Inhibition of USP36

Abstract

The present disclosure relates to compounds of formula (I)-(VI), which can be used as modulators of USP36. The compounds are also used to inhibit USP36 and treat diseases or disorders associated with inhibiting USP36. For example, the present disclosure relates to compounds and compositions for inhibiting USP36, methods for treating diseases associated with inhibiting USP36 (e.g., certain forms of cancer), and methods for synthesizing these compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 840,737, filed on April 30, 2019, which is incorporated herein by reference in its entirety. Field of the Invention

[0003] The present disclosure relates to compounds useful for inhibiting ubiquitin-specific peptidase 36 (USP36) and methods for preparing the same. USP36 inhibitors are useful for treating various forms of cancer. Background of the Invention

[0005] Aggressive cancers include subtypes of pancreatic, colorectal, lung, brain, ovarian, and prostate cancers and are primarily characterized by rapid tumor formation, growth, and spread. They often present significant challenges to effective treatment and are particularly prone to developing drug resistance, so treatment options are exhausted relatively quickly and the prognosis is often poor. Aggressive cancers present a significant unmet medical need and an opportunity to develop therapies that can selectively target rapidly proliferating cancer cells while maintaining favorable treatment margins.

[0006] Cell proliferation consumes a lot of energy, especially for activities in the nucleolus. These include transcription and assembly of ribosomal RNA (rRNA), ribosome biogenesis, cell cycle progression, DNA replication and repair, stress signaling, and cell survival. As cell proliferation rates increase, a state of nucleolar stress results, in which upregulation of ribosome biogenesis and elevated associated metabolic resources are essential for maintaining nucleolar integrity. Loss of integrity interferes with cell replication processes and can promote cell death. This link between ribosome biogenesis, nucleolar integrity, and cell viability can be used as a mechanism for chemotherapy and suggests that cells with the highest levels of nucleolar stress may be affected to varying degrees. Almost all cancer cell types show evidence of nucleolar stress with a large number and / or increased number of nucleoli, and nucleolar size can sometimes be used as a prognostic indicator of clinical outcome. This is consistent with findings showing that higher proliferation rates (a hallmark feature of aggressive cancer) are associated with larger signs of nucleolar stress. In addition, the significant differences in ribosome biogenesis in different cancer types reflect the different proliferation rates. Rapid cell proliferation rates are associated with increased levels of over-activation of ribosome biogenesis. Given that aggressive cancer cells are characterized by rapid division, they are often in a state of relatively high nucleolar stress, have significantly increased metabolic demands, and may be particularly susceptible to perturbations in ribosome production. Therefore, aggressive cancers are suitable targets for therapeutic inhibition of ribosome biogenesis.

[0007] Furthermore, this pathway could provide selective cytotoxicity to cancer cells while reducing the risk of widespread genotoxicity typical of many other cancer treatments. Ribosome biogenesis and nucleolar integrity can be affected by inhibition of USP36. It is a deubiquitinating enzyme (DUB) known to be overexpressed in many human cancers, including subtypes of breast, lung and ovarian cancers. USP36 supports ribosome biogenesis and nucleolar integrity by deubiquitinating a large number of nucleolar proteins, such as c-MYC, DHX33 and RNA Pol 1, and stabilizing them for ubiquitination-mediated proteasomal degradation.

[0008] The DUB activity of USP36 on nucleolar MYC may be an important component of the therapeutic effect, as tight regulation of MYC levels is known to be essential for normal cell growth and proliferation. MYC controls the expression of most, if not all, actively transcribed genes in the human genome and coordinates many cellular processes. It plays a direct role in ribosome biogenesis, RNA transcription, and protein synthesis, and shows enriched localization in the nucleolus. Notably, pathological activation or overexpression of MYC contributes to the development of malignant tumors. The ubiquitination state-dependent regulation of MYC stability and activity involves multiple enzymes including USP36. MYC levels were significantly reduced after USP36 knockdown, and this change was associated with suppressed cell proliferation. This is consistent with the well-established view that ribosome biogenesis induced by high MYC activity is an important component of cell growth and tumorigenesis. Reduced ribosome production due to USP36 inhibition is expected to counteract MYC-induced nucleolar hyperactivity and starve cells of resources required to maintain proliferation. In addition, USP36 is a target gene of MYC, suggesting the existence of a positive feedback regulatory loop. Summary of the invention

[0009] Disclosed are compounds of formula (I), and pharmaceutically acceptable salts, hydrates, solvates, isomers and tautomers thereof:

[0010]

[0011] in:

[0012] R1 is selected from:

[0013] (C1-C4)alkyl optionally substituted with 1-3 R2,

[0014] (C3-C6)cycloalkyl optionally substituted with 1 R3,

[0015] optionally substituted with 1-2 R4 aryl,

[0016] is substituted with 1 heteroaryl of R5,

[0017] A bicyclic heteroaryl group optionally substituted with 1 (C1-C4) alkyl group,

[0018] a partially saturated bicyclic group optionally substituted with 1 halogen, and

[0019]

[0020] Each R2 is independently selected from:

[0021] (C1-C4)alkyl,

[0022] (C3-C6)cycloalkyl,

[0023] (C6-C 12 ) spirocycloalkyl,

[0024] aryl optionally substituted with 1 halogen or -OR6, and

[0025] 3-6 membered heterocyclic group;

[0026] R3 is (C1-C4) alkyl;

[0027] Each R4 is independently selected from (C1-C4)alkyl optionally substituted with halogen, -OR6, halogen, and 3-6 membered heterocyclyl;

[0028] R5 is an aryl group substituted with one halogen;

[0029] R6 is selected from aryl and (C1-C4)alkyl optionally substituted with halogen;

[0030] L is –NHC(O)–;

[0031] x is 0 or 1;

[0032] Ar1 is heteroaryl or bicyclic heteroaryl, and it is optionally substituted with 1 (C1-C4) alkyl;

[0033] Ar2 is aryl or heteroaryl, which is optionally substituted with 1-2 R7;

[0034] Each R7 is independently selected from: aryl, halogen, trifluoromethyl and -NHS(O)2R8;

[0035] R8 is aryl optionally substituted with 1 R9; and

[0036] R9 is halogen or aryl.

[0037] The conditions are:

[0038] (i) if Ar2 has 0-1 substituents, Ar1 is not thiazolyl; and

[0039] (ii) the compound is not:

[0040]

[0041] 2-((4-Fluorophenyl)sulfonamido)-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzamide.

[0042] In another aspect, disclosed is a method for treating, preventing, inhibiting or eliminating a disease or condition associated with USP36 activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present disclosure relates to compounds that can modulate the activity of ubiquitin-specific peptidase 36 (USP36). The present disclosure features methods of treating, preventing, or ameliorating a disease or condition in which USP36 plays a role by administering a therapeutically effective amount of a compound of any one of formulas (I)-(VI) or a pharmaceutically acceptable salt thereof to a patient in need thereof. The methods of the present disclosure can be used to treat a variety of USP36-dependent diseases and conditions by inhibiting the activity of USP36. Inhibition of USP36 provides a new method for treating diseases, including but not limited to certain forms of cancer.

[0045] definition

[0046] The articles "a" and "an" are used in this disclosure to refer to one or more (eg, at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element.

[0047] Unless otherwise stated, the term "and / or" used in this disclosure means "and" or "or".

[0048] The term "optionally substituted" is understood to mean that a given chemical moiety may (but not necessarily) be bonded to other substituents. Unless otherwise specifically defined, the optional substituents are bonded to the chemical moiety with any chemically feasible regiochemistry and / or stereochemistry (if applicable). For example, the optionally substituted alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have a substituent that replaces one or more hydrogen atoms. For example, it may be bonded to any of the listed optional substituents at any point on the chain. Therefore, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any other functional groups. As used herein, "optionally substituted" also refers to substituted or unsubstituted, and its meaning is as described below.

[0049] As used herein, the term "substituted" means that the specified group or part bears one or more of the substituents, wherein the substituent can be attached to the specified group or part at one position. Unless otherwise specifically defined, the substituent can be bonded to the chemical part by any chemically feasible regiochemistry and / or stereochemistry (if applicable).

[0050] As used herein, the term "unsubstituted" means that the designated group bears no substituents.

[0051] As used herein, the term "aryl" refers to a monocyclic aromatic hydrocarbon group having one aromatic ring, the monocyclic aromatic hydrocarbon group having a total of 5 to 14 ring atoms, such as phenyl. Unless otherwise specifically defined, an "aryl" group is unsubstituted.

[0052] As used herein, the term "heteroaryl" refers to a monocyclic aromatic group of 5 to 14 ring atoms, which contains one or more ring heteroatoms selected from N, O and S, and the remaining ring atoms are C. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, thien-2-yl, isothiazolyl, thiazolyl, thiadiazolyl, triazolyl, triazinyl. Unless specifically defined otherwise, a "heteroaryl" group is unsubstituted.

[0053] As used herein, the term "bicyclic heteroaryl" refers to a bicyclic aromatic group containing one or more ring heteroatoms selected from N, O and S, with the remaining ring atoms being C. Examples include, but are not limited to, indolyl, quinolyl, benzopyranyl, indazolyl, benzimidazolyl, thieno[3,2-b]thiophene, imidazo[1,2-b]pyrazolyl, furano[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolonyl, and indolinyl. nyl), dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, tetrazo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, furano[3,2-c]pyridinyl, furano[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furano[2,3-b]pyridinyl, 1,5-naphthyridinyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, 6,7-dihydro-4H-thieno[3.2-c]pyran. Unless otherwise specifically defined, the "bicyclic heteroaryl" group is unsubstituted.

[0054] As used herein, the term "halogen" or "halo" refers to fluorine (ie, "F" or "fluoro"), chlorine (ie, "Cl" or "chloro"), bromine (ie, "Br" or "bromo"), or iodine (ie, "I" or "iodo").

[0055] As used herein, the term "(C1-C4) alkyl" refers to a straight or branched saturated hydrocarbon containing 1-4 carbon atoms. Examples of (C1-C4) alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, and tert-butyl. "C1 alkyl" refers to an alkyl chain containing 1 carbon atom, such as methyl. "C2 alkyl" refers to an alkyl chain containing 2 carbon atoms, such as ethyl. "C3 alkyl" refers to an alkyl chain containing 3 carbon atoms, such as propyl or isopropyl. "C4 alkyl" refers to an alkyl chain containing 4 carbon atoms, such as butyl, isobutyl, sec-butyl, or tert-butyl. Unless otherwise specifically defined, a "(C1-C4) alkyl" group is unsubstituted.

