Heterocyclic compound and application thereof in medicine

Abstract

The present invention relates to a heterocyclic compound represented by general formula (I), or a stereoisomer, a deuterated compound, a pharmaceutically acceptable salt, a solvate, a prodrug, a metabolite or a co-crystal thereof, and further comprises a pharmaceutical composition and use thereof in drugs for treating MRGPRX4 dependent diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, a pharmaceutical composition thereof and use thereof in medicine. Background Art

[0002] Mas-related gene G protein-coupled receptors (MRGPRs) are a group of isolated receptors with limited expression in very specific tissues. Members of the MRGPR family are divided into nine subclasses, namely MRGPRA-H and MRGPRX. The MRGPRX (MRGX) subfamily is expressed in small diameter sensory neurons of the dorsal root ganglion, keratinocytes and a small number of other tissues. The MRGPRX family consists of four subtypes (MRGPRX1-X4) that are expressed in primates but not found in rodents. To date, no non-primate ortholog of MRGPRX4 has been identified.

[0003] MRGPRX4 is activated by multiple other components of bile, including bile acids and their metabolites, and heme metabolites, including bilirubin and urobilin. Bile acids and bilirubin are highly elevated in cholestatic pruritus, while urobilin, which is a potent itch-inducing mediator in mouse models, may be important for itch sensation in cases where urobilin is elevated, such as uremic pruritus. In addition, MRGPRX4 is a receptor for urobilin, which is a potent mediator of itch induction in mouse models, and may be important for itch sensation in conditions where urobilin is elevated, such as uremic pruritus. Therefore, regulating MRGPRX4 may treat itch-related conditions, pain-related conditions, or autoimmune conditions, among others.

[0004] The MRGPRX4 receptor represents a fundamentally new drug target, and the development of effective MRGPRX4 receptor antagonists and agonists can be used to treat MRGPRX4-related diseases. Summary of the Invention

[0005] The purpose of the present invention is to provide a novel heterocyclic compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, a pharmaceutical composition thereof and its use in medicine.

[0006] One or more embodiments of the present application provide a compound represented by formula (I), or a stereoisomer, deuterated substance, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof:

[0007]

[0008] Ring A is selected from a 6-8 membered aryl group or a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S;

[0009] X1 is selected from C 1-6 Alkylene or -C(O)-; the C 1-6 The alkylene group is optionally further substituted with C 1-6 Substitution of alkyl groups;

[0010] A1 and A2 are each independently selected from C or N;

[0011] R1 is independently selected from halogen, cyano, carboxyl, -C(O)NH2, C 1-6 Haloalkyl, 5-membered heterocyclic group; the 5-membered heterocyclic group contains 3 to 4 heteroatoms selected from N or O, and the 5-membered heterocyclic group is optionally further substituted by a substituent of =O;

[0012] R2 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl or 5-12 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, 3-6 membered cycloalkyl, 6-8 membered aryl, 5-12 membered heteroaryl or 3-6 membered heterocycloalkyl is optionally further substituted with C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocycloalkyl, C 2-6 Alkynyl, -C(O)NH2, cyano, halogen substitution;

[0013] m and n are each independently selected from 0, 1, 2, 3, and 4.

[0014] One or more embodiments of the present application provide a compound, or a stereoisomer, deuterated substance, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or cocrystal thereof, wherein:

[0015] Ring A is selected from a 6-membered aryl group or a 5-6-membered heteroaryl group; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S;

[0016] X1 is selected from C 1-4 Alkylene; the C 1-4 The alkylene group is optionally further substituted with C 1-4 Substitution of alkyl groups;

[0017] A1 and A2 are both selected from N;

[0018] R1 is independently selected from halogen, cyano, carboxyl, -C(O)NH2, C 1-4 alkyl halide;

[0019] R2 are each independently selected from halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 6-8 membered aryl, 5-12 membered heteroaryl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl, 6-8 membered aryl or 5-12 membered heteroaryl, 3-6 membered heterocycloalkyl may further be C 1-4 Alkyl, C 1-4 Alkoxy, cyano, halogen, 4-6 membered heterocycloalkyl, -C(O)NH2 substituents;

[0020] m is selected from 1, 2, 3, and 4;

[0021] n is each independently selected from 0, 1, 2, 3, and 4.

[0022] One or more embodiments of the present application provide a compound, or a stereoisomer, deuterated substance, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or cocrystal thereof, wherein:

[0023] Ring A is selected from a 6-membered aryl group;

[0024] X1 is selected from C 1-4 Alkylene; the C 1-4 The alkylene group is optionally further substituted with C 1-4 Substitution of alkyl groups;

[0025] A1 and A2 are both selected from N;

[0026] R1 are each independently selected from halogen, carboxyl;

[0027] R2 are each independently selected from halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, 6-8 membered aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered condensed ring heteroaryl; the C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, 6-8 membered aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused ring heteroaryl are optionally further C 1-4 Alkyl, C1-4 Alkoxy, cyano, halogen, 4-6 membered heterocycloalkyl, -C(O)NH2 substituents;

[0028] m is selected from 1, 2, 3, and 4;

[0029] n is independently selected from 0, 1, 2, 3, and 4.

[0030] One or more embodiments of the present application provide a compound, or a stereoisomer, deuterated substance, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or cocrystal thereof, wherein the compound is selected from the following structures:

[0031]

[0032]

[0033] In one or more embodiments of the present application, the MRGPRX4-dependent disorder is an itch-related disorder, a pain-related disorder, or an autoimmune disorder.

[0034] Pruritus-related diseases include pruritus caused by chronic pruritus, cholestatic pruritus, contact dermatitis, allergic inflammation, atopic dermatitis, cholestasis, late-stage renal failure, hemodialysis, eczematous dermatitis, uremia and other diseases.

[0035] In one or more embodiments of the present application, the pruritus-related disorder is cholestatic pruritus, uremic pruritus, chronic induced urticaria, chronic spontaneous urticaria, or atopic dermatitis.

[0036] In one or more embodiments of the present application, the pain-related condition is pain caused by arthritis, back pain, cancer pain, central pain syndrome, acute pain, chronic pain, dermatomyositis, diabetic peripheral neuropathy (DPN), endometriosis, fibromyalgia, leg pain, low back pain-hematuria syndrome, lupus, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, osteoarthritis, postherpetic neuralgia (shingles), psoriatic arthritis, rheumatoid arthritis (RA), sciatica, herpes zoster, trigeminal neuralgia, neuropathic pain, etc.

[0037] In one or more embodiments of the present application, the autoimmune disease is chronic inflammation, multiple sclerosis, dermatitis, rhinitis, tendonitis, asthma, autoinflammatory disease, or allergic reaction.

[0038] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0039] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0040] "Alkylene" refers to a divalent group derived from an alkane, which may be straight or branched chain.

[0041] "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted with one or more substituents.

