser (BECKMANCOULTER), followed by the addition of 20 μl of recombinant 17bHSD13 (N2-K300). The enzyme reaction was initiated by adding 20 μl of a substrate solution containing NAD (SIGMA, N1511) and estradiol (SIGMA, E8875) using a CERTUS-FLEX dispenser (GYGER). After each addition, the plate was centrifuged for 1 min at 150×g (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 D310) in 50 mM Tris-Cl, pH 7.4). After 2.5 h, the reaction was stopped by adding 20 μl 0.6% formic acid (MERCK 5.33002) and the samples were analyzed using LC-MS / MS.

[0998] SCIEX LC-MS / MS system: The samples were injected with a CTC analytical injector (SHIMATZU LC pump LC20) and analyzed on a SCIEX API 5000 LCMSMS system with the following settings. The 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 containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.5 min, linearly increased to 100% B from 0.5 to 1 min, maintained at 100% B from 1 to 1.6 min, and then returned 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 equipped with a triple quadrupole mass spectrometer, TURBOV ion source, in multiple reaction monitoring (MRM) mode, positive polarity, with an APCI probe. The MRM pairs were m / z 273.1 to m / z 107.0 and m / z 271.3 to 107.0 for estradiol and estrone, respectively. The dwell time for each transition was 100 ms, and the depolarization and collision energies were 100 and 40, respectively. Data from the MS signals were expressed using the area under the curve (AUC). Ratio = estrone / (estrone + estradiol)

[0999] In vitro 17bHSD13 cell assay

[1000] Inhibition of 17bHSD13 was measured in a cell-based assay in HEK293S cells overexpressing HSD17β13, and the conversion of estradiol to estrone was measured by LCMS / MS.

[1001] The cells were seeded at 10Kc / w in 30 μl of culture medium (DMEM containing GLUTAMAX+10% FBS) in a 384-well plate (GREINER cell culture plate 384w black / transparent poly-D-lysine). After allowing the cells to attach for 6 h, 0.15 μl of 10 concentrations of compounds and 0.03 μl of 10 mM estradiol (Sigma, E8875) in DMSO were added using an ECHO dispenser (Kerman Coulter). After 18 h of cell culture, 20 μl of culture medium was transferred to a GREINERPP 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.

[1002] SCIEX LC-MS / MS system: The samples were injected with a CTC analytical injector (SHIMATZU LC pump LC20) and analyzed on a SCIEX API 5000 LCMSMS system with the following settings. The 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 containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.5 min, linearly increased to 100% B from 0.5 to 1 min, maintained at 100% B from 1 to 1.6 min, and then returned 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 equipped with a triple quadrupole mass spectrometer, TURBOV ion source, in multiple reaction monitoring (MRM) mode, positive polarity, with an APCI probe. The MRM pairs were m / z 273.1 to m / z 107.0 and m / z 271.3 to 107.0 for estradiol and estrone, respectively. The dwell time for each transition was 100 ms, and the depolarization and collision energies were 100 and 40, respectively. Data from the MS signals were expressed using the area under the curve (AUC). Ratio = estrone / (estrone + estradiol)

[1003] In vitro 17bHSD4 enzyme assay

[1004] Compounds (0.2 μl) at 10 concentrations in DMSO were added to a GREINERFLUOTRAC 2003 84-well plate (781076) using an ECHO dispenser (BECKMANCOULTER). 80 nl of 10 mM estradiol (Sigma, E8875) was added using an Echo dispenser. Enzyme reactions were initiated by adding 40 μl of a mixture containing recombinant 17bHSD4 (M1-N311) and NAD using a MULTIDROP COMBI dispenser (THERMO FISHER). The final assay conditions were 40 nM 17bHSD4, 0.125 mM NAD, 15 μM estradiol and various concentrations of compounds 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 for 1 min at 150 x g (EPPENDORF, 5810R, A-4-81). The formation of NADH was measured at zero time (t0) and 1.5 h (t1) by fluorescence intensity (FI) (Ex360 / Em460) in a PHERASTAR FSX (BMG Laboratory Technology Company (BMGLABTECH)). The FI for each sample was calculated as the FI at t1 minus the FI at t0.

[1005] In vitro 17bHSD9 cell assay

[1006] Inhibition of 17bHSD9 was measured in a cell-based assay overexpressing HSD17β9 in HEK293S cells, and the conversion of retinol to retinal was measured by LCMS / MS.