[0056] As used herein, the term "(C3-C6) cycloalkyl" refers to a monocyclic saturated ring containing 3-6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "C3 cycloalkyl" refers to a cycloalkyl containing 3 carbon atoms, such as cyclopropyl. "C4 cycloalkyl" refers to a cycloalkyl containing 4 carbon atoms, such as cyclobutyl. "C5 cycloalkyl" refers to a cycloalkyl containing 5 carbon atoms, such as cyclopentyl. "C6 cycloalkyl" refers to a cycloalkyl containing 6 carbon atoms, such as cyclohexyl. Unless otherwise specifically defined, a "(C3-C6) cycloalkyl" group is unsubstituted.

[0057] As used herein, the term "3-6 membered heterocyclyl" refers to a monocyclic ring containing a total of 3-6 carbon atoms and heteroatoms selected from oxygen, nitrogen or sulfur, and the rings are either saturated or partially unsaturated. Examples of heterocyclyl rings include, but are not limited to, oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl and oxazolidinone. Unless otherwise specifically defined, a "3-6 membered heterocyclyl" group is unsubstituted.

[0058] As used herein, the term "partially saturated bicyclic radical" refers to a bicyclic group consisting of 6-12 carbon atoms in which an unsaturated or partially saturated ring is fused to a fully unsaturated ring. Examples of partially saturated bicyclic radicals include, but are not limited to, indanyl and tetrahydronaphthyl. Unless otherwise specifically defined, a "partially saturated bicyclic radical" group is unsubstituted.

[0059] As used herein, the term "(C6-C 12") Spirocycloalkyl" refers to a bicyclic ring system having 6-12 carbon atoms, wherein the rings are interconnected by a single atom. The size and nature of the rings may be different, or the size and nature may be the same. Examples include, but are not limited to, spirohexane, spiroheptane, spirooctane, spironane, spirodecane, spironoundane, and spirododecane. "C6 spirocycloalkyl" refers to a spirocycloalkyl having 6 carbon atoms, such as spirohexane. "C7 spirocycloalkyl" refers to a spirocycloalkyl having 7 carbon atoms, such as spiroheptane. "C8 spirocycloalkyl" refers to a spirocycloalkyl having 8 carbon atoms, such as spirooctane. "C9 spirocycloalkyl" refers to a spirocycloalkyl having 9 carbon atoms, such as spirononane. "C 10 "Spirocycloalkyl" refers to a spirocycloalkyl group having 10 carbon atoms, such as spirodecane. 11 "Spirocycloalkyl" refers to a spirocycloalkyl group having 11 carbon atoms, such as spiroundecane. 12 "Spirocycloalkyl" refers to a spirocycloalkyl group having 12 carbon atoms, such as spirododecane. Unless otherwise specifically defined, "(C6-C 12 )spirocycloalkyl" groups are unsubstituted.

[0060] As used herein, the term "isomer" refers to compounds having the same composition and molecular weight but different physical and / or chemical properties. The structural differences may lie in the ability to form (e.g., geometric isomers) or rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, or as individual enantiomers or diastereomers.

[0061] As used herein, the term "pharmaceutical composition" refers to a composition wherein the individual components or ingredients are themselves pharmaceutically acceptable, e.g., acceptable for oral use where oral administration is contemplated, acceptable for topical administration where topical administration is contemplated, and acceptable for intravenous administration where intravenous administration is contemplated.

[0062] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of this disclosure do not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is a solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0063] "Pharmaceutically acceptable salts" are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Representative pharmaceutically acceptable salts include, for example, water-soluble and water-insoluble salts such as acetate, ansorlate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, etopoate, esylate, fumarate, fiunarate, glucoheptonate, gluconate, glutamate, α-glycollylarsanilate, hexafluorophosphate, hexylisophthalate, hydroxylamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, The compounds of formula (I)-(VI) may form salts that are also within the scope of the present disclosure. Unless otherwise stated, reference herein to compounds of formula I is to be understood as including reference to salts thereof.

[0064] Novel USP36 inhibitors are provided. Unless otherwise indicated, "USP36 inhibitor compounds" as used herein refer to compounds having a detectable IC of 10 micromolar or less when tested according to the USP36 inhibition biochemical assay described in Example 9 below. 50 The USP36 inhibitor compounds disclosed herein can be administered at therapeutically effective levels.

[0065] A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0066] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to cause improvement in one or more symptoms of a disorder, or to prevent the development of a disorder, or to cause regression of the disorder.

[0067] The term "carrier" as used in this disclosure includes carriers, excipients, and diluents, and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting an agent from one organ or part of the body of a subject to another organ or part of the body.

[0068] The term "treating" with respect to a subject refers to ameliorating at least one symptom of a disorder in a subject. Treating includes curing, ameliorating, or at least partially ameliorating a disorder.

[0069] Unless otherwise indicated, the term "disorder" as used in this disclosure refers to, and is used interchangeably with, the terms disease, condition, or disorder.

[0070] The terms "administering" or "administration" as used in this disclosure refer to directly administering a disclosed compound, a pharmaceutically acceptable salt or composition of a disclosed compound to a subject, or administering a pharmaceutically acceptable salt or composition of a compound to a subject, which can form an equivalent amount of the active compound in the subject.

[0071] Compounds of the Disclosure

[0072] The present disclosure relates to compounds capable of modulating USP36 or pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers thereof, which can be used to treat diseases and disorders associated with the modulation of USP36. The present disclosure further relates to compounds for inhibiting USP36 or pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers thereof.

[0073] Unless otherwise indicated herein, all isomeric forms of a particular compound are provided by the present disclosure, including mixtures thereof. All tautomeric forms are also intended to be included.

[0074] Unless otherwise indicated, compounds of formula (I)-(VI) may contain one or more stereocenters and therefore exist in different stereoisomeric forms. Unless otherwise indicated, all stereoisomeric forms of compounds of formula (I)-(VI), including enantiomeric forms (even in the absence of asymmetric carbon atoms, may exist), rotamer forms, atropisomers and diastereomeric forms and mixtures thereof (including racemic mixtures) are intended to form part of the present disclosure. In addition, the present disclosure includes all geometric and positional isomers. For example, if a compound of any of formula (I)-(VI) contains a double bond or a fused ring, both the cis and trans forms and mixtures are included within the scope of the present disclosure. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compound may be in racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected in racemic form, enantiomerically pure form, or any other form in terms of stereochemistry. A single stereoisomer of a compound of the present disclosure may, for example, be substantially free of other isomers, or may, for example, be a racemate or mixed with all other or other selected stereoisomers. In some embodiments of the present disclosure, the compound of formula (I)-(VI) is an enantiomer. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In some embodiments, the compound of formula (I)-(VI) may be a (+) or (-) enantiomer.

[0075] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by reacting with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acyl chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. In addition, some compounds of formula (I)-(VI) can be atropisomers (e.g., substituted biaryls) and are considered part of the present disclosure. Enantiomers can also be separated using chiral HPLC columns.

[0076] In addition, unless otherwise stated, the present disclosure includes all geometric and positional isomers (e.g., 4-pyridyl and 3-pyridyl). For example, if the compounds of the present disclosure contain double bonds or fused rings, both cis and trans forms and mixtures are included within the scope of the present disclosure. If the compound contains a double bond, unless otherwise stated, the substituent can be an E or Z configuration. If the compound contains a disubstituted cycloalkyl, unless otherwise stated, the cycloalkyl substituent can have a cis or trans configuration.

[0077] Compounds of the present disclosure and pharmaceutically acceptable salts and stereoisomers thereof may exist in their tautomeric forms (e.g., as amides or imino ethers). In addition, the present disclosure includes all keto-enol and imine-enamine forms of the compounds. All such tautomeric forms are considered herein as part of the present disclosure.

[0078] The use of the term "salts" and the like is intended to apply equally to the salts of the enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers and racemates of the compounds of the invention.

[0079] When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, whether pure or in a suitable inert solvent. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, whether pure or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese salts, potassium salts, sodium salts, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0080] When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Suitable acids for preparing pharmaceutically acceptable acid addition salts include acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0081] The compounds of formula (I)-(VI) may form acid addition salts or base addition salts, which may be pharmaceutically acceptable salts.

[0082] Disclosed are compounds of formula (I) and pharmaceutically acceptable salts, hydrates, solvates, isomers and tautomers thereof:

[0083]

[0084] in:

[0085] R1 is selected from:

[0086] (C1-C4)alkyl optionally substituted with 1-3 R2,

[0087] (C3-C6)cycloalkyl optionally substituted with 1 R3,

[0088] optionally substituted with 1-2 R4 aryl,

[0089] is substituted with 1 heteroaryl of R5,

[0090] A bicyclic heteroaryl group optionally substituted with 1 (C1-C4) alkyl group,

[0091] a partially saturated bicyclic group optionally substituted with 1 halogen, and

[0092]

[0093] Each R2 is independently selected from:

[0094] (C1-C4)alkyl,

[0095] (C3-C6)cycloalkyl,

[0096] (C6-C 12 ) spirocycloalkyl,

[0097] aryl optionally substituted with 1 halogen or -OR6, and

[0098] 3-6 membered heterocyclic group;

[0099] R3 is (C1-C4) alkyl;

[0100] Each R4 is independently selected from (C1-C4)alkyl optionally substituted with halogen, -OR6, halogen, and 3-6 membered heterocyclyl;

[0101] R5 is an aryl group substituted with one halogen;

[0102] R6 is selected from aryl and (C1-C4)alkyl optionally substituted with halogen;

[0103] L is –NHC(O)–;

[0104] x is 0 or 1;

[0105] Ar1 is heteroaryl or bicyclic heteroaryl, and it is optionally substituted with 1 (C1-C4) alkyl;

[0106] Ar2 is aryl or heteroaryl, which is optionally substituted with 1-2 R7;

[0107] Each R7 is independently selected from: aryl, halogen, trifluoromethyl and -NHS(O)2R8;

[0108] R8 is aryl optionally substituted with 1 R9; and

[0109] R9 is halogen or aryl,

[0110] The conditions are:

[0111] (i) if Ar2 has 0-1 substituents, Ar1 is not thiazolyl; and

[0112] (ii) the compound is not:

[0113]

[0114] 2-((4-Fluorophenyl)sulfonamido)-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzamide.