[0042] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0043] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0044] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and even more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

[0045] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8 membered (e.g., 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl and naphthyl. The aryl group may optionally be further substituted with one or more substituents.

[0046] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heteroaryl group, and the 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, and pyrrolopyridinyl. The heteroaryl group may be further substituted with one or more substituents.

[0047] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene, thiophene, oxetanyl, thiophene ... pyranyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The “heterocyclyl” or “heterocycle” may be further substituted with one or more substituents.

[0048] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic ring system, preferably having 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0049] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic ring. The 1, 2, or 3 N or S atoms optionally substituted in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; the "heterocycloalkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocycloalkyl” include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0050] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 Rq5 、=NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; Rq2 、R q3 is selected from H or C1-6 alkyl; wherein R q4 、R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0051] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0052] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0053] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0054] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0055] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0056] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0057] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl. DETAILED DESCRIPTION

[0058] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0059] Example 1

[0060] 2-Fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 1)

[0061] 2-fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0062]

[0063] first step:

[0064] 3-((7-Chloro-5-(trifluoromethyl)-1H-indazol-1-yl)methyl)-2-fluorobenzoic acid (1b)

[0065] methyl 2-fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0066] In a 100 mL round-bottom flask, 1a (1.74 g, 8.09 mmol), cesium carbonate (6.57 g, 20.23 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (2 g, 8.09 mmol) were dissolved in acetonitrile (30 mL) and refluxed for 3 h. The reaction was monitored by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 1b as an off-white solid (1.3 g, 85% yield).

[0067] LC-MS m / z(ESI)=381.02[M+1].

[0068] Step 2:

[0069] Methyl 2-fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (1c)

[0070] methyl 2-fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0071] In a 100 mL round-bottom flask, 1b (100 mg, 0.26 mmol), cesium carbonate (211.25 mg, 0.65 mmol), phenylboronic acid (38.39 mg, 0.32 mmol), and DPPF palladium dichloride (19.02 mg, 0.03 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 1c as a colorless oil (45 mg, 46% yield).

[0072] LC-MS m / z(ESI)=379.13[M+1].

[0073] Step 3:

[0074] 2-Fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 1)

[0075] 2-fluoro-3-((4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0076] In a 100 mL round-bottom flask, 1c (45 mg, 0.12 mmol) and sodium hydroxide (14.28 mg, 0.36 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 1 as a white solid (40 mg, 93% yield).

[0077] LC-MS m / z(ESI)=365.25[M+1].

[0078] 1 HNMR(400MHz,DMSO-d6)δ13.26(s,1H),7.88–7.82(m,2H),7.48–

[0079] 7.27 (m, 7H), 5.64 (s, 2H).

[0080] 19 F NMR(377MHz,DMSO-d6)δ-54.99,-116.35.

[0081] Example 2

[0082] 3-((3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0083] 3-((3,5-Dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 2)

[0084]

[0085] first step:

[0086] Methyl 3-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0087] Methyl 3-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (2b)

[0088] In a 50 mL single-necked flask, 2a (500 mg, 2.86 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (740 mg, 2.86 mmol) were dissolved in 10 mL of acetonitrile. Cesium carbonate (2.33 g, 7.14 mmol) was added and the mixture was allowed to react at 70°C for 4 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 20:0-10:1) to afford 2b as a white solid (942 mg, 97% yield).

[0089] LCMS m / z (ESI) = 341.1 [M+1].

[0090] Step 2:

[0091] Methyl 3-((3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0092] Methyl 3-((3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (2c)

[0093] In a 50 mL single-necked bottle, 2b (200 mg, 0.59 mmol) and phenylboronic acid (108 mg, 0.88 mmol) were dissolved in 5 mL of 1,4-dioxane and 1 mL of water. 1,1-Bis(diphenylphosphino)diboronium iron palladium(II) chloride (42 mg, 0.06 mmol) and cesium carbonate (480 mg, 1.47 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:0-10:1) to obtain 2c as a white solid (168 mg, yield: 84.5%).

[0094] LCMS m / z (ESI) = 339.2 [M+1].

[0095] Step 3:

[0096] 3-((3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0097] 3-((3,5-Dimethyl-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 2)

[0098] In a 50 mL single-necked vial, 2c (168 mg, 0.5 mmol) was dissolved in a mixture of methanol (4 mL) and water (1 mL). Sodium hydroxide (30 mg, 0.75 mmol) was added and the mixture was allowed to react at 40°C for 1 h. The reaction was monitored by LCMS. The mixture was diluted with water, the methanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 2 as a white solid (30.72 mg, yield: 19.0%).

[0099] LCMS m / z (ESI) = 325.2 [M+1].

[0100] 1 H NMR(400MHz,DMSO-d6)δ7.80(td,1H),7.47–7.36(m,2H),7.33–7.20(m,5H),5.34(s,2H),2.25(s,3H),2.13(s,3H)

[0101] Example 3

[0102] 2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0103] 2-Fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 3)

[0104]

[0105] first step:

[0106] Methyl-2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)ben zoate

[0107] Methyl 2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (3a)

[0108] In a 50 mL single-necked flask, 1b (150 mg, 0.39 mmol) and m-tolylboronic acid (81 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:0-8:1) to afford 3a as a white solid (120 mg, yield: 77.6%).

[0109] LCMS m / z (ESI) = 393.1 [M+1].

[0110] Step 2:

[0111] 2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic aci d

[0112] 2-Fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 3)

[0113] In a 50 mL single-necked vial, 3a (120 mg, 0.31 mmol) was dissolved in a mixture of methanol (4 mL) and water (1 mL). Sodium hydroxide (18 mg, 0.46 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the methanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 3 as a white solid (63.48 mg, yield: 54.9%).

[0114] LCMS m / z (ESI) = 379.1 [M+1].

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,1H),7.86(td,1H),7.58(td,1H),7.32(q,2H),7.19(dd,3H),5.56(s,2H),2.32(s,3H).

[0116] Example 4

[0117] 2-fluoro-3-((4-(pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic benzoate

[0118] Methyl 2-fluoro-3-((4-(pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (Compound 4)

[0119]

[0120] first step:

[0121] Methyl-2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)ben zoate

[0122] Methyl 2-fluoro-3-((4-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (4a)

[0123] In a 50 mL single-necked bottle, 1b (150 mg, 0.39 mmol) and 4-pyridineboronic acid pinacol ester (121 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried. The crude product was purified by silica gel column chromatography (PE:EA = 10:0-2:1) to afford 4a as a white solid (44 mg, yield: 29.3%).

[0124] LCMS m / z (ESI) = 380.2 [M+1].

[0125] Step 2:

[0126] 2-fluoro-3-((4-(pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoi c acid

[0127] 2-Fluoro-3-((4-(pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 4)

[0128] In a 50 mL single-necked vial, 4a (44 mg, 0.12 mmol) was dissolved in a mixture of methanol (4 mL) and water (1 mL). Sodium hydroxide (7 mg, 0.17 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the methanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 4 as a white solid (15.03 mg, yield: 35.5%).