[1007] The cells were seeded at 10Kc / w in 30μl of culture medium (DMEM containing GLUTAMAX+10% FBS) in a 384-well plate (GREINER cell culture plate 384w black / transparent poly-D-lysine). After allowing the cells to attach for 6 hours, 0.15μl of 10 concentrations of compounds and 0.015μl of 10mM all-trans retinol (Cayman Chemical, 20241) were added in DMSO using an ECHO dispenser (Cayman Coulter). After 18 hours of cell culture, 20μl of culture medium was transferred to a GREINER PP 384-well plate (781280) using a BRAVO dispensing robot (AGILENT) and 40μl of 50% acetonitrile was added. Samples were analyzed using LC-MS / MS.

[1008] SCIEX LC-MS / MS system: The samples were injected with a CTC analytical injector (SHIMATZU LC pump LC20) and analyzed on a SCIEX API 5000 LCMSMS system with the following settings. The 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 containing 0.2% formic acid) and B (acetonitrile containing 0.2% formic acid). The LC gradient profile was as follows: 50% B from 0 to 0.1 min, linearly increased to 100% B from 0.1 to 0.8 min, maintained at 100% B from 0.8 to 1.5 min, then returned to 50% B from 1.5 to 1.6 min, and maintained during the run. The run time was 2 min, and the retention times of retinol and retinal were approximately 1.54 min and 1.62 min, respectively. Detection was performed on an API 5000 LC / MS / MS system equipped with a triple quadrupole mass spectrometer, TURBOV ion source, in multiple reaction monitoring (MRM) mode, positive polarity, with an ESI probe. For retinol and retinal, the MRM pairs were m / z 269.3 to m / z 93.0 and m / z 285.2 to 161.0, respectively. The dwell time for each transition was 100 ms, and the depolarization and collision energies were 50 and 25, respectively. Data from the MS signal used the area under the curve (AUC). Ratio = retinal / (retinal + retinol).

[1009] Data analysis

[1010] GENEDATA SCREENER for curve fitting and IC calculation 50 value.

[1011] The compound effects were calculated using the following formula;

[1012] Compound effect % = -100x((X-min) / (max-min))

[1013] Where X represents the effect in the presence of the test compound, min is DMSO and max is the maximal inhibition of the enzyme using a known inhibitor as control.

[1014] Table 3

[1015]

[1016]

[1017]

[1018]

[1019] The data in Table 3 may be from a single experiment or the average of two or more experiments.

[1020] Assay A: Metabolic Stability of Human Hepatocytes

[1021] Hepatocyte metabolic stability was determined according to the method described in Jacobson et al., An optimized automated assay for determination of metabolic stability using hepatocytes: assay validation, variance component analysis, and in vivo relevance. Assay Drug Dev Technol 2007, 5(3), 403–415. DOI: 10.1089 / adt.2007.059, which is incorporated herein by reference. A concentration of 10 6 Cryopreserved hepatocytes were prepared at 400 μg / mL of viable cells / mL. After thawing, the hepatocytes were incubated for 10 min to warm to 37°C, and then the test compound dissolved in acetonitrile was added to a final concentration of 1 μM. At 0.5, 5, 15, 30, 45, 60, 80, 100, and 120 min, the incubation system was mixed, and a 20 μL aliquot was transferred to a well in a separate plate containing 80 μL of MeCN at each time point to terminate the reaction. The quenched plate was then vortexed, then centrifuged, and the supernatant analyzed by LC-MS / MS. Peak areas were determined from extracted ion chromatograms, and the in vitro intrinsic clearance of the parent compound (in vitro CLint, in μL / min / 10 6 cells) were calculated from the slope in the regression analysis of the natural logarithm of the parent concentration versus time curve.

[1022] Assay B: Cytochrome P450 Inhibition 2C9

[1023] The inhibition of 2C9 was determined using a fluorescence-based method in a 96-well format (Crespi, CL et al., Microtiterplate 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). Except for CYP2D6 (CYPEX LTD, Dundee, UK), the recombinant human enzymes used were all prepared in-house. Different coumarin substrates that were bioconverted to fluorescent metabolites were used as probes for each individual CYP. The levels of metabolites formed were measured using a fluorescence plate reader (SPECTRAMAX GEMINIXS, MOLECULARDEVICES, Sunnyvale, CA, 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, pH 7.4 potassium phosphate buffer and water (concentration and volume were CYP dependent) was added to each well in a black 96-well plate. Different concentrations of the test substrate were added. After a pre-incubation of 10 min, the cofactor NADPH was added to initiate the reaction. After 20-50 min (CYP and substrate dependent), the reaction was terminated by adding trisbase / MeCN (20:80). The plate was transferred to a fluorescence plate reader, where the wavelength was set individually for the different coumarin substrates and their respective fluorescent metabolites. The responses were exported to Excel, where the IC 50 The curves (percent inhibition versus concentration) were plotted and the IC values ​​for each tested substrate and enzyme were calculated using XL-Fit. 50 value.