[0115] In some embodiments, the compound of formula (I) is further given by the compound of formula (Ia) and pharmaceutically acceptable salts, hydrates, solvates, isomers and tautomers thereof:

[0116]

[0117] in:

[0118] R1 is selected from:

[0119] (C1-C4)alkyl optionally substituted with 1-3 R2,

[0120] (C3-C6) cycloalkyl, which is optionally substituted with one R3 or condensed with an aryl group to form a bicyclic group which is optionally substituted with one halogen,

[0121] optionally substituted with 1-2 R4 aryl,

[0122] is substituted with 1 heteroaryl of R5,

[0123] A bicyclic heteroaryl group optionally substituted with 1 (C1-C4) alkyl group,

[0124] A partially saturated bicyclic group, and

[0125]

[0126] R2 is selected from:

[0127] (C1-C4)alkyl,

[0128] (C3-C6)cycloalkyl, which is optionally fused with a (C3-C6)cycloalkyl to form a spiro ring,

[0129] aryl optionally substituted with 1 halogen, and

[0130] 3-6 membered heterocyclic group;

[0131] R3 is (C1-C4) alkyl;

[0132] R4 is selected from (C1-C4)alkyl optionally substituted with halogen, -OR6, halogen and 3-6 membered heterocyclyl;

[0133] R5 is an aryl group substituted with one halogen;

[0134] R6 is selected from aryl and (C1-C4)alkyl optionally substituted with halogen;

[0135] L is –NHC(O)–;

[0136] x is 0 or 1;

[0137] Ar1 is heteroaryl or bicyclic heteroaryl, and is optionally substituted with 1 (C1-C4) alkyl;

[0138] Ar2 is aryl or heteroaryl, which is optionally substituted with 1-2 R7;

[0139] R7 is selected from the group consisting of aryl, halogen, trifluoromethyl and –NHS(O)2R8;

[0140] R8 is aryl optionally substituted with 1 R9; and

[0141] R9 is halogen or aryl.

[0142] In some embodiments, R1 is selected from (C1-C4)alkyl optionally substituted with 1-3 R2, (C3-C6)cycloalkyl optionally substituted with 1 R3, aryl optionally substituted with 1-2 R4, heteroaryl substituted with 1 R5, bicyclic heteroaryl substituted with 1 (C1-C4)alkyl, and

[0143] In some embodiments, R1 is (C1-C4) alkyl optionally substituted with 1-3 R2. In some embodiments, R1 is C1 alkyl substituted with 1 R2. In some embodiments, R1 is C1 alkyl substituted with 2 R2. In some embodiments, R1 is C1 alkyl substituted with 3 R2. In some embodiments, R1 is unsubstituted C1 alkyl. In some embodiments, R1 is C2 alkyl substituted with 1 R2. In some embodiments, R1 is C2 alkyl substituted with 2 R2. In some embodiments, R1 is C2 alkyl substituted with 3 R2. In some embodiments, R1 is unsubstituted C2 alkyl. In some embodiments, R1 is methyl substituted with 1 R2. In some embodiments, R1 is methyl substituted with 2 R2. In some embodiments, R1 is methyl substituted with 3 R2. In some embodiments, R1 is unsubstituted methyl. In some embodiments, R1 is ethyl substituted with 1 R2. In some embodiments, R1 is ethyl substituted with 2 R2. In some embodiments, R1 is ethyl substituted with 3 R2. In some embodiments, R1 is unsubstituted ethyl.

[0144] In some embodiments, R1 is (C3-C6)cycloalkyl optionally substituted with 1 R3. In some embodiments, R1 is C6cycloalkyl optionally substituted with 1 R3. In some embodiments, R1 is C6cycloalkyl substituted with 1 R3. In some embodiments, R1 is cyclohexyl optionally substituted with 1 R3. In some embodiments, R1 is cyclohexyl substituted with 1 R3.

[0145] In some embodiments, R1 is aryl optionally substituted with 1-2 R4. In some embodiments, R1 is aryl substituted with 1 R4. In some embodiments, R1 is aryl substituted with 2 R4. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is phenyl substituted with 1 R4. In some embodiments, R1 is phenyl substituted with 2 R4. In some embodiments, R1 is unsubstituted phenyl. In some embodiments, R1 is indanyl substituted with 1 R4. In some embodiments, R1 is unsubstituted indanyl. In some embodiments, R1 is unsubstituted tetrahydronaphthyl.

[0146] In some embodiments, R1 is heteroaryl substituted with 1 R5. In some embodiments, R1 is pyrazolyl substituted with 1 R5.

[0147] In some embodiments, R1 is a bicyclic heteroaryl substituted with 1 (C1-C4) alkyl. In some embodiments, R1 is a bicyclic heteroaryl substituted with 1 C3 alkyl. In some embodiments, R1 is a bicyclic heteroaryl substituted with 1 isopropyl. In some embodiments, R1 is indazolyl substituted with 1 (C1-C4) alkyl. In some embodiments, R1 is indazolyl substituted with 1 C3 alkyl. In some embodiments, R1 is indazolyl substituted with 1 isopropyl.

[0148] In some embodiments, R1 is

[0149] In some embodiments, R2 is selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, (C6-C 12 ) spirocycloalkyl, aryl optionally substituted with 1 halogen or -OR6, and 3-6 membered heterocyclyl.

[0150] In some embodiments, R2 is (C1-C4) alkyl. In some embodiments, R2 is C1 alkyl. In some embodiments, R2 is methyl.

[0151] In some embodiments, R2 is (C3-C6)cycloalkyl.

[0152] In some embodiments, R2 is (C6-C 12 )spirocycloalkyl. In some embodiments, R2 is C8 spirocycloalkyl. In some embodiments, R2 is spirooctane. In some embodiments, R2 is spiro[5.2]octane.

[0153] In some embodiments, R2 is aryl optionally substituted with 1 halogen or -OR6. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is unsubstituted phenyl. In some embodiments, R2 is aryl substituted with 1 halogen. In some embodiments, R2 is aryl substituted with 1 Cl. In some embodiments, R2 is phenyl substituted with 1 halogen. In some embodiments, R2 is phenyl substituted with 1 Cl. In some embodiments, R2 is aryl substituted with 1 -OR6. In some embodiments, R2 is phenyl substituted with 1 -OR6.

[0154] In some embodiments, R2 is a 3-6 membered heterocyclyl. In some embodiments, R2 is a 5-membered heterocyclyl. In some embodiments, R2 is a pyrrolidinyl.

[0155] In some embodiments, R2 is selected from the group consisting of: methyl, cyclopropyl fused to cyclohexyl, pyrrolidinyl, and phenyl optionally substituted with 1 -Cl.

[0156] In some embodiments, R3 is (C1-C4) alkyl. In some embodiments, R3 is C4 alkyl. In some embodiments, R3 is tert-butyl.

[0157] In some embodiments, R4 is selected from (C1-C4)alkyl optionally substituted with halogen, -OR6, halogen, and 3-6 membered heterocyclyl.

[0158] In some embodiments, R4 is (C1-C4) alkyl optionally substituted with halogen. In some embodiments, R4 is C1 alkyl optionally substituted with halogen. In some embodiments, R4 is unsubstituted C1 alkyl. In some embodiments, R4 is C1 alkyl substituted with halogen. In some embodiments, R4 is C1 alkyl substituted with 1 halogen. In some embodiments, R4 is C1 alkyl substituted with 2 halogens. In some embodiments, R4 is C1 alkyl substituted with 3 halogens. In some embodiments, R4 is C1 alkyl substituted with 2 Fs. In some embodiments, R4 is C1 alkyl substituted with 3 Fs. In some embodiments, R4 is methyl optionally substituted with halogen. In some embodiments, R4 is unsubstituted methyl. In some embodiments, R4 is methyl substituted with halogen. In some embodiments, R4 is methyl substituted with 1 halogen. In some embodiments, R4 is methyl substituted with 2 halogens. In some embodiments, R4 is methyl substituted with 3 halogens. In some embodiments, R4 is methyl substituted with 2 Fs. In some embodiments, R2 is difluoromethyl. In some embodiments, R4 is C1 alkyl substituted with 3 Fs. In some embodiments, R4 is trifluoromethyl. In some embodiments, R4 is C3 alkyl optionally substituted with halogen. In some embodiments, R4 is unsubstituted C3 alkyl. In some embodiments, R4 is isopropyl optionally substituted with halogen. In some embodiments, R4 is unsubstituted isopropyl.

[0159] In some embodiments, R4 is -OR6.

[0160] In some embodiments, R4 is a halogen. In some embodiments, R4 is a halogen selected from F, Cl, Br, and I. In some embodiments, R4 is a halogen selected from Cl, Br, and I. In some embodiments, R4 is a halogen selected from F, Cl, and Br. In some embodiments, R4 is a halogen selected from F, Cl, and I. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Br. In some embodiments, R4 is I.

[0161] In some embodiments, R4 is a 3-6 membered heterocyclyl. In some embodiments, R4 is a 5-membered heterocyclyl. In some embodiments, R4 is a pyrrolidinyl.

[0162] In some embodiments, R4 is selected from the group consisting of: methyl, isopropyl, trifluoromethyl, -Cl, and pyrrolidinyl.

[0163] In some embodiments, R5 is aryl substituted with 1 halogen. In some embodiments, R5 is aryl substituted with 1 halogen selected from F, Cl, Br and I. In some embodiments, R5 is aryl substituted with 1 F. In some embodiments, R5 is aryl substituted with 1 Cl. In some embodiments, R5 is aryl substituted with 1 Br. In some embodiments, R5 is aryl substituted with 1 I. In some embodiments, R5 is phenyl substituted with 1 halogen. In some embodiments, R5 is phenyl substituted with 1 halogen selected from F, Cl, Br and I. In some embodiments, R5 is phenyl substituted with 1 F. In some embodiments, R5 is phenyl substituted with 1 Cl. In some embodiments, R5 is phenyl substituted with 1 Br. In some embodiments, R5 is phenyl substituted with 1 I.

[0164] In some embodiments, R6 is selected from aryl and (C1-C4)alkyl optionally substituted with halogen.

[0165] In some embodiments, R6 is aryl. In some embodiments, R6 is phenyl.

[0166] In some embodiments, R6 is (C1-C4) alkyl optionally substituted with halogen. In some embodiments, R6 is C1 alkyl optionally substituted with halogen. In some embodiments, R6 is unsubstituted C1 alkyl. In some embodiments, R 46In some embodiments, R6 is a C1 alkyl substituted with halogen. In some embodiments, R6 is a C1 alkyl substituted with 1 halogen. In some embodiments, R6 is a C1 alkyl substituted with 2 halogens. In some embodiments, R6 is a C1 alkyl substituted with 3 halogens. In some embodiments, R6 is a C1 alkyl substituted with 2 Fs. In some embodiments, R6 is a C1 alkyl substituted with 3 Fs. In some embodiments, R6 is a methyl optionally substituted with halogen. In some embodiments, R6 is an unsubstituted methyl. In some embodiments, R6 is a methyl substituted with halogen. In some embodiments, R6 is a methyl substituted with 1 halogen. In some embodiments, R6 is a methyl substituted with 2 halogens. In some embodiments, R6 is a methyl substituted with 3 halogens. In some embodiments, R6 is a methyl substituted with 2 Fs. In some embodiments, R6 is a difluoromethyl. In some embodiments, R6 is a C1 alkyl substituted with 3 Fs. In some embodiments, R6 is a trifluoromethyl. In some embodiments, R6 is a C3 alkyl group optionally substituted with halogen. In some embodiments, R6 is an unsubstituted C3 alkyl group. In some embodiments, R6 is an isopropyl group optionally substituted with halogen. In some embodiments, R6 is an unsubstituted isopropyl group.