[0129] LCMS m / z (ESI) = 366.1 [M+1].

[0130] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,2H),8.56(s,1H),7.86(td,1H),7.60(td,1H),7.48–7.41(m,2H),7.33(t,1H),5.59(s,2H).

[0131] Example 5

[0132] 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0133] 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 5)

[0134]

[0135] first step:

[0136] 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0137] Methyl 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (5a)

[0138] In a 50 mL single-necked bottle, 1b (150 mg, 0.39 mmol) and (4-chloro-3-cyanophenyl)boronic acid (107 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried. The crude product was purified by silica gel column chromatography (PE:EA = 15:0-4:1) to afford 5a as a white solid (62 mg, yield: 36.0%).

[0139] LCMS m / z (ESI) = 438.2 [M+1].

[0140] Step 2:

[0141] 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0142] 3-((4-(4-chloro-3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 5)

[0143] In a 50 mL single-necked vial, 5a (62 mg, 0.14 mmol) was dissolved in a mixture of ethanol (4 mL) and water (1 mL). Sodium hydroxide (9 mg, 0.21 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the ethanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 5 as a white solid (13.76 mg, yield: 22.9%).

[0144] LCMS m / z (ESI) = 424.2 [M+1].

[0145] 1 HNMR(400MHz,DMSO-d6)δ8.46(d,1H),8.03(d,1H),7.90–7.80(m,2H),7.73(dd,1H),7.61(td,1H),7.33(t,1H),5.57(s,2H).

[0146] Example 6

[0147] 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluor obenzoic acid

[0148] 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 6)

[0149]

[0150] first step:

[0151] 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-flu orobenzoate

[0152] Methyl 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (6a)

[0153] In a 50 mL single-necked flask, 1b (150 mg, 0.39 mmol) and (5-chloropyridin-3-yl)boronic acid (62 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diboronium palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried. The crude product was purified by silica gel column chromatography (PE:EA = 10:0-2:1) to afford 6a as a white solid (56 mg, yield: 34.4%).

[0154] LCMS m / z (ESI) = 414.1 [M+1].

[0155] Step 2:

[0156] 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluor obenzoic acid

[0157] 3-((4-(5-chloropyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 6)

[0158] In a 50 mL single-necked vial, 6a (56 mg, 0.17 mmol) was dissolved in a mixture of ethanol (4 mL) and water (1 mL). Sodium hydroxide (10 mg, 0.26 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the ethanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 6 as a white solid (32.65 mg, yield: 60.4%).

[0159] LCMS m / z (ESI) = 400.1 [M+1].

[0160] 1 HNMR(400MHz,DMSO-d6)δ7.98–7.90(m,1H),7.69(dd,2H),7.29(t,1H),7.22(d,1H),6.68(d,1H),6.60(td,1H),5.94(s,2H).

[0161] Example 7

[0162] 2-fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0163] 2-Fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 7)

[0164]

[0165] first step:

[0166] 2-fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0167] Methyl 2-fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (7a)

[0168] In a 50 mL single-necked bottle, 1b (150 mg, 0.39 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (145 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)dichloroferronichloridopalladium(II) (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried. The crude product was purified by silica gel column chromatography (PE:EA = 15:1-4:1) to afford 7a as a white liquid (142 mg, yield: 86.1%).

[0169] LCMS m / z (ESI) = 419.2 [M+1].

[0170] Step 2:

[0171] 2-fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0172] 2-Fluoro-3-((4-(pyrazolo[1,5-a]pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 7)

[0173] In a 50 mL single-necked vial, 7a (142 mg, 0.34 mmol) was dissolved in a mixture of ethanol (4 mL) and water (1 mL). Sodium hydroxide (20 mg, 0.51 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the ethanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 7 as a white solid (68.42 mg, 49.9% yield).

[0174] LCMS m / z (ESI) = 405.2 [M+1].

[0175] 1 HNMR(400MHz,DMSO-d6)δ8.73(d,1H),8.45(s,1H),8.02(s,1H),7.84(td,1H ),7.68(d,1H),7.60–7.53(m,1H),7.33(dd,2H),6.97(td,1H),5.59(s,2H).

[0176] Example 8

[0177] 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methy l)-2-fluorobenzoic acid

[0178] 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 8)

[0179]

[0180] first step:

[0181] 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methy l)-2-fluorobenzoate

[0182] Methyl 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0183] In a 50 mL single-necked flask, 1b (150 mg, 0.39 mmol) and (1,5-dimethyl-1H-indazol-6-yl)boronic acid (113 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at 100°C for 8 h. The reaction was monitored by TLC. The reaction mixture was filtered and dried, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 15:1 to 1:1) to afford 8a as a white liquid (170 mg, yield: 97.8%).

[0184] LCMS m / z (ESI) = 447.2 [M+1].

[0185] Step 2:

[0186] 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methy l)-2-fluorobenzoate

[0187] 3-((4-(1,5-dimethyl-1H-indazol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 8)

[0188] In a 50 mL single-necked vial, 8a (170 mg, 0.39 mmol) was dissolved in a mixture of ethanol (4 mL) and water (1 mL). Sodium hydroxide (23 mg, 0.58 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the ethanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 8 as a white solid (45.62 mg, yield: 27.7%).

[0189] LCMS m / z (ESI) = 433.2 [M+1].

[0190] 1 HNMR(400MHz,DMSO-d6)δ8.19(d,1H),7.97(d,1H),7.87(td,1H),7.63(t,1 H),7.61–7.47(m,2H),7.35(t,1H),5.61(s,2H),3.99(s,3H),2.16(d,3H).

[0191] Example 9

[0192] 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0193] 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 9)

[0194]

[0195] first step:

[0196] 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0197] Methyl 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (9a)

[0198] In a 50 mL single-necked bottle, 1b (150 mg, 0.39 mmol) and ((3-chloro-5-(pyrrolidin-1-yl)phenyl)boronic acid (134 mg, 0.59 mmol) were dissolved in 3 mL of 1,4-dioxane and 0.5 mL of water. 1,1-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (29 mg, 0.04 mmol) and cesium carbonate (322 mg, 0.99 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 8 h. The reaction was monitored by TLC. The reaction solution was filtered and dried. The crude product was purified by silica gel column chromatography (PE:EA = 15:1-5:1) to obtain 9a as a white liquid (174 mg, yield: 91.6%).

[0199] LCMS m / z (ESI) = 482.2 [M+1].

[0200] Step 2:

[0201] 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0202] 3-((4-(3-chloro-5-(pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 9)

[0203] In a 50 mL single-necked vial, 9a (170 mg, 0.39 mmol) was dissolved in a mixture of ethanol (4 mL) and water (1 mL). Sodium hydroxide (23 mg, 0.58 mmol) was added and the mixture was allowed to react at 50°C for 2 h. The reaction was monitored by LCMS. The mixture was diluted with water, the ethanol was evaporated, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The product was extracted with EA, and most of the solvent was removed under reduced pressure. The mixture was then lyophilized to afford compound 9 as a white solid (73.26 mg, 43.3% yield).