[1024] Assay C: CB1 agonism assay

[1025] Evaluation of compounds' agonist activity at human CB1 receptors expressed in transfected CHO cells was determined by measuring their effects on cAMP regulation using the HTRF assay.

[1026] Experimental protocol: Cells were suspended in HBSS buffer (INVITROGEN) supplemented with 20 mM HEPES (pH 7.4) and then plated in microplates at a density of 5.103 cells / well in the presence of either: HBSS (basal control), 30 nM of a reference agonist (stimulated control), or various concentrations (EC 50Determination) or test compound. Thereafter, the adenylate cyclase activator NKH 477 was added at a final concentration of 3 μM. After incubation at 37°C for 20 min, the cells were lysed and the fluorescent acceptor (D2-labeled cAMP) and the fluorescent donor (anti-cAMP antibody labeled with a europium cryptate) were added. After 60 min at room temperature, the fluorescence transfer was measured at gex=337 nm and gem=620 and 665 nm using a microplate reader (RUBYSTAR, BMG). The cAMP concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). The results are expressed as a percentage of the control response to 30 nM CP 55940. The standard reference agonist is CP 55940, which is tested at several concentrations in each experiment to generate a concentration-response curve, from which its EC is calculated. 50 value.

[1027] 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.

[1028] Table 4

[1029]

[1030]

[1031]

[1032] The data in Table 4 may be from a single experiment or the average of two or more experiments.

[1033] Metabolic studies

[1034] In vitro studies to identify metabolites of Example 87 produced Metabolite 1 and Metabolite 2 as defined below. Metabolites 1 and 2 were subsequently synthesized and characterized.

[1035] Metabolite 1: 3-(3-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)-2,5,6-trifluorophenyl hydrosulfate

[1036]

[1037] 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 using NaHCO3. Freeze drying gave the desired product as a sodium salt (23 mg, 30%); HRMS (ESI) m / z [M+H] + C 15 H 14 Calculated value for F3N3O7S: 436.0426, found value: 436.0429.

[1038] 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

[1039]

[1040] Ag2O (2.5 eq) was added 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, 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 H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase. The acetate group and ester were hydrolyzed in MeCN (0.07 M) by treatment with TEA (12 eq.) and LiBr (40 eq.) at room temperature for 4 h. 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, Preparation Method D (Gradient: 0-100%) to give the title compound; HRMS (ESI) m / z [MH] -C 21 H 21 F3N3O 10 Calculated value: 532.1179, found value: 532.1195.

[1041] The above description of the illustrative embodiments is intended only to make other persons skilled in the art aware of the applicant's specification, its principles and its practical application, so that other persons skilled in the art can easily adapt and apply this specification in its many forms, as they may best suit the requirements of a particular purpose. This specification and its specific examples, although indicating embodiments of this specification, are intended only for illustrative purposes. Therefore, this specification is not limited to the illustrative embodiments described in this specification and can be modified differently. In addition, it should be understood that, for the sake of clarity, the different features of this specification described in the context of the separate embodiments can also be combined to form a single embodiment. On the contrary, for the sake of brevity, the different features of this specification described in the context of a single embodiment can also be combined to form a sub-combination thereof.

Claims

1. A compound having formula (I); in, A is selected from Each R A are independently selected from H, halo, R X 、-OR x and -CN, where each R X is independently C optionally substituted with one to three F 1-3 alkyl; R B is halogenated, -CHF2, -CF3, -OCHF2 or -OCF3; X 1 , X 2 and X 3 one of which is selected from NH, O and S, and X 1 , X 2 and X 3 The other two are independently selected from N and CR Y , where each R Y are independently H, -CN, -C(=O)N(R 7 )2 or R XA , where R XA is independently C optionally substituted with one to three F 1-3 alkyl; R 1 and R 2 This is so that; (i)R 1 and R 2 Together with the N atom to which they are attached, they form a ring system, wherein the ring system is optionally substituted by one or more R C Substitute, where each R C Independently selected from 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; (ii) R 1 Selected from R 8 and R 4A , and R 2 Selected from R 8A and H; or (iii) R 1 YesR 5A And R 2 YesR 8B ; Each R 3 Independently C 1-4 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by one or more independently selected from R 4X , R 5x 、-O(R 4X )、-O(R 5X ) and F are substituted by groups; 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 is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, each of which is optionally substituted by one or more independently selected from 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 halogenated group substitution; R 4A is a 5-membered monocyclic heteroaryl group, which is optionally substituted by one or more independently selected from 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 halogenated group substitution; Each R 5 , R 5A and R 5B is independently phenyl, each of which is optionally substituted by one or more independently selected from 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 halogenated group substitution; Each R 4X is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, each of which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3X and halogenated group substitution; Each R 5X are independently phenyl, each of which is optionally substituted by one or more independently selected from -OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)N(R 7B 2. R 3x and halogenated group substitution; R 6 It is C 1-4 Alkoxy, which is optionally substituted by one or more independently selected from R 4X , R 5x and group substitution of F; Each R 7 , R 7A , R 7B and R 7C Independently H, C 1-4 Alkyl or C 3-6 Cycloalkyl; R 8 , R 8A , R 8B Independently C 1-4 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by one or more independently selected from 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 group substitution; wherein the ring system is a saturated or partially saturated, monocyclic, bicyclic or tricyclic 4-13 membered ring comprising one N atom and optionally one or two additional heteroatoms independently selected from N, O and S; and wherein 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. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein (i)X 1 It is N, X 2 is O and X 3 is N; (ii)X 1 It is N, X 2 is N and X 3 It is O; (iii)X 1 Yes CR Y , X 2 Yes CR Y And X 3 It is S; (iv)X 1 It's O, X 2 is N and X 3 Yes CR Y ; (v)X 1 It is N, X 2 is O and X 3 Yes CR Y ; (vi)X 1 Yes CR Y , X 2 is N and X 3 It is O; (vii)X 1 It's O, X 2 is N and X 3 is N; (viii)X 1 It is N, X 2 is N and X 3 It is S; (ix)X 1 Yes CR Y , X 2 is S and X 3 Yes CR Y ;or (x)X 1 Yes CR Y , X 2 is N and X 3 It’s S.