[0167] In some embodiments, R6 is selected from the group consisting of: phenyl, isopropyl, difluoromethyl, and trifluoromethyl.

[0168] In some embodiments, x is 0. In some embodiments, x is 1.

[0169] In some embodiments, Ar1 is heteroaryl or bicyclic heteroaryl, and it is optionally substituted with 1 (C1-C4) alkyl. In some embodiments, Ar1 is heteroaryl optionally substituted with 1 (C1-C4) alkyl. In some embodiments, Ar1 is heteroaryl substituted with 1 (C1-C4) alkyl. In some embodiments, Ar1 is isothiazolyl substituted with 1 C1 alkyl. In some embodiments, Ar1 is isothiazolyl substituted with 1 methyl. In some embodiments, Ar1 is unsubstituted heteroaryl. In some embodiments, Ar1 is unsubstituted 1,2,3-thiadiazolyl. In some embodiments, Ar1 is 1,2,4-thiadiazolyl. In some embodiments, Ar1 is unsubstituted thiazolyl. In some embodiments, Ar1 is bicyclic heteroaryl optionally substituted with 1 (C1-C4) alkyl. In some embodiments, Ar1 is bicyclic heteroaryl substituted with 1 (C1-C4) alkyl. In some embodiments, Ar1 is unsubstituted bicyclic heteroaryl. In some embodiments, Ar1 is unsubstituted 6,7-dihydro-4H-thieno[3.2-c]pyran.

[0170] In some embodiments, Ar2 is aryl or heteroaryl, which is optionally substituted with 1-2 R7. In some embodiments, Ar2 is unsubstituted aryl. In some embodiments, Ar2 is aryl substituted with 1 R7. In some embodiments, Ar2 is phenyl substituted with 1 R7. In some embodiments, Ar2 is aryl substituted with 2 R7. In some embodiments, Ar2 is phenyl substituted with 2 R7. In some embodiments, Ar2 is unsubstituted heteroaryl. In some embodiments, Ar2 is heteroaryl substituted with 1 R7. In some embodiments, Ar2 is pyridyl substituted with 1 R7. In some embodiments, Ar2 is 1,2,3-thiadiazolyl substituted with 1 R7. In some embodiments, Ar2 is heteroaryl substituted with 2 R7.

[0171] In some embodiments, R7 is selected from aryl, halogen, trifluoromethyl, and -NHS(O)2R8. In some embodiments, R7 is aryl. In some embodiments, R7 is phenyl. In some embodiments, R7 is halogen. In some embodiments, R7 is halogen selected from F, Cl, Br, I. In some embodiments, R7 is F. In some embodiments, R7 is Cl. In some embodiments, R7 is Br. In some embodiments, R7 is I. In some embodiments, R7 is trifluoromethyl. In some embodiments, R7 is -NHSO(O)2R8.

[0172] In some embodiments, R8 is aryl optionally substituted with 1 R9. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is aryl substituted with 1 R9. In some embodiments, R8 is phenyl optionally substituted with 1 R9. In some embodiments, R8 is unsubstituted phenyl. In some embodiments, R8 is phenyl substituted with 1 R9.

[0173] In some embodiments, R9 is halogen or aryl. In some embodiments, R9 is halogen. In some embodiments, R9 is a halogen selected from F, Cl, Br and I. In some embodiments, R9 is F. In some embodiments, R9 is Cl. In some embodiments, R9 is Br. In some embodiments, R9 is I. In some embodiments, R9 is aryl. In some embodiments, R9 is phenyl.

[0174] In some embodiments, the compound of formula (I) is selected from the compounds listed in Table A.

[0175] In some embodiments, the present disclosure relates to compounds of formula (I), which are further given by compounds of formula (II) and pharmaceutically acceptable salts, hydrates, solvates, isomers and tautomers thereof:

[0176]

[0177] in:

[0178] Y is N or CH;

[0179] R 10 is hydrogen or a halogen; and

[0180] R 11 It is halogen or (C1-C3) alkyl substituted with halogen.

[0181] In some embodiments, R 10 is hydrogen or halogen. In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 is a halogen selected from F, Cl, Br and I. In some embodiments, R 10 is hydrogen or Cl. In some embodiments, R 10 For Cl.

[0182] In some embodiments, R 11 is halogen or (C1-C3)alkyl substituted with halogen. 11 is a halogen selected from F, Cl, Br and I. In some embodiments, R 11 is a (C1-C3)alkyl group substituted with halogen. 11 is (C1-C3)alkyl substituted with 1 halogen. 11 is (C1-C3)alkyl substituted with 2 halogens. 11 is (C1-C3)alkyl substituted with 3 halogens. 11 is a C1 alkyl substituted with halogen. 11 is a C1 alkyl substituted with 1 halogen. 11 is a C1 alkyl substituted with 2 halogens. 11 is a C1 alkyl group substituted with 3 halogens. 11 is methyl substituted with halogen. 11 is methyl substituted with 1 halogen. 11 is methyl substituted with 2 halogens. 11 is a methyl group substituted with 3 halogens. 11 is Cl or trifluoromethyl. In some embodiments, R11 In some embodiments, R 11 It is trifluoromethyl.

[0183] In some embodiments, the compound of formula (II) is selected from:

[0184]

[0185]

[0186]

[0187] or a pharmaceutically acceptable salt or isomer thereof.

[0188] In some embodiments, the present disclosure relates to compounds of formula (I), which are further given by compounds of formula (III) and pharmaceutically acceptable salts, hydrates, solvates, isomers and tautomers thereof:

[0189]

[0190] in:

[0191] Z is N or CH;

[0192] R 12 is hydrogen or (C1-C4)alkyl substituted with 1 or more halogen atoms; and

[0193] R 13 is aryl or halogen.

[0194] In some embodiments, R 12 is hydrogen or (C1-C4) alkyl substituted with 1 or more halogen atoms. 12 is (C1-C4) alkyl substituted with 1 or more halogen atoms. 12 is (C1-C4)alkyl substituted with 1 halogen. 12 is (C1-C4)alkyl substituted with 2 halogens. 12 is (C1-C4)alkyl substituted with 3 halogens. 12 is a C1 alkyl substituted with halogen. 12 is a C1 alkyl substituted with 1 halogen. 12 is a C1 alkyl substituted with 2 halogens. 12 is a C1 alkyl group substituted with 3 halogens. 12 is methyl substituted with halogen.12 is methyl substituted with 1 halogen. 12 is methyl substituted with 2 halogens. 12 is a methyl group substituted with 3 halogens. 12 is hydrogen or trifluoromethyl. 12 In some embodiments, R 12 It is trifluoromethyl.

[0195] In some embodiments, R 13 is aryl or halogen. 13 In some embodiments, R 13 In some embodiments, R 13 is a halogen selected from F, Cl, Br and I. In some embodiments, R 13 is phenyl or Cl. In some embodiments, R 13 In some embodiments, R 13 For Cl.

[0196] In some embodiments, the compound of formula (III) is selected from:

[0197]

[0198] or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the present disclosure relates to a compound of formula (I), which is further given by a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, isomer or tautomer thereof:

[0200]

[0201] in:

[0202] R 14 is an aryl group substituted with a halogen; and

[0203] R 15 It is an aromatic group.

[0204] In some embodiments, R 14 is aryl substituted with halogen. 14 is aryl substituted with 1 halogen. 14 is an aryl group substituted with one halogen selected from F, Cl, Br and I. In some embodiments, R 14 is aryl substituted with 1 Cl. 14is phenyl substituted with halogen. 14 is phenyl substituted with 1 halogen. 14 is phenyl substituted with 1 halogen selected from F, Cl, Br and I. In some embodiments, R 14 It is a phenyl group substituted with 1 Cl.

[0205] In some embodiments, R 15 In some embodiments, R 15 It is phenyl.

[0206] In some embodiments, the compound of formula (IV) is:

[0207]

[0208] or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the present disclosure relates to a compound of formula (I), which is further given by a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, isomer or tautomer thereof:

[0210]

[0211] in:

[0212] R 16 is halogen; R 17 is a (C1-C4)alkyl group substituted with halogen; and

[0213] R 18 It is an aryl group substituted with halogen.

[0214] In some embodiments, R 16 In some embodiments, R 16 is a halogen selected from F, Cl, Br and I. In some embodiments, R 16 For Cl.

[0215] In some embodiments, R 17 is (C1-C4)alkyl substituted with halogen. 17 is a C1 alkyl substituted with halogen. 17 is a C1 alkyl group substituted with 3 halogens. 17 is a C1 alkyl substituted with 3 halogens selected from F, Cl, Br and I. In some embodiments, R 17 is a C1 alkyl substituted with 3 Fs. 17 is methyl substituted with halogen.17 is a methyl group substituted with 3 halogens. 17 is a methyl group substituted with 3 halogens selected from F, Cl, Br and I. In some embodiments, R 17 is a methyl group substituted with 3 Fs. In some embodiments, R 17 It is trifluoromethyl.

[0216] In some embodiments, R 18 is aryl substituted with halogen. 18 is aryl substituted with 1 halogen. 18 is an aryl group substituted with one halogen selected from F, Cl, Br and I. In some embodiments, R 18 is aryl substituted with 1 Cl. 18 is phenyl substituted with halogen. 18 is phenyl substituted with 1 halogen. 18 is phenyl substituted with 1 halogen selected from F, Cl, Br and I. In some embodiments, R 18 It is a phenyl group substituted with 1 Cl.

[0217] In some embodiments, the compound of formula (V) is:

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the present disclosure relates to a compound of formula (I), which is further given by a compound of formula (VI) or a pharmaceutically acceptable salt, hydrate, solvate, isomer or tautomer thereof:

[0221]

[0222] in:

[0223] R 19 is a halogen;

[0224] R 20 is a (C1-C4)alkyl group substituted with halogen; and

[0225] R 21 It is an aryl group substituted with halogen.

[0226] In some embodiments, R 19 In some embodiments, R 19 is a halogen selected from F, Cl, Br and I. In some embodiments, R19 For Cl.

[0227] In some embodiments, R 20 is (C1-C4)alkyl substituted with halogen. 20 is a C1 alkyl substituted with halogen. 20 is a C1 alkyl group substituted with 3 halogens. 20 is a C1 alkyl substituted with 3 halogens selected from F, Cl, Br and I. In some embodiments, R 20 is a C1 alkyl substituted with 3 Fs. 20 is methyl substituted with halogen. 20 is a methyl group substituted with 3 halogens. 20 is a methyl group substituted with 3 halogens selected from F, Cl, Br and I. In some embodiments, R 20 is a methyl group substituted with 3 Fs. In some embodiments, R 20 It is trifluoromethyl.

[0228] In some embodiments, R 21 is aryl substituted with halogen. 21 is aryl substituted with 1 halogen. 21 is an aryl group substituted with one halogen selected from F, Cl, Br and I. In some embodiments, R 21 is aryl substituted with 1 Cl. 21 is phenyl substituted with halogen. 21 is phenyl substituted with 1 halogen. 21 is phenyl substituted with 1 halogen selected from F, Cl, Br and I. In some embodiments, R 21 It is a phenyl group substituted with 1 Cl.