[0204] LCMS m / z (ESI) = 468.2 [M+1].

[0205] 1HNMR(400MHz,DMSO-d6)δ8.36(d,1H),7.83(td,1H),7.54(td,1H),7.30(t,1H) ,6.62(d,1H),6.50(dt,2H),5.53(s,2H),3.26–3.20(m,4H),1.97–1.90(m,4H).

[0206] Example 10

[0207] 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 10)

[0208] 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0209]

[0210] first step:

[0211] Methyl 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (10c)

[0212] methyl 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fl uorobenzoate

[0213] In a 100 mL round-bottom flask, 1b (200 mg, 0.53 mmol), cesium carbonate (431.72 mg, 1.33 mmol), 2-chlorophenylboronic acid pinacol ester (107.74 mg, 0.69 mmol), and DPPF palladium dichloride (38.78 mg, 0.05 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 hours. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 10c as a colorless oil (190 mg, yield: 87.15%).

[0214] LC-MS m / z(ESI)=413.13[M+1].

[0215] Step 2:

[0216] 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 10)

[0217] 3-((4-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0218] In a 100 mL round-bottom flask, 10c (190 mg, 0.46 mmol) and sodium hydroxide (46.17 mg, 1.15 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 10 as a white solid (175 mg, 95.58% yield).

[0219] LC-MS m / z(ESI)=399.03[M+1].

[0220] 1 HNMR(DMSO-d6)δ13.34(s,1H),8.25(d,1H),7.86(td,1H),7.61–7.52(m,2H),7.47–7.37(m,3H),7.34(t,1H),5.60(s,2H).

[0221] 19 F NMR(DMSO-d6)δ-58.73,-115.73.

[0222] Example 11

[0223] 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 11)

[0224] 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0225]

[0226] first step:

[0227] Methyl 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (11c)

[0228] methyl 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fl uorobenzoate

[0229] In a 100 mL round-bottom flask, 1b (200 mg, 0.53 mmol), cesium carbonate (431.72 mg, 1.33 mmol), 3-chlorophenylboronic acid pinacol ester (107.74 mg, 0.69 mmol), and DPPF palladium dichloride (38.78 mg, 0.05 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 hours. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 11c as a colorless oil (200 mg, yield: 91.74%).

[0230] LC-MS m / z(ESI)=413.23[M+1].

[0231] Step 2:

[0232] 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 11)

[0233] 3-((4-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0234] In a 100 mL round-bottom flask, 11c (200 mg, 0.49 mmol) and sodium hydroxide (58.25 mg, 1.46 mmol) were dissolved in ethanol and water (6:1 mL) and the mixture was heated to reflux for 3 h. The reaction was complete as monitored by LCMS. The mixture was then concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 11 as a white solid (170 mg, 87.17% yield).

[0235] LC-MS m / z(ESI)=399.13[M+1].

[0236] 1 HNMR(DMSO-d6)δ13.35(s,1H),8.42(d,1H),7.87(td,1H),7.60(td,1H),7.51–7.42(m,3H),7.38(dt,1H),7.33(t,1H),5.56(s,2H).

[0237] 19 F NMR(377MHz,DMSO-d6)δ-57.91,-115.71.

[0238] Example 12

[0239] 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 12)

[0240] 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0241]

[0242] first step:

[0243] Methyl 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (12c)

[0244] methyl 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fl uorobenzoate

[0245] In a 100 mL round-bottom flask, 1b (200 mg, 0.53 mmol), cesium carbonate (431.72 mg, 1.33 mmol), 4-chlorophenylboronic acid pinacol ester (107.74 mg, 0.69 mmol), and DPPF palladium dichloride (38.78 mg, 0.05 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 hours. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 12c as a colorless oil (210 mg, yield: 96.33%).

[0246] LC-MS m / z(ESI)=413.23[M+1].

[0247] Step 2:

[0248] 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 12)

[0249] 3-((4-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluoroben zoic acid

[0250] In a 100 mL round-bottom flask, 12c (210 mg, 0.51 mmol) and sodium hydroxide (61.17 mg, 1.53 mmol) were dissolved in ethanol and water (7:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 12 as a white solid (190 mg, 94.06% yield).

[0251] LC-MS m / z(ESI)=399.03[M+1].

[0252] 1 HNMR(DMSO-d6)δ13.34(s,1H),8.36(d,1H),7.86(td,1H),7.59(td,1H),7.54–7.48(m,2H),7.46–7.40(m,2H),7.33(t,1H),5.56(s,2H).

[0253] 19 F NMR(DMSO-d6)δ-57.91,-115.72.

[0254] Example 13

[0255] 3-((4-Bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 13)

[0256] 3-((4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0257]

[0258] first step:

[0259] 3-((4-Bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 13)

[0260] 3-((4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0261] In a 100 mL round-bottom flask, 1b (80 mg, 0.21 mmol) and sodium hydroxide (21.15 mg, 0.53 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 13 as a white solid (30 mg, 39.24% yield).

[0262] LC-MS m / z(ESI)=366.95[M+1].

[0263] 1 HNMR(DMSO-d6)δ13.39(s,1H),8.40(d,1H),7.85(td,1H),7.54(td,1H),7.32(t,1H),5.53(s,2H).

[0264] 19 F NMR(DMSO-d6)δ-60.54,-115.78.

[0265] Example 14

[0266] 3-((4-Ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 14)

[0267] 3-((4-ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0268]

[0269]

[0270] first step:

[0271] Methyl 2-fluoro-3-((4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (14b)

[0272] methyl 2-fluoro-3-((4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0273] In a 100 mL round-bottom flask, 14a (100 mg, 0.61 mmol), cesium carbonate (496.88 mg, 1.53 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (150.56 mg, 0.61 mmol) were dissolved in acetonitrile (10 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 14b as a colorless oil (170 mg, 84.57% yield).

[0274] LC-MS m / z(ESI)=331.02[M+1].

[0275] Step 2:

[0276] Methyl 3-((4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (14c)

[0277] methyl 3-((4-ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenz oate

[0278] In a 100 mL round-bottom flask, 14b (280 mg, 0.85 mmol), potassium carbonate (293.25 mg, 2.13 mmol), and dimethyl (1-diazo-2-oxopropyl)phosphonate (211.75 mg, 1.1 mmol) were dissolved in methanol (10 mL) and allowed to react at room temperature for 4 h. The reaction was monitored by LCMS. The methanol was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 30:1) to afford 14c as a pale yellow solid (140 mg, 50.54%).

[0279] LC-MS m / z(ESI)=327.13[M+1].

[0280] Step 3:

[0281] 3-((4-Ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 14)

[0282] methyl 2-fluoro-3-((4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0283] In a 100 mL round-bottom flask, 14c (140 mg, 0.43 mmol) and sodium hydroxide (42.92 mg, 1.08 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 14 as a white solid (60 mg, 44.73% yield).