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

4. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 It is N, X 2 is O and X 3 It is N.

5. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 and X 3 One of them is S and X 1 , X 2 and X 3 The other two are independently CR Y .

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein each R Ais independently H or halo.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein each R A are independently H or F.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein A is 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, wherein R B It's F.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a ring system, wherein the ring system is optionally substituted by one or more R C replace.

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

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R 1 and R 2 Together with the N atom to which they are attached, they 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 the ring system is optionally substituted by one or more R C substituted, and wherein the heterocycloalkyl is a saturated ring comprising one N atom and optionally one further heteroatom selected from N, O and S.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a ring system which is optionally substituted by one or more R C Substituted 4-8 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl is a saturated ring containing one N atom and optionally one additional heteroatom selected from N, O and S.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a ring system which is optionally substituted by one or more RC Substituted 5-7 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl is a saturated ring containing one N atom and one additional heteroatom selected from N, O and S.

15. A compound of any one of claims 1 to 14 having formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring system is optionally substituted by one to three independently selected R 3 , R 4 and R 5 The group is substituted.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II): in J is selected from O, S, CH2, NH and a covalent bond, G is absent or, together with the carbon atom to which it is attached, forms C 3-6 Cycloalkane ring; Z is such that (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 Cycloalkylene, (ii) when G is absent and J is NH, Z is selected from CH2, CH2CH2, C 3-6 Cycloalkylene and C(═O), and (iii) When G and the carbon atom to which it is attached form C 3-6 In the case of a cycloalkane ring, Z is CH2; x is selected from 0 to 3; and Each R 9 Independently selected from R 3 , R 4 and R 5 , or a pharmaceutically acceptable salt thereof.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III): in J is selected from O, S, CH2, NH and a covalent bond, x is selected from 0 to 3; Each R 9 Independently selected from R 3 , R 4 and R 5 ;and R E is H or halogenated, or a pharmaceutically acceptable salt thereof.

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

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, wherein R 1 Selected from R 8 and R 4A , and R 2 Selected from R 8A and H.

20. The compound of claim 19 having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 is one or two independently selected from R 4B and R 5B The group substituted C 1-4 alkyl.

21. The compound of claim 19 having formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4A yes Where X 4 and X 5 are independently N or CH, and R 10 YesR 3 or R 5x .

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 19 to 21, wherein R 8A It is C 1-4 alkyl.

23. A compound of formula (I) as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 5A And R 2 YesR 8B .

24. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 23, wherein R 8B It is C 1-4 alkyl.

25. A compound of formula (I) as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C optionally substituted with one to three F 1-4 alkyl.

26. A compound of formula (I) as described in any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein each R 4 and R 4B is independently a monocyclic or bicyclic 5- to 9-membered heteroaryl group, each of which is optionally substituted by one or more independently selected from OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl)-C(=O)N(R 7B 2. R 3X and halogenated groups.

27. A compound of formula (I) as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each R 5 , R 5A and R 5B are independently phenyl, each of which is optionally substituted by one or more independently selected from OH, -CN, C 1-4 Alkoxy, -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)N(R 7B 2. R 3X and halogenated groups.

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

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

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

31. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 27 for use in the treatment of a liver disease selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD, NASH, liver fibrosis, cirrhosis, isolated steatosis, liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).

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

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

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