[0229] In some embodiments, the compound of formula (VI) is:

[0230]

[0231] or a pharmaceutically acceptable salt thereof.

[0232] The compound of formula (I) is not:

[0233] 2-((4-Fluorophenyl)sulfonamido)-N-(4-phenylthiazol-2-yl)benzamide;

[0234] 2-[[(4-Chlorophenyl)sulfonyl]amino]-N-[4-(2,5-dimethoxyphenyl)-2-thiazolyl]-benzamide;

[0235] N-[4-(1,3-Benzodioxin-5-yl)-2-thiazolyl]-2-[[(4-chlorophenyl)sulfonyl]amino]-benzamide;

[0236] N-[4-(3,4-dimethoxyphenyl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0237] N-[4-(2,4-dimethoxyphenyl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0238] 2-[[(4-Chlorophenyl)sulfonyl]amino]-N-[4-(2,4-dimethoxyphenyl)-2-thiazolyl]-benzamide;

[0239] 2-[[(4-Chlorophenyl)sulfonyl]amino]-N-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-thiazolyl]-benzamide;

[0240] N-[4-(2,5-dimethoxyphenyl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0241] 2-[[(4-Chlorophenyl)sulfonyl]amino]-N-[4-(3,4-dimethoxyphenyl)-2-thiazolyl]-benzamide;

[0242] N-[4-(2,5-dimethoxyphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0243] N-[4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0244] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-[4-(4-fluorophenyl)-2-thiazolyl]-benzamide;

[0245] N-[4-(2,4-dimethoxyphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0246] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-(3-phenyl-1,2,4-thiadiazol-5-yl)-benzamide;

[0247] N-[4-(4-ethoxyphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0248] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-[4-(4-methoxyphenyl)-2-thiazolyl]-benzamide;

[0249] N-[4-(3,4-dimethoxyphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0250] N-[4-(4-methoxyphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0251] N-[4-(4-ethoxyphenyl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0252] N-[4-(1,3-Benzodioxin-5-yl)-2-thiazolyl]-2-[[(4-fluorophenyl)sulfonyl]amino]-benzamide;

[0253] N-[4-(4-methoxy-3-methylphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0254] N-[4-(1,3-Benzodioxin-5-yl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0255] N-[4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0256] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-[4-(4-methoxy-3-methylphenyl)-2-thiazolyl]-benzamide;

[0257] N-[4-(4-Fluorophenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0258] N-[4-(4-Methylphenyl)-2-thiazolyl]-2-[(phenylsulfonyl)amino]-benzamide;

[0259] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-[4-(4-methylphenyl)-2-thiazolyl]-benzamide;

[0260] 2-[[(4-Fluorophenyl)sulfonyl]amino]-N-[4-[4-(1-methylethyl)phenyl]-2-thiazolyl]-benzamide; or

[0261] 2-[[(4-Chlorophenyl)sulfonyl]amino]-N-[4-(2-naphthyl)-2-thiazolyl]-benzamide.

[0262] Non-limiting specific embodiments of USP36 inhibitor compounds are shown in Table A below.

[0263] Methods of preparing the disclosed compounds

[0264] The compounds of the present disclosure can be prepared by a variety of methods including standard chemistry. Suitable synthetic routes are described in the examples given below.

[0265] The compounds disclosed herein, i.e., compounds of formula (I)-(VI) or pharmaceutically acceptable salts thereof, can be prepared by methods known in the art of organic synthesis (such as those described in part by the synthesis schemes described in the Examples). In the schemes described below, it is well known that protecting groups for sensitive or reactive groups are used when necessary, according to general principles or chemistry. Protecting groups are manipulated according to standard methods for organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are obvious to those skilled in the art. The selection process and its reaction conditions and order of implementation should be consistent with the preparation of compounds of formula (I)-(VI).

[0266] Those skilled in the art will recognize that stereocenters are present in compounds of formula (I)-(VI). Therefore, the present disclosure includes possible stereoisomers (unless otherwise specified and / or specified in the synthesis), and includes not only racemic compounds but also individual enantiomers and / or diastereomers. Unless otherwise specified, when a compound is required to be a single enantiomer or diastereomer, it can be obtained by stereoselective synthesis or by splitting the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Elel, SH Wilen and LN Mander (Wiley-Interscience, 1994).

[0267] Methods of Using the Disclosed Compounds

[0268] One aspect of the disclosure relates to a compound of any one of formula (I)-(VI) for use in medicine. Another aspect of the disclosure relates to a method of regulating USP36, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of formula (I)-(VI). Another aspect of the disclosure relates to a method of inhibiting one or more USP36, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of formula (I)-(VI). In another aspect, the disclosure relates to a method of inhibiting USP36, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of formula (I)-(VI).

[0269] USP36 inhibitor compounds can be used to develop pharmaceutical compositions suitable for treating certain cancer forms, including but not limited to pancreatic cancer, colorectal cancer, lung cancer, brain cancer, ovarian cancer or prostate cancer. USP36 inhibitor compounds can be used to treat disease states that respond to inhibition of USP36. The present disclosure relates to the treatment of certain cancer forms. Inhibition of USP36 will selectively induce cancer cell cycle arrest and apoptosis by reducing ribosome biogenesis and transcription, disrupting downstream protein synthesis and negatively affecting nucleolar morphology. Based on the relationship between USP36, MYC and ribosome production, the upregulation of MYC-induced nucleolar stress provides a marker for different levels of nucleolar stress and the subsequent vulnerability to interrupted ribosome biogenesis. Therefore, it has the potential to provide a mechanism to identify cancer cell types that may be most sensitive to USP36 inhibition.

[0270] The present disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound of any one of formulae (I)-(VI) and a pharmaceutically acceptable carrier.

[0271] The present disclosure also includes pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical compositions reported herein may be provided in unit dosage forms (e.g., capsules, tablets, etc.). In some embodiments, the pharmaceutical compositions reported herein may be provided in oral dosage forms. In some embodiments, the oral dosage form of any one of the compounds of formula (I)-(VI) may be a capsule. In some embodiments, the oral dosage form of any one of the compounds of formula (I)-(VI) is a tablet. In some embodiments, the oral dosage form comprises one or more fillers, disintegrants, lubricants, glidants, anti-adherents and / or antistatic agents. In some embodiments, the oral dosage form is prepared by dry mixing. In some embodiments, the oral dosage form is a tablet and is prepared by dry granulation.

[0272] Compositions according to the present invention can be used for administration in any suitable manner, such as oral or oral administration. When administered orally, the compound of formula I can be prepared into a mixture with an excipient suitable for preparing oral dosage forms such as tablets in a solution or suspension, in a hard or soft capsule form including a gelatin capsule form, a capsule or a lozenge. Suspensions for oral administration can be prepared according to any method known to those skilled in the art. For example, the suspension can be an oily suspension, in which the compound of any one of formulas (I)-(VI) is suspended in a liquid suspension containing, for example, a vegetable oil such as olive oil, sesame oil or coconut oil. The liquid suspension may also contain mineral oil.

[0273] The compositions may also be administered topically, e.g., for application to the skin, e.g., in the form of a cream, paste, lotion, gel, ointment, poultice, paste, plaster, skin patch, etc., or for ophthalmic use, e.g., in the form of eye drops, lotion or gel formulations.

[0274] The composition can also be administered parenterally, such as intravenously. Intravenous injection forms include, but are not limited to, push injections and drips. In some embodiments, the intravenous dosage form is sterile or capable of being sterilized before being administered to a subject because they generally bypass the subject's natural defenses against contaminants. Examples of intravenous dosage forms include, but are not limited to, water for injection USP; aqueous vehicles include, but are not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-soluble vehicles, including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0275] The form that is easy to flow is such as solution, emulsion and suspension, and can also be used for example intralesional injection, or can be rectally administered such as enema or suppository, or intranasal administration such as nasal spray or aerosol. Coarse crystal powder can be formulated for suction, such as delivery to nose, sinus, throat or lung. Transdermal composition / device and vaginal suppository can also be used for delivering compound of the present invention. Composition can also comprise the reagent that strengthens the compound (or other activating agent) delivery with formula I, such as liposome, polymer or copolymer (such as branched polymer).

[0276] The pharmaceutical composition of the present invention may also include one or more additives. Additives well known in the art include, for example, antitackifiers, defoamers, buffers, antioxidants (for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, malic acid, fumaric acid, potassium pyrosulfite, sodium bisulfite, sodium metabisulfite and tocopherol, such as alpha-tocopherol (vitamin E)), preservatives, chelating agents, viscosity modifiers, tension agents, flavoring agents, coloring agents, flavor enhancers, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants and mixtures thereof. The amount of such additives may be easily determined by those skilled in the art according to the desired specific properties, and may be formulated to make the compound with formula I stable, such as not reduced by antioxidant additives.

[0277] The additives may also include thickeners. Suitable thickeners may be those known and used in the art, including, for example, pharmaceutically acceptable polymeric materials and inorganic thickeners. Exemplary thickeners for use in the pharmaceutical compositions of the present invention include polyacrylates and polyacrylate copolymer resins, such as polyacrylic acid and polyacrylic acid / methacrylic acid resins; cellulose and cellulose derivatives including: alkyl celluloses, such as methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, such as hydroxypropyl-cellulose and hydroxypropylalkyl-celluloses, such as hydroxypropyl-methyl-cellulose; acylated celluloses, such as cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate and hydroxypropylethylcellulose phthalate; and salts thereof, such as carboxymethylcellulose. polyvinyl pyrrolidone, including, for example, poly-N-vinyl pyrrolidone and vinyl pyrrolidone copolymers, such as vinyl pyrrolidone-vinyl acetate copolymer; polyvinyl resins, including, for example, polyvinyl acetate and alcohols, and other polymeric materials, including gum tragacanth, gum arabic, alginates such as alginic acid and its salts, such as sodium alginate; and inorganic thickeners such as atapulgite, bentonite and silicates including hydrophilic silica products, such as alkylated (e.g., methylated) silica gels, particularly colloidal silica products.

[0278] Such thickeners as described above may be included, for example, to provide a sustained release effect. However, when oral administration is intended, the use of a thickener may not be necessary. On the other hand, the use of a thickener is indicated, for example, in the case of foreseeing topical application.