[0284] LC-MS m / z(ESI)=313.09[M+1].

[0285] 1 HNMR(400MHz,DMSO-d6)δ13.39(s,1H),8.46(d,1H),7.85(td,1H),7.53(td,1H),7.31(t,1H),5.53(s,2H),4.33(s,1H).

[0286] 19 F NMR(377MHz,DMSO-d6)δ-60.62,-115.83.

[0287] Example 15

[0288] 3-(3-Cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 15)

[0289] 3-((3-cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0290]

[0291] first step:

[0292] Methyl 3-((4-bromo-3-cyano-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (15b)

[0293] methyl 3-((4-bromo-3-cyano-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0294] In a 100 mL round-bottom flask, 15a (139.22 mg, 0.81 mmol), cesium carbonate (659.79 mg, 2.03 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (200 mg, 0.81 mmol) were dissolved in acetonitrile (10 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 15b as a white solid (140 mg, yield: 72.38%).

[0295] LC-MS m / z(ESI)=339.25[M+1].

[0296] Step 2:

[0297] Methyl 3-(3-cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (15c)

[0298] methyl 3-((3-cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0299] In a 100 mL round-bottom flask, 15b (140 mg, 0.42 mmol), cesium carbonate (342.11 mg, 1.05 mmol), phenylboronic acid (75.73 mg, 0.62 mmol), and DPPF palladium dichloride (30.71 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 15c as a colorless oil (126 mg, 89.46% yield).

[0300] LC-MS m / z(ESI)=336.13[M+1].

[0301] Step 3:

[0302] 3-(3-Cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 15)

[0303] 3-((3-cyano-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0304] In a 100 mL round-bottom flask, 15c (126 mg, 0.38 mmol) and sodium hydroxide (37.57 mg, 0.94 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 15 as a white solid (70 mg, 57.37% yield).

[0305] LC-MS m / z(ESI)=322.69[M+1].

[0306] 1 HNMR(400MHz,DMSO-d6)δ13.41(s,1H),8.58(s,1H),7.86(td,1H),7.68–7.64(m ,2H),7.60(td,1H),7.49(dd,2H),7.41–7.36(m,1H),7.32(t,1H),5.59(s,2H).

[0307] 19 F NMR(377MHz,DMSO-d6)δ-115.75.

[0308] Example 16

[0309] 2-Fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 16)

[0310] 2-fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0311]

[0312] first step:

[0313] Methyl 2-fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (16a)

[0314] methyl 2-fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate

[0315] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 3-methoxyphenylboronic acid (79.01 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated under reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 16a as a white solid (130 mg, yield: 84.58%).

[0316] LC-MS m / z(ESI)=395.53[M+1].

[0317] Step 2:

[0318] 2-Fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 16)

[0319] 2-fluoro-3-((4-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0320] In a 100 mL round-bottom flask, 16a (130 mg, 0.33 mmol) and sodium hydroxide (39.57 mg, 0.99 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 16 as a white solid (110 mg, 87.64% yield).

[0321] LC-MS m / z(ESI)=395.08[M+1].

[0322] 1 H NMR(DMSO-d6)δ13.38(s,1H),8.32(d,1H),7.86(td,1H),7.61–7.54(m,1H),7 .31(dt,3H),7.20–7.14(m,1H),7.12–7.05(m,2H),5.55(s,2H),3.33(s,3H).

[0323] Example 17

[0324] 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 17)

[0325] 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0326]

[0327] first step:

[0328] Methyl 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (17a)

[0329] Methyl 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0330] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 4-chloro-3-methylphenylboronic acid (88.61 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 17a as a white solid (136 mg, 81% yield).

[0331] LC-MS m / z(ESI)=427.91[M+1].

[0332] Step 2:

[0333] 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 17)

[0334] 3-((4-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0335] In a 100 mL round-bottom flask, 17a (136 mg, 0.32 mmol) and sodium hydroxide (38.24 mg, 0.96 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 17 as a white solid (85 mg, 64% yield).

[0336] LC-MS m / z(ESI)=413.77[M+1].

[0337] 1 HNMR(DMSO-d6)δ13.38(s,1H),8.34(d,1H),7.86(td,1H),7.58(td,1H),7.47(d,1H),7.40(d,1H),7.33(t,1H),7.24(dd,1H),5.56(s,2H).

[0338] 19 F NMR(377MHz,DMSO-d6)δ-57.87,-115.75.

[0339] Example 18

[0340] 2-Fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 18)

[0341] 2-fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0342]

[0343] first step:

[0344] Methyl 2-fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (18a)

[0345] Methyl 2-fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benz oate

[0346] In a 100 mL round-bottom flask, 1b (200 mg, 0.53 mmol), cesium carbonate (431.72 mg, 1.33 mmol), methylboronic acid (37.91 mg, 0.63 mmol), and DPPF palladium dichloride (38.74 mg, 0.05 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 18a as a white solid (140 mg, 83% yield).

[0347] LC-MS m / z(ESI)=317.56[M+1].

[0348] Step 2:

[0349] 2-Fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 18)

[0350] 2-fluoro-3-((4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0351] In a 100 mL round-bottom flask, 18a (140 mg, 0.44 mmol) and sodium hydroxide (53.12 mg, 1.33 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 18 as a white solid (30 mg, 23% yield).

[0352] LC-MS m / z(ESI)=317.56[M+1].

[0353] 1 HNMR(DMSO-d6)δ13.37(s,1H),7.88–7.79(m,2H),7.47(td,1.9Hz,1H),7.30(t,1H),5.45(s,2H),2.09(s,3H).

[0354] Example 19

[0355] 2-Fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 19)

[0356] 2-fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0357]

[0358] first step:

[0359] Methyl 3-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (19b)

[0360] Methyl 3-((5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0361] In a 100 mL round-bottom flask, 19a (870 mg, 4.05 mmol), cesium carbonate (3297 mg, 10.12 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (1000 mg, 4.05 mmol) were dissolved in acetonitrile (30 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 19b as a yellow solid (650 mg, 43% yield).

[0362] LC-MS m / z(ESI)=382.76[M+1].

[0363] Step 2:

[0364] Methyl 2-fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (19c)

[0365] Methyl 2-fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benz oate

[0366] In a 100 mL round-bottom flask, 19b (500 mg, 1.32 mmol), cesium carbonate (1072 mg, 3.3 mmol), phenylboronic acid (191.96 mg, 1.57 mmol), and DPPF palladium dichloride (96.58 mg, 0.13 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 19c as a yellow solid (120 mg, 46% yield).

[0367] LC-MS m / z(ESI)=379.13[M+1].

[0368] Step 3:

[0369] 2-Fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 19)

[0370] 2-fluoro-3-((5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0371] In a 100 mL round-bottom flask, 19c (120 mg, 0.32 mmol) and sodium hydroxide (38.09 mg, 0.95 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 19 as a white solid (95 mg, 81% yield).

[0372] LC-MS m / z(ESI)=365.78[M+1].

[0373] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.88-7.80(m,3H),7.53(s,1H),7.46–7.40(m,2H),7.36(ddt,2H),7.29(t,1H),5.62(s,2H).

[0374] 19 F NMR(377MHz,DMSO-d6)δ-58.40,-116.50.

[0375] Example 20

[0376] 2-Fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 20)

[0377] 2-fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0378]

[0379] first step:

[0380] Methyl 3-((3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (20b)

[0381] Methyl 3-((3-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0382] In a 100 mL round-bottom flask, 19a (870 mg, 4.05 mmol), cesium carbonate (3297 mg, 10.12 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (1000 mg, 4.05 mmol) were dissolved in acetonitrile (30 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 20b as a yellow solid (600 mg, 42% yield).

[0383] LC-MS m / z(ESI)=382.76[M+1].

[0384] Step 2:

[0385] Methyl 2-fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (20c)

[0386] Methyl 2-fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benz oate

[0387] In a 100 mL round-bottom flask, 20b (500 mg, 1.32 mmol), cesium carbonate (1072 mg, 3.3 mmol), phenylboronic acid (191.96 mg, 1.57 mmol), and DPPF palladium dichloride (96.58 mg, 0.13 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 20c as a yellow solid (327 mg, 65% yield).

[0388] LC-MS m / z(ESI)=379.13[M+1].

[0389] Step 3:

[0390] 2-Fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 20)

[0391] 2-fluoro-3-((3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0392] In a 100 mL round-bottom flask, 20c (120 mg, 0.32 mmol) and sodium hydroxide (38.09 mg, 0.95 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 20 as a white solid (186 mg, 59% yield).

[0393] 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),7.77(td,1H),7.55–7.46(m,5H),7.26–7.15(m,2H),6.97(s,1H),5.53(s,2H).

[0394] 19 F NMR(377MHz,DMSO-d6)δ-60.46,-116.08.

[0395] Example 21

[0396] 3-((4-(Benzothiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 21)

[0397] 3-((4-(benzo[b]thiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-flu orobenzoic acid

[0398]

[0399]

[0400] first step:

[0401] Methyl 3-((4-(Benzothiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (21a)

[0402] Methyl 3-((4-(benzo[b]thiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)meth yl)-2-fluorobenzoate

[0403] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135.28 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was refluxed under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 10:1) to afford 21a as a pale yellow solid (126 mg, 74% yield).

[0404] LC-MS m / z(ESI)=435.31[M+1].

[0405] Step 2:

[0406] 3-((4-(Benzothiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 21)

[0407] 3-((4-(benzo[b]thiophen-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-flu orobenzoic acid

[0408] In a 100 mL round-bottom flask, 21a (126 mg, 0.32 mmol) and sodium hydroxide (34.81 mg, 0.87 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 21 as a white solid (82 mg, 67% yield).

[0409] LC-MS m / z(ESI)=421.11[M+1].

[0410] 1 H NMR(DMSO-d6)δ13.39(s,1H),8.37(d,1H),8.07(d,1H),7.91(d,1H),7.87(td,1H) ,7.82(d,1H),7.61(td,1H),7.50(dd,1H),7.39(dd,1H),7.34(t,1H),5.58(s,2H).

[0411] 19 F NMR(377MHz,DMSO-d6)δ-57.73,-115.76.

[0412] Example 22

[0413] 2-Fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 22)

[0414] 2-fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0415]

[0416] first step:

[0417] Methyl 2-fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoate (22a)

[0418] Methyl 2-fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyraz ol-1-yl)methyl)benzoate

[0419] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thieno[2,3-b]pyridine (135.86 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was refluxed under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 10:1) to afford 22a as a pale yellow solid (130 mg, 76% yield).

[0420] LC-MS m / z(ESI)=436.67[M+1].

[0421] Step 2:

[0422] 2-Fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 22)

[0423] 2-fluoro-3-((4-(thieno[2,3-b]pyridin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzoic acid

[0424] In a 100 mL round-bottom flask, 22a (130 mg, 0.3 mmol) and sodium hydroxide (35.83 mg, 0.9 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was then concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 22 as a white solid (130 mg, 67% yield).

[0425] LC-MS m / z(ESI)=422.11[M+1].

[0426] 1 H NMR(400MHz,DMSO-d6)δ13.39(s,1H),8.59(d,1H),8.47(d,1H),8.29(d,1H),7 .96(d,1H),7.87(td,1H),7.63(td,1H),7.51(d,1H),7.35(t,1H),5.61(s,2H).

[0427] 19F NMR(377MHz,DMSO-d6)δ-57.80,-115.68.

[0428] Example 23

[0429] 3-((4-(5-chlorothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 23)

[0430] 3-((4-(5-chlorothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-flu orobenzoic acid

[0431]

[0432] first step:

[0433] Methyl 3-((4-(5-chlorothien-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (23a)

[0434] Methyl 3-((4-(5-chlorothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0435] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 5-chlorothiophene-2-boronic acid pinacol ester (126.05 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated under reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 23a as a yellow oil (160 mg, 98% yield).

[0436] LC-MS m / z(ESI)=419.22[M+1].

[0437] Step 2:

[0438] 3-((4-(5-chlorothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 23)

[0439] 3-((4-(5-chlorothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-flu orobenzoic acid

[0440] In a 100 mL round-bottom flask, 23a (160 mg, 0.38 mmol) and sodium hydroxide (38.21 mg, 0.96 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 23 as a white solid (104 mg, 65% yield).

[0441] LC-MS m / z(ESI)=405.11[M+1].

[0442] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,1H),7.85(td,1H),7.57(td,1H),7.32(t,1H),7.15(d,1H),7.03(d,1H),5.54(s,2H).

[0443] 19 F NMR(377MHz,DMSO-d6)δ-58.84,-115.80.

[0444] Example 24

[0445] 3-((4-(5-Carbamoylthiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 24)

[0446] 3-((4-(5-carbamoylthiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0447]

[0448]

[0449] first step:

[0450] Methyl 3-((4-(5-cyanothiophene-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (24a)

[0451] methyl 3-((4-(5-cyanothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methy l)-2-fluorobenzoate

[0452] In a 100 mL round-bottom flask, 1b (150 mg, 0.39 mmol), cesium carbonate (317.67 mg, 0.98 mmol), 5-cyanothiophene-2-boronic acid pinacol ester (122.25 mg, 0.52 mmol), and DPPF palladium dichloride (28.51 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 24a as a yellow oil (135 mg, yield: 84.56%).

[0453] LC-MS m / z(ESI)=410.22[M+1].

[0454] Step 2:

[0455] 3-((4-(5-Carbamoylthiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 24)

[0456] 3-((4-(5-carbamoylthiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0457] In a 100 mL round-bottom flask, 24a (135 mg, 0.33 mmol) and sodium hydroxide (32.98 mg, 0.83 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 24 as a white solid (20 mg, 14% yield).