[0279] Although the dosage of any of the compounds of formula (I)-(VI) will vary depending on the activity and / or toxicity of the specific compound, the condition being treated, and the physical form of the pharmaceutical composition for administration, it can be indicated by way of guidance that a dosage selected within the range of 1 to 2000 mg / kg body weight per day is generally appropriate. Those of ordinary skill in the art are familiar with methods for determining appropriate dosages. Example

[0280] Materials and instruments

[0281] All solvents used are commercially available and can be used without further purification. The reaction is usually carried out using anhydrous solvents under an inert nitrogen atmosphere. Proton NMR spectra are recorded using a Bruker 400MHz NMR spectrometer. The deuterated solvent (DMSO-d6) usually contains 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (for 1H being set to δ 0.00). LCMS analysis is carried out on the SHIMADZU LCMS consisting of UFLC 20-AD and LCMS 2020MS detectors. The column used is Shim-pack XR-ODS, 2.2 μm, 3.0x50 mm. The instrument uses reversed phase conditions (acetonitrile / water, containing 10mM ammonium bicarbonate).

[0282] The definitions used in the following scheme and elsewhere in this paper are:

[0283]

[0284]

[0285] Example 1

[0286] Synthesis of N-(4-[[(1S)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide and N-(4-[[(1R)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (16)

[0287]

[0288] Step 1. Ethyl 5-[5-(trifluoromethyl)pyridine-3-carboxylate]-1,2,3-thiadiazole-4-carboxylate

[0289] Under nitrogen atmosphere, POCl3 (11.0 mL, 113 mmol) was added dropwise to a stirred mixture of 5-amino-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (1.50 g, 8.66 mmol) and 5-(trifluoromethyl)pyridine-3-carboxylic acid (1.99 g, 10.4 mmol) in pyridine (40 mL) at 0 ° C. Under nitrogen atmosphere, the resulting mixture was stirred at 25 ° C for 2 hours. The reaction mixture was poured into water / ice (100 mL). The mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution) at 0 ° C. The resulting mixture was extracted with CH2Cl2 (3x600 mL). The combined organic layer was washed with 1M HCl (600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give ethyl 5-[5-(trifluoromethyl)pyridine-3-amide]-1,2,3-thiadiazole-4-carboxylate (1.10 g, 37%) as a yellow solid. LCMS (ES, m / z): 347 [M+H] + .

[0290] Step 2. 5-[5-(Trifluoromethyl)pyridine-3-carboxylic acid]-1,2,3-thiadiazole-4-carboxylic acid

[0291] To a solution of ethyl 5-[5-(trifluoromethyl)pyridine-3-amide]-1,2,3-thiadiazole-4-carboxylate (1.10 g, 3.17 mmol) in EtOH (60 mL) was added NaOH (8 mol / L in water) (60 mL). The resulting mixture was stirred at 25 °C for 2 hours. The mixture was acidified to pH 3 with 1 M HCl at 0 °C. The volatiles were evaporated. The solid was collected by filtration, washed with water (100 mL), and dried under infrared. 5-[5-(trifluoromethyl)pyridine-3-amide]-1,2,3-thiadiazole-4-carboxylic acid (1 g, 96%) was obtained as a white solid. LCMS (ES, m / z): 319 [M+H] + .

[0292] Step 3. tert-Butyl N-[1-(4-chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl]carbamate

[0293] Pyrrolidine (200 mg, 2.81 mmol) was added to a stirred mixture of [(tert-butoxycarbonyl)amino](4-chlorophenyl)acetic acid (500 mg, 1.75 mmol), HOBT (476 mg, 3.52 mmol), EDCI (674 mg, 3.52 mmol) and DIEA (701 mg, 5.42 mmol) in DMF (5 mL). The resulting mixture was stirred at 26 ° C for 2 hours. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18 Silica gel, 80g, 20-35um; mobile phase, aqueous solution containing 0.1% FA and ACN (gradient from 0% to 80% in 50 minutes); detector, UV 254nm. Thus, tert-butyl N-[1-(4-chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl]carbamate (400mg, 64%) was obtained as a yellow oil. LCMS (ES, m / z): 339,341 [M+H] + .

[0294] Step 4. tert-Butyl N-[1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamate

[0295] Under nitrogen atmosphere, DIBAl-H (1 mol / L hexane solution) (10 mL, 9.92 mmol) was added dropwise to a stirred solution of tert-butyl N-[1-(4-chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl]carbamate (300 mg, 0.84 mmol) in THF (10 mL) at 0 ° C. The resulting mixture was stirred for 3 hours at 25 ° C. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18 Silica gel, 80 g, 20-35 um; mobile phase, aqueous solution containing 0.1% FA and ACN (gradient from 0% to 100% in 30 minutes); detector, UV 254 nm. The product fractions were concentrated in vacuo to give tert-butyl N-[1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamate (150 mg, 52%) as a yellow oil. LCMS (ES, m / z): 325, 327 [M+H] + .

[0296] Step 5. 1-(4-Chlorophenyl)-2-(pyrrolidin-1-yl)ethylamine dihydrochloride

[0297] To a stirred solution of tert-butyl N-[1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamate (180 mg, 0.55 mmol) in 1,4-dioxane (1 mL) was added HCl (gas) in 1,4-dioxane (4 M, 2 mL) at 0°C. The resulting mixture was stirred at 26°C for 1 hour. The mixture was concentrated in vacuo to give 1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethylamine dihydrochloride (150 mg, 86%) as a white solid. The product was used in the next step without further purification. LCMS (ES, m / z): 225, 227 [M-2HCl+H] + .

[0298] Step 6. N-(4-[[(1S)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide and N-(4-[[(1R)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (16)

[0299] HATU (372 mg, 0.96 mmol), DIEA (316 mg, 2.39 mmol) and 1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethylamine dihydrochloride (150 mg, 0.48 mmol) were added to a stirred mixture of 5-[5-(trifluoromethyl)pyridine-3-amide]-1,2,3-thiadiazole-4-carboxylic acid (157 mg, 0.48 mmol) in DMF (3 mL). The resulting mixture was stirred at 26 ° C for 2 hours. The resulting mixture was poured into water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18Silica gel, 40 g, 20-35 um; mobile phase, aqueous solution containing 0.1% FA and ACN (gradient from 0% to 80% in 30 minutes); detector, UV 254 nm. The product fraction was concentrated in vacuo to give a racemic product. The racemate was separated by preparative chiral HPLC using the following conditions (column: CHIRALPAK IG, 2x25 cm, 5 μm; mobile phase A: Hex (0.1% TEA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30 B to 30 B in 13.5 minutes; 220 / 254 nm; RT1: 6.837; RT2: 11.035). The product fraction was concentrated in vacuo and then dissolved in ACN (5 mL) and H2O (5 mL). The mixture was lyophilized to give the first eluting isomer of N-(4-[[(1S)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide as a white solid (11.3 mg, 4%) and the second eluting isomer of N-(4-[[(1R)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide as a white solid (12.4 mg, 5%).

[0300] First eluting isomer: 1 H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.46 (br s, 1H), 9.47 (br s, 2H), 9.10 (s, 1H), 8.59 (s, 1H), 7.65 (d, J = 6.8Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 5.78 (br s,1H),3.85-3.38(m,6H),2.05-1.98(m,4H).LCMS(ES,m / z):525,527[M+H] + .

[0301] Second eluting isomer (16): 1 H-NMR (DMSO-d6, 400MHz) δ (ppm): 10.46 (br s, 1H), 9.51-9.38 (m, 2H), 9.10 (s, 1H), 8.59 (s, 1H), 7.64 (d, J = 7.6Hz, 2H), 7.48 (d, J = 2Hz, 2H), 5.78 (br s,1H),3.84-3.40(m,6H),2.02-1.90(m,4H).LCMS(ES,m / z):525,527[M+H] + .

[0302] Example 2

[0303] Synthesis of 2-(4-chlorobenzenesulfonyl)-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (17)

[0304]

[0305] Step 1. 2-Nitro-N-(4-phenylthiazol-2-yl)-4-(trifluoromethyl)benzamide

[0306] At 0 ° C, DIEA (10.2 mL, 61.9 mmol) and 4-phenylthiazole-2-amine (4.00 g, 22.7 mmol) were added to a stirred mixture of 2-nitro-4-(trifluoromethyl)benzoic acid (5.00 g, 21.3 mmol) and HATU (12.0 g, 31.6 mmol) in DMF (30 mL). The resulting mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with water / ice (100 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2-nitro-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (2.00 g, 23%) as a light brown solid. LCMS (ES, m / z): 394 [M+H] + .

[0307] Step 2. 2-Amino-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide

[0308] Under hydrogen atmosphere, a mixture of 2-nitro-N-(4-phenylthiazol-2-yl)-4-(trifluoromethyl)benzamide (2.00 g, 5.08 mmol) and Pd / C (200 mg, 10%) in MeOH (50 mL) was stirred at 25°C for 2 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column (column, C 18 Silica gel; mobile phase, aqueous solution containing FA (0.1%) and ACN (gradient from 10% to 50% in 40 minutes); detector, UV 254 / 220nm) to give 2-amino-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (1.07g, 54%) as a dark yellow solid. LCMS (ES, m / z): 364 [M+H] + .

[0309] Step 3. 2-(4-Chlorobenzenesulfonyl)-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (17)

[0310] A mixture of 2-amino-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (100 mg, 0.27 mmol) and 4-chlorobenzene-1-sulfonyl chloride (290 mg, 1.37 mmol) in pyridine (5 mL) was stirred at 60 ° C for 5 hours. The mixture was cooled to room temperature, diluted with water / ice (20 mL), and extracted with DCM (3x10 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18 Silica gel, 80 g, 20-35 um; mobile phase, water (0.1% FA) and ACN (gradient from 0% to 100% in 30 minutes); detector, UV 254 / 220 nm. The collected fractions were lyophilized to give 2-(4-chlorobenzenesulfonyl)-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (23.1 mg, 16%) as a white solid.

[0311] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.89 (br s, 1H), 10.44 (br s,1H),7.96-7.91(m,3H),7.79-7.66(m,4H),7.57(d,J=8.4Hz,2H),7.49-7.45(m,3H),7.38-7.34(m,1H).LCMS(ES,m / z): 538,540[M+H] + .

[0312] Example 3

[0313] Synthesis of 5-(3-chlorobenzamido)-N-[2-(3-chlorophenyl)propan-2-yl]-1,2,3-thiadiazole-4-carboxamide (18)

[0314]

[0315] Step 1. Ethyl 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylate

[0316] To a mixture of 3-chlorobenzoic acid (2.20 g, 13.2 mmol) and HATU (5.00 g, 13.2 mmol) in DMF (60 mL) at 0°C was added 5-amino-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (2.00 g, 11.0 mmol) and DIEA (5.90 mL, 32.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (2.50 g, 73%) as a white solid. LCMS (ES, m / z): 312,314 [M+H] + .

[0317] Step 2. 5-(3-Chlorobenzamido)-1,2,3-thiadiazole-4-carboxylic acid

[0318] A mixture of ethyl 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylate (2.50 g, 7.62 mmol) and NaOH (0.60 g, 15.0 mmol) in H2O (20 mL) and EtOH (30 mL) was stirred at 25°C for 16 hours. The resulting mixture was partially concentrated under reduced pressure. The mixture was acidified to pH 3 with HCl (1 N). The precipitated solid was collected by filtration, washed with water (10 mL) and dried in vacuo to give 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylic acid (2.00 g, 88%) as a white solid. LCMS (ES, m / z): 284, 286 [M+H] + .