[0458] LC-MS m / z(ESI)=414.55[M+1].

[0459] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.07(s,1H),7.73(d,1H),7.69(td,1H),7.46(s,1H),7.36–7.28(m,1H),7.18–7.11(m,2H),5.49(s,2H).

[0460] 19 F NMR(377MHz,DMSO-d6)δ-58.83,-118.74.

[0461] Example 25

[0462] 3-((3-(Difluoromethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 25)

[0463] 3-((3-(difluoromethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0464]

[0465] first step:

[0466] Methyl 3-((4-bromo-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (25b)

[0467] Methyl 3-((4-bromo-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0468] In a 100 mL round-bottom flask, 25a (250 mg, 1.27 mmol), cesium carbonate (1030 mg, 3.18 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (313.56 mg, 1.27 mmol) were dissolved in acetonitrile (10 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 25b as a colorless liquid (356 mg, 77% yield).

[0469] LC-MS m / z(ESI)=364.23[M+1].

[0470] Step 2:

[0471] Methyl 3-((4-bromo-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (25c)

[0472] Methyl 3-((3-(difluoromethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0473] In a 100 mL round-bottom flask, 25b (150 mg, 0.26 mmol), cesium carbonate (333.97 mg, 1.03 mmol), phenylboronic acid (75.55 mg, 0.62 mmol), and DPPF palladium dichloride (29.97 mg, 0.04 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 25c as a colorless oil (110 mg, 74% yield).

[0474] LC-MS m / z(ESI)=361.13[M+1].

[0475] Step 3:

[0476] 3-((3-(Difluoromethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid (Compound 25)

[0477] 3-((3-(difluoromethyl)-4-phenyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid

[0478] In a 100 mL round-bottom flask, 25c (110 mg, 0.31 mmol) and sodium hydroxide (30.56 mg, 0.76 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 25 as a white solid (50 mg, 46% yield).

[0479] LC-MS m / z(ESI)=347.25[M+1].

[0480] 1 HNMR(400MHz,DMSO-d6)δ8.26(s,1H),7.62(td,1H),7.53–7.48(m,2H),7.40(d d,2H),7.34–7.27(m,1H),7.25(td,1H),7.10(t,1H),7.06(s,1H),5.44(s,2H).

[0481] 19 F NMR(377MHz,DMSO-d6)δ-109.76,-119.22.

[0482] Example 26

[0483] 2-Fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 26)

[0484] 2-fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoic acid

[0485]

[0486] first step:

[0487] Methyl 3-((4-bromo-3-isopropyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate (26b)

[0488] Methyl 3-((4-bromo-3-isopropyl-1H-pyrazol-1-yl)methyl)-2-fluorobenzoate

[0489] In a 100 mL round-bottom flask, 26a (300 mg, 1.58 mmol), cesium carbonate (1292.52 mg, 3.96 mmol), and methyl 3-(bromomethyl)-2-fluorobenzoate (390.35 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL) and refluxed for 3 h. The reaction was monitored for completion by TLC. The acetonitrile was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 20:1) to afford 26b as a colorless liquid (402 mg, 71% yield).

[0490] LC-MS m / z(ESI)=356.31[M+1].

[0491] Step 2:

[0492] Methyl 2-fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoate (26c)

[0493] Methyl 2-fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoate

[0494] In a 100 mL round-bottom flask, 26b (100 mg, 0.28 mmol), cesium carbonate (229.29 mg, 0.71 mmol), phenylboronic acid (37.78 mg, 0.31 mmol), and DPPF palladium dichloride (14.98 mg, 0.02 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to reflux under nitrogen for 8 h. After completion of the reaction, 1,4-dioxane was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA = 10:1) to afford 26c as a colorless oil (87 mg, 88% yield).

[0495] LC-MS m / z(ESI)=353.53[M+1].

[0496] Step 3:

[0497] 2-Fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoic acid (Compound 26)

[0498] 2-fluoro-3-((3-isopropyl-4-phenyl-1H-pyrazol-1-yl)methyl)benzoic acid

[0499] In a 100 mL round-bottom flask, 26c (87 mg, 0.24 mmol) and sodium hydroxide (24.69 mg, 0.62 mmol) were dissolved in ethanol and water (6:1 mL) and refluxed for 3 h. The reaction was complete as monitored by LCMS. The mixture was concentrated under reduced pressure and the pH was adjusted to acidic with 6N dilute hydrochloric acid. The precipitated solid was filtered and the filter cake was collected to afford compound 26 as a white solid (73 mg, 90% yield).

[0500] LC-MS m / z(ESI)=339.58[M+1].

[0501] Biological test cases

[0502] 1. MRGPRX4 Activity Detection

[0503] HEK-293 cells stably expressing MRGPRX4 were cultured in DMEM medium containing 10% FBS and 1% double-antibody at 37°C and 5% CO2. Cells in the exponential growth phase were collected and seeded in 384-well plates at a seeding density of 2×10 410 μL per well. Add 2 μL of the graded diluted compound to each well and incubate with the cells for 45 minutes. After the incubation, add 2 μL of deoxycholic acid (MCE, Cat: #HY-N0593) to each well and continue incubating for 45 minutes. After the incubation, use the IP-one Gq kit (PE, Cat: #62IPAPEB) according to the instructions for IP1 content detection. Substitute the HTRF value into GraphPad 8.0 to calculate the fitted IC 50 .

[0504] Table 1 MRGPRX4 activity test results of compounds

[0505] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound 1 A Compound 14 B Compound 3 B Compound 16 A Compound 6 B Compound 17 A Compound 7 A Compound 19 B Compound 9 A Compound 21 A Compound 11 B Compound 22 A Compound 12 B Compound 23 A Compound 13 B Compound 24 A

[0506] Note: A≤3μM, 3μM<B≤10μM.

[0507] Conclusion: The above compounds have a good antagonistic effect on MRGPRX4.

[0508] 2. Pharmacokinetic Studies in Mice

[0509] 2.1 Experimental Animals

[0510] Species: ICR mice, SPF. Source: Chengdu Dashuo Laboratory Animal Co., Ltd. Number of animals required: 18 male mice. Animal selection: No randomization was performed.

[0511] 2.2 Experimental plan:

[0512] Eighteen ICR male mice were fasted overnight (with free access to water) and divided into an intravenous (iv) administration group (nine mice) and an oral (ig) administration group (nine mice). Blood (0.1 mL) was collected from the jugular venous plexus at 0, 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration (three animals at each time point). Plasma was isolated by centrifugation at 4°C for 5 minutes after anticoagulation with EDTA-K2 and stored at -80°C until assayed. Unchanged drug concentrations in plasma were determined by LC / MS / MS.

[0513] 2.3 Drug configuration:

[0514] The test drug was weighed into a 5 mL centrifuge tube, and 5% dimethyl sulfoxide and 95% 30% HP-β-CD were added in sequence. After addition, the mixture was sonicated and vortexed to obtain a transparent clear solution (iv administration concentration: 0.1 mg / mL, ig administration concentration: 1 mg / mL).

[0515] 2.4 Preparation of standard curve:

[0516] Take 25 μL of blank mouse plasma, add 25 μL of the prepared standard solution, 25 μL of internal standard, and 225 μL of methanol, vortex mix for 2 minutes, centrifuge at 3200 rpm at 4°C for 20 minutes, and take the supernatant for LC-MS / MS analysis.

[0517] 2.5 Blood sample collection:

[0518] Blood was collected from the submandibular vein or other suitable veins at the time of blood collection. About 0.03 mL of blood was collected for each sample. The collected samples were anticoagulated with sodium heparin and placed on ice for future use.

[0519] 2.6 Plasma sample processing:

[0520] Blood samples must be centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Plasma samples must be stored in a -80°C freezer before analysis.

[0521] 2.7 Plasma sample analysis:

[0522] Take 25 μL of mouse plasma, 25 μL of internal standard, and 250 μL of methanol, vortex mix for 2 min, centrifuge at 3200 rpm at 4°C for 20 min, and take the supernatant for LC-MS / MS analysis.

[0523] 2.8 Data Processing:

[0524] Detect the blood concentration of the test substance and draw the plasma drug concentration-time curve. When drawing the drug-time curve and calculating the parameters (may appear in C max Before and after), BLQ (including "No peak") was calculated as 0. The pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on the blood drug concentration data at different time points, such as peak drug concentration (C max ), area under the curve (AUC 0-t ), half-life (T 1 / 2 ), oral bioavailability (F%), apparent clearance (CL) and steady-state distribution volume (Vss), etc.

[0525] The compound of the present invention has good pharmacokinetic characteristics in mice.

[0526] 3. Pharmacokinetic study in rats

[0527] Healthy adult SD rats weighing 180-220g were fasted overnight (with free access to water) and divided into tail vein and oral administration groups. For the tail vein administration group, 0.1mL of blood was collected from the orbital venous plexus before and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. Plasma was separated by centrifugation at 4°C for 5 minutes and stored at -20°C for testing. For the oral administration group, 0.1mL of blood was collected from the orbital venous plexus before and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. The blood was processed in the same manner as the intravenous administration group. Plasma unchanged drug concentration was determined by LC-MS / MS.

[0528] Conclusion: The test compounds have good exposure levels in mice.

[0529] 4. Construction of Humanized MRGPRX4 Mice

[0530] CRISPR / Cas9 technology was used to create ROSA26CAG-loxp-STOP-loxP-hMRGPRX4 CDS-P2A-EGFP-WPRE-PA knock-in mice and Mrgpra3 iCre-P2A-tdtomato WPRE-PA knock-in mice, respectively. The two transgenic mouse strains were mated to obtain transgenic mice that specifically express hMRGPRX4, providing an animal model for studying the function of hMRGPRX4 and screening anti-itch drugs targeting hMRGPRX4.

[0531] Conclusion: The test compound can significantly inhibit the number of scratching in mice.

[0532] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound represented by formula (I), or a stereoisomer, deuterated form, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof: Ring A is selected from a 6-8 membered aryl group or a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; X1 is selected from C 1-6 Alkylene or -C(O)-; the C 1-6 The alkylene group is optionally further substituted with C 1-6 Substitution of alkyl groups; A1 and A2 are each independently selected from C or N; R1 is independently selected from halogen, cyano, carboxyl, -C(O)NH2, C 1-6 Haloalkyl, 5-membered heterocyclic group; the 5-membered heterocyclic group contains 3 to 4 heteroatoms selected from N or O, and the 5-membered heterocyclic group is optionally further substituted by a substituent of =O; R2 are each independently selected from halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl or 5-12 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-8 membered aryl or 5-12 membered heteroaryl are optionally further substituted with C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocycloalkyl, C 2-6 Alkynyl, -C(O)NH2, cyano, halogen substitution; m and n are each independently selected from 0, 1, 2, 3, and 4.

2. The compound according to claim 1, or a stereoisomer, deuterated form, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof, wherein: Ring A is selected from a 6-membered aryl group or a 5-6-membered heteroaryl group; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; X1 is selected from C 1-4 Alkylene; the C 1-4 The alkylene group is optionally further substituted with C 1-4 Substitution of alkyl groups; A1 and A2 are both selected from N; R1 is independently selected from halogen, cyano, carboxyl, -C(O)NH2, C 1-4 alkyl halide; R2 are each independently selected from halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 6-8 membered aryl, 5-12 membered heteroaryl or 3-6 membered heterocycloalkyl; the C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 A haloalkyl group, a 3-6 membered cycloalkyl group, a 6-8 membered aryl group, a 5-12 membered heteroaryl group or a 3-6 membered heterocycloalkyl group is optionally further substituted with a C 1-4 Alkyl, C 1-4 Alkoxy, cyano, halogen, 4-6 membered heterocycloalkyl, -C(O)NH2 substituents; m is selected from 1, 2, 3, and 4; n is independently selected from 0, 1, 2, 3, and 4.

3. The compound according to claim 4, or a stereoisomer, deuterated form, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof, wherein: Ring A is selected from a 6-membered aryl group; X1 is selected from C 1-4 Alkylene; the C 1-4 The alkylene group is optionally further substituted with C 1-4 Substitution of alkyl groups; A1 and A2 are both selected from N; R1 are each independently selected from halogen, carboxyl; R2 are each independently selected from halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, 6-8 membered aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered condensed ring heteroaryl; the C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 A haloalkyl group, a 6-8 membered aryl group, a 5-6 membered monocyclic heteroaryl group or an 8-10 membered fused ring heteroaryl group is optionally further substituted with C 1-4 Alkyl, C 1-4 Alkoxy, cyano, halogen, 4-6 membered heterocycloalkyl, -C(O)NH2 substituents; m is selected from 1, 2, 3, and 4; n is independently selected from 0, 1, 2, 3, and 4.

4. The compound according to claim 3, or a stereoisomer, deuterated form, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof, wherein the compound is selected from the following structures:

5. A pharmaceutical composition comprising: The compound according to any one of claims 1 to 4, or a stereoisomer, deuterated form, pharmaceutically acceptable salt, solvate, prodrug, metabolite or cocrystal thereof; One or more pharmaceutically acceptable carriers and / or excipients.

6. Use of the pharmaceutical composition of claim 5 or the compound of any one of claims 1 to 4, or its stereoisomers, deuterated substances, pharmaceutically acceptable salts, solvates, prodrugs, metabolites or cocrystals in a medicament for treating MRGPRX4-dependent disorders.

7. The use according to claim 6, wherein the MRGPRX4-dependent disorder is an itch-related disorder, a pain-related disorder or an autoimmune disorder.

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