[0319] Step 3. 5-(3-Chlorobenzamido)-N-[2-(3-chlorophenyl)propan-2-yl]-1,2,3-thiadiazole-4-carboxamide (18)

[0320] To a stirred mixture of 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylic acid (200 mg, 0.63 mmol) and HATU (361 mg, 0.94 mmol) in DMF (5 mL) at 0°C was added 2-(3-chlorophenyl)propan-2-amine (129 mg, 0.76 mmol) and DIEA (315 uL, 1.90 mmol). The resulting mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1). The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 30x150mm, 5um; mobile phase, A: water (10mmol / L NH4HCO3) and B: ACN (gradient of 30% to 60% in 7 minutes); detector, UV 254nm. The product fraction (RT: 6.44min) was lyophilized to give 5-(3-chlorobenzamido)-N-[2-(3-chlorophenyl)propan-2-yl]-1,2,3-thiadiazole-4-carboxamide (53.6mg, 19%) as a white solid.

[0321] 1 H-NMR (DMSO, 400MHz) δ (ppm): 12.13 (s, 1H), 9.21 (s, 1H), 7.90 (br s,1H),7.85-7.75(m,2H),7.70-7.59(m,1H),7.52(s,1H),7.50-7.45(m,1H),7 .38-7.34(m,1H),7.28-7.27(m,1H),1.79(s,6H).LCMS(ES,m / z): 435,437[M+H] + .

[0322] Example 4

[0323] Synthesis of N-[(4-chlorophenyl)methyl]-5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxamide (24)

[0324]

[0325] Step 1. Ethyl 5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylate

[0326] To a stirred mixture of 3-(trifluoromethyl)benzoic acid (177 mg, 0.93 mmol) and HATU (444 mg, 1.16 mmol) in DMF (9 mL) at 0°C was added 5-amino-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (150 mg, 0.87 mmol) and DIEA (386 uL, 2.33 mmol). The resulting mixture was stirred at 25°C for 16 hours. The reaction was quenched by the addition of water (10 mL) at room temperature. The solid was collected by filtration, washed with water (3x7 mL), and dried under UV to give 5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (160 mg, 50%) as a yellow solid. LCMS (ES, m / z): 346 [M+H] + .

[0327] Step 2. 5-[3-(Trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid

[0328] To a stirred mixture of NaOH (66 mg, 1.65 mmol) in EtOH (3 mL) and H2O (3 mL) was added ethyl 5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylate (160 mg, 0.46 mmol) in portions at 0°C. The resulting mixture was stirred at 25°C for 3 hours. The resulting mixture was partially concentrated under reduced pressure. The mixture was acidified to pH 6 with HCl (1N). The precipitated solid was collected by filtration, washed with water (10 mL), and dried under UV to give 5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid (100 mg, 68%) as an off-white solid. LCMS (ES, m / z): 318 [M+H]+.

[0329] Step 3. N-[(4-chlorophenyl)methyl]-5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxamide (24)

[0330] To a stirred mixture of 5-[3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid (100 mg, 0.31 mmol) in DMF (3 mL) was added HATU (170 mg, 0.44 mmol), 1-(4-chlorophenyl)methylamine (51 mg, 0.36 mmol) and DIEA (150 μL, 0.89 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 4 hours. The mixture was diluted with water (15 mL) and extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC column (XBridge Prep C 18 OBD column, 5um, 19x150mm; mobile phase, A: water (containing 0.05% TFA) and ACN (gradient from 55% to 85% in 7 minutes); detector, UV254nm) purification. The product fraction (RT: 6.68min) was lyophilized to obtain N-[(4-chlorophenyl)methyl]-5-[3-(trifluoromethyl)benzamide]-1,2,3-thiadiazole-4-carboxamide (33mg, 24%) as an off-white solid.

[0331] 1 H-NMR (DMSO, 400MHz) δ (ppm): 9.42 (br s,1H),8.04-8.00(m,2H),7.95-7.90(m,1H),7.76-7.72(m,1H),7.69-7.47(m ,1H),7.44-7.29(m,4H),4.52(d,J=6.4Hz,2H).LCMS(ES,m / z):441,443[M+H] + .

[0332] Example 5

[0333] Synthesis of N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxamide (25)

[0334]

[0335] Step 1. 5-Chloro-N-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-inden-2-amine

[0336] To a stirred mixture of 5-chloro-2,3-dihydro-1H-inden-2-one (200 mg, 1.20 mmol), 4-methoxybenzylamine (247 mg, 1.80 mmol) in DCM (5 mL) were added AcOH (0.1 mL) and STAB (763 mg, 3.60 mmol). The reaction mixture was stirred at 25 °C for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 5-chloro-N-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-inden-2-amine (140 mg, 41%) as a yellow solid. LCMS (ES, m / z): 288, 290 [M+H] + .

[0337] Step 2. 5-Chloro-2,3-dihydro-1H-inden-2-amine

[0338] Under nitrogen atmosphere, a mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-inden-2-amine (120 mg, 0.42 mmol) and (NH4)2Ce(NO3)6 (86 mg, 0.16 mmol) in ACN (2 mL) and H2O (0.5 mL) was stirred at 25 °C for 16 hours. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18 Silica gel (80 g, 20 um); mobile phase, water (containing 0.05% TFA), ACN (gradient from 0% to 80% in 30 minutes); detector, UV 254 nm. The collected fractions were concentrated to obtain 5-chloro-2,3-dihydro-1H-indene-2-amine (30 mg, 42%) as a yellow solid. LCMS (ES, m / z): 168, 170 [M+H] + .

[0339] Step 3. Ethyl 5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylate

[0340] At 0 ° C, NaH (24 mg, 0.60 mmol, 60%) was added to a stirred mixture of 5-amino-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (100 mg, 0.52 mmol) in DCM (5 mL). After stirring for 10 minutes, a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride (151 mg, 0.59 mmol) in DCM (1 mL) was added dropwise to the above mixture at 0 ° C. The resulting mixture was stirred at 25 ° C for 16 hours under a nitrogen atmosphere. The mixture was then poured into water (5 mL) and extracted with EtOAc (3x5 mL). The combined organic layer was washed with brine (8 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1) to give ethyl 5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylate (120 mg, 54%) as a white solid. LCMS (ES, m / z): 380, 382 [M+H] + .

[0341] Step 4. 5-[2-Chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid

[0342] At 25 ° C, a mixture of 5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (120 mg, 0.40 mmol) and NaOH (32 mg, 0.81 mmol) in EtOH (3 mL) and H2O (1 mL) was stirred for 16 hours. The resulting mixture was acidified to pH 5 with HCl (1 N) and extracted with EtOAc (3x5 mL). The combined organic layer was washed with brine (2x8 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C 18 Silica gel; mobile phase, water (containing 0.1% TFA) and ACN (gradient from 0% to 90% in 30 minutes); detector, UV 254nm). The collected fractions were concentrated to give 5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid (100 mg, 69%) as a white solid. LCMS (ES, m / z): 352,354 [M+H] + .

[0343] Step 5. N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxamide (25)

[0344] A mixture of 5-[2-chloro-3-(trifluoromethyl)benzamido]-1,2,3-thiadiazole-4-carboxylic acid (30 mg, 0.08 mmol), HATU (44 mg, 0.12 mmol), 5-chloro-2,3-dihydro-1H-inden-2-amine (15 mg, 0.09 mmol) and DIEA (29 mg, 0.23 mmol) in DMF (3 mL) was stirred at 25 ° C for 16 hours. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C 18 Silica gel (40 g, 20-35 um); mobile phase, A: water (containing 0.1% FA), B: ACN (gradient from 0% to 60% in 30 minutes); detector, UV 254 nm. The product fraction was lyophilized to obtain N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-[2-chloro-3-(trifluoromethyl)benzamide]-1,2,3-thiadiazole-4-carboxamide (12 mg, 29%) as an off-white solid.

[0345] 1 H-NMR (CD3OD, 400MHz) δ (ppm): 8.09-8.07 (m, 2H), 7.75-7.71 (m, 1H), 7.26-7.17 (m, 3H) ,4.99-4.91(m,1H),3.40-3.38(m,2H),3.14-3.01(m,2H).LCMS(ES,m / z):501,503[M+H] + .

[0346] Example 6

[0347] Synthesis of (S)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (first eluting isomer) and (R)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (second eluting isomer) (29)

[0348]

[0349] Step 1. Ethyl 5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxylate

[0350] At 0 ° C, POCl3 (2.80 mL, 30.0 mmol) was added dropwise to a stirred mixture of 5-amino-1,2,3-thiadiazole-4-carboxylic acid ethyl ester (400 mg, 2.31 mmol) and 5-(trifluoromethyl)pyridine-3-carboxylic acid (530 mg, 2.77 mmol) in pyridine (20 mL). The resulting mixture was stirred at 25 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water / ice (20 mL), the mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution), and extracted with EtOAc (3x 50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give ethyl 5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxylate (610 mg, 71%) as a yellow solid. LCMS (ES, m / z): 347 [M+H] + .

[0351] Step 2. 5-(5-(Trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxylic acid

[0352] A mixture of ethyl 5-[5-(trifluoromethyl)pyridine-3-amido]-1,2,3-thiadiazole-4-carboxylate (600 mg, 1.73 mmol) in NaOH (8M) (20 mL) and EtOH (20 mL) was stirred at 25 °C for 2 hours. The resulting mixture was partially concentrated under reduced pressure. The mixture was acidified to pH 3 with 1 M HCl at 0 °C. The solid was collected by filtration, washed with water (3x20 mL), and dried under infrared. 5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxylic acid (500 mg, 83%) was obtained as a white solid. LCMS (ES, m / z): 319 [M+H] + .

[0353] Step 3. (S)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (first eluting isomer) and (R)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (second eluting isomer) (29)

[0354] To a stirred mixture of 5-[5-(trifluoromethyl)pyridine-3-amido]-1,2,3-thiadiazole-4-carboxylic acid (70 mg, 0.22 mmol) in DMF (2 mL) at 0°C were added HATU (126 mg, 0.33 mmol), DIEA (0.11 mL, 0.66 mmol) and 5-chloro-2,3-dihydro-1H-inden-2-amine (44 mg, 0.26 mmol). The resulting mixture was stirred at 25°C for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the racemic product. The racemate was separated by chiral preparative HPLC under the following conditions: column: CHIRALPAK AD-H SFC, 5x25 cm, 5 μm; mobile phase A: Hex (0.1% IPA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 5B to 5B in 45 minutes; 254 / 220 nm; RT1: 19.839; RT2: 33.398. The collected fractions were concentrated under reduced pressure to give (S)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (first eluting isomer) (3.7 mg, 4%) as a white solid and (R)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-(5-(trifluoromethyl)nicotinamido)-1,2,3-thiadiazole-4-carboxamide (second eluting isomer) (5.3 mg, 5%) as a white solid.

[0355] First eluting isomer: 1 H-NMR (DMSO, 400MHz) δ (ppm): 12.64 (br s,1H),9.70-9.62(m,1H),9.39(s,1H),9.32(s,1H),8.68(s,1H),7.32-7.21(m,3H) ,4.95-4.89(m,1H),3.28-3.22(m,2H),3.17-3.01(m,2H).LCMS(ES,m / z): 468[M+H] + .

[0356] Second eluting isomer (29): 1H-NMR (DMSO, 400MHz) δ (ppm): 12.64 (br s,1H),9.74-9.68(m,1H),9.39(s,1H),9.32(s,1H),8.68(s,1H),7.32-7.21(m,3H) ,4.95-4.90(m,1H),3.28-3.23(m,2H),3.17-3.01(m,2H).LCMS(ES,m / z): 468[M+H] + .

[0357] Example 7

[0358] Synthesis of 5-[2-chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (34)

[0359]

[0360] Step 1. Methyl 5-(2-chloro-3-(trifluoromethyl)benzamido)-3-methylisothiazole-4-carboxylate

[0361] To a stirred solution of 2-chloro-3-(trifluoromethyl)benzoic acid (240 mg, 1.07 mmol) in DCM (3 mL) at 0 ° C, (COCl) 2 (5 mL) and DMF (0.01 mL) were added dropwise. The resulting mixture was stirred at room temperature (25 ° C) for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in DCM (5 mL). The freshly prepared acid chloride solution was then added dropwise to a stirred mixture of 5-amino-3-methylisothiazole-4-carboxylic acid methyl ester (140 mg, 0.81 mmol) and TEA (200 μL, 1.43 mmol) in DCM (10 mL) at 0 ° C. The resulting mixture was stirred at 25 ° C for 6 h. The mixture was poured into water (10 mL) and extracted with CH2Cl2 (3x10 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluted with 1:1 PE / EtOAc) to give methyl 5-(2-chloro-3-(trifluoromethyl)benzamido)-3-methylisothiazole-4-carboxylate (100 mg, 32%) as a yellow solid. LCMS (ES, m / z): 379, 381 [M+H] + .

[0362] Step 2. 5-[2-Chloro-3-(trifluoromethyl)benzamido]-3-methyl-1,2-thiazole-4-carboxylic acid

[0363] A mixture of 5-(2-chloro-3-(trifluoromethyl)benzamido)-3-methylisothiazole-4-formic acid methyl ester (100 mg, 0.26 mmol) and LiOH (7 mg, 0.29 mmol) in THF (2 mL) and H2O (2 mL) was stirred at 60 ° C for 16 hours. The mixture was cooled to room temperature, acidified to pH 4 with HCl (1 N), and extracted with EtOAc (3x10 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C 18 Silica gel; mobile phase, ACN in water, gradient from 0% to 80% in 30 minutes; detector, UV 254nm). The collected fractions were concentrated to give 5-[2-chloro-3-(trifluoromethyl)benzamido]-3-methyl-1,2-thiazole-4-carboxylic acid (60 mg, 63%) as a white solid. LCMS (ES, m / z): 365, 367 [M+H] + .

[0364] Step 3. 5-[2-Chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (34)

[0365] To a stirred solution of 5-[2-chloro-3-(trifluoromethyl)benzamido]-3-methyl-1,2-thiazole-4-carboxylic acid (40 mg, 0.11 mmol) in DCM (5 mL) was added (COCl)2 (63 mg, 0.49 mmol). The reaction mixture was stirred at 25 °C for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in DCM (3 mL) and the freshly prepared acid chloride solution was added dropwise to a stirred mixture of 1-(4-chlorophenyl)methylamine (19 mg, 0.13 mmol) and TEA (40 μL, 0.30 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for another 16 hours. The mixture was diluted with water (15 mL) and extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column, XBridge Prep C 18OBD column, 19x150mm 5um; mobile phase, A: water (containing 0.05% TFA) and BACN (gradient of 50% to 83% in 7 minutes); detector, UV 254nm) purification. The collected fractions (RT: 6.54min) were lyophilized to obtain 5-[2-chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-3-methyl-1,2-thiazole-4-carboxamide (28.2mg, 52%) as a white solid.

[0366] 1 H-NMR (CD3OD, 400MHz) δ (ppm): 8.02-8.00 (m, 1H), 7.95-7.93 (m, 1H), 7.69-7.65 ( m,1H),7.39-7.34(m,4H),4.56(s,2H),2.57(s,3H).LCMS(ES,m / z): 488,490[M+H] + .

[0367] Example 8

[0368] Synthesis of 2-[2-chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxamide (35)

[0369]

[0370] Step 1. 2-Amino-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylic acid ethyl ester

[0371] A mixture of oxacyclohexane-4-one (2.84 g, 28.4 mmol) and ethyl cyanoformate (3.60 g, 34.1 mmol), TEA (6.30 mL, 43.1 mmol) and sulfur (0.90 g, 26.6 mmol) in EtOH (20 mL) was stirred at 55 °C for 5 hours. The reaction mixture was cooled to room temperature, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give ethyl 2-amino-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylate (2.00 g, 31%) as a yellow solid. LCMS (ES, m / z): 228 [M+H] + .

[0372] Step 2. Ethyl 2-[2-chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylate

[0373] A solution of 2-chloro-3-(trifluoromethyl)benzoic acid (325 mg, 1.38 mmol) and DMF (0.1 mL) in SOCl2 (10 mL) was stirred at 80 °C for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in DCM (5 mL). The freshly prepared acid chloride solution was then added dropwise to a stirred mixture of ethyl 2-amino-4H, 6H, 7H-thieno[3,2-c]pyran-3-carboxylate (305 mg, 1.21 mmol) and TEA (335 μL, 2.42 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred for another 3 hours at 25 °C. The reaction mixture was poured into ice / water (10 mL) and extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine (2x 5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 15:1) to give ethyl 2-[2-chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylate (200 mg, 38%) as a yellow solid. LCMS (ES, m / z): 434, 436 [M+H] + .

[0374] Step 3. 2-[2-Chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylic acid

[0375] A mixture of ethyl 2-[2-chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylate (200 mg, 0.46 mmol) and NaOH (33 mg, 0.83 mmol) in H2O (3 mL) and EtOH (3 mL) was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, acidified to pH 3 with HCl (1N aqueous solution), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-[2-chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylic acid (150 mg, 80%) as a yellow solid. LCMS (ES, m / z): 406,408 [M+H] + .

[0376] Step 4. 2-[2-Chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxamide (35)

[0377] To a mixture of 2-[2-chloro-3-(trifluoromethyl)benzamido]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxylic acid (100 mg, 0.22 mmol) and HATU (101 mg, 0.27 mmol) in DMF (3 mL) at 25 °C was added 1-(4-chlorophenyl)methylamine (37 mg, 0.27 mmol) and DIEA (110 μL, 0.67 mmol). The reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column, XBridge Prep C 18 OBD column, 19x150mm, 5um; mobile phase, A: water (10mmol / L NH4HCO3) and B: ACN (gradient from 22% to 52% over 7 minutes); detector, UV 254nm). The product fraction (RT 6.15min) was lyophilized to give 2-[2-chloro-3-(trifluoromethyl)benzamido]-N-[(4-chlorophenyl)methyl]-4H,6H,7H-thieno[3,2-c]pyran-3-carboxamide (8.6mg, 7%) as a yellow solid.

[0378] 1 H-NMR (DMSO, 400MHz) δ (ppm): 11.80 (s, 1H), 8.30-8.27 (m, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.93 (d, J = 7.6Hz, 1H), 7.72-7.68 (m ,1H),7.38-7.32(m,4H),4.71(s,2H),4.41(d,J=6.4Hz,2H),3.89-3.87(m,2H),2.80(s,2H).LCMS(ES,m / z):529,531[M+H] + .

[0379] Example 9

[0380] USP36 inhibition biochemical assay protocol

[0381] USP36 enzymatic assays were performed in a final volume of 6 μL of buffer containing 20 mM Tris-HCl pH 8.0, (Corning 46-031-CM), 3 mM 2-mercaptoethanol (Sigma, M6250), 0.03% BGG (Sigma, G7516) and 0.01% Triton X-100 (Sigma, 93443). Test compounds were serially diluted in DMSO (Sigma, G7516) to obtain a 10-point, 3-fold series. Nanoliter amounts were pre-distributed into 1536 assay plates (Corning, 9110BC) to achieve a concentration response range of 26.6 μM to 1.35 nM. 3 μL of 2x enzyme was added to the assay plate, pre-incubated with compound for 30 minutes, then 3 μL of 2x substrate was added to initiate the reaction (2 nM human USP36 (81-461) and 25 nM Ub-Rh110MP (UbiQ, UbiQ-126) final concentrations. Enzyme and substrate concentrations and incubation times were optimized for maximum signal-to-noise ratio while maintaining linear initial velocity conditions at a fixed substrate concentration below Km.

[0382] The fluorescence signal was measured on an EnVision Plate Reader (PerkinElmer) equipped with a 485 nm excitation filter and a 535 nm emission filter. Measurements were taken at 2.5 minute intervals over 10 minutes and the curves show a linear progression.

[0383] The rate was calculated as follows: Rate = ((Final FLU - Initial FLU) / 600 sec), where Final FLU = fluorescence at 10 min, Initial FLU = fluorescence at 0 min and 600 = duration of reaction in seconds.

[0384] Data are reported as percent inhibition compared to control wells based on the following equation: %inh = 100*((Rate - AveLow) / (AveHigh - AveLow)), where Rate = the measured rate of fluorescence produced during the assay, AveLow = the average rate of the no enzyme control (n = 32), and AveHigh = the average rate of the DMSO control (n = 32).

[0385] IC 50 The values ​​were determined by curve fitting using the standard 4-parameter logistic fit algorithm included in the Activity Base software package (IDBS) using XE Designer equation model 205. The data were fitted using the Levenberg Marquardt algorithm. The IC values ​​for specific compounds are reported in Table A. 50 value.

[0386] Table A

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] The present disclosure enables those skilled in the relevant art to make and use the invention provided herein according to multiple and varied embodiments. Various changes, modifications and improvements of the present disclosure that are easily conceivable to those skilled in the art, including certain changes, modifications, substitutions and improvements, are also part of the present disclosure. Therefore, the foregoing description is to illustrate the discovery provided herein by way of example. In addition, the above description and examples are examples of the present invention rather than limitations. Therefore, the scope of the present invention is set forth in the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, the compound being selected from:

2. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers, excipients or vehicles.

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