Synthesis of Novel EP4 Antagonists and Their Use in Cancer and Inflammation

Abstract

The present invention provides a novel compound that effectively antagonizes EP4, which is a compound represented by Formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula I: wherein: R 1 is selected from -CH3, -CHF2 and -CF3; R 2 is selected from C2-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkyl substituted by halogen, C3-C6 cycloalkyl substituted by halogen; R 3 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 alkyl substituted by fluorine; R 4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by halogen, C1-C6 alkoxy substituted by halogen.

Description

Technical Field

[0001] The present invention relates to the fields of chemistry and medicine. Specifically, the present invention relates to pyrazole derivatives and their uses. Background Art

[0002] Prostaglandin E2 (PGE2) is an endogenous bioactive lipid. PGE2 elicits a wide range of upstream and downstream-dependent biological responses by activating prostaglandin receptors (Legler, D.F. et al, Histol. J. Biochem. Cell Biol. 2010, 42, p. 198-201), and is involved in regulating many physiological and pathological processes including inflammation, pain, renal function, cardiovascular system, lung function, and cancer. It has been reported that PGE2 is highly expressed in cancerous tissues of various cancers, and it has been confirmed that PGE2 is associated with the occurrence, growth, and development of a patient's cancer and disease conditions. It is generally believed that PGE2 is associated with the activation of cell proliferation and cell death (apoptosis), and plays an important role in the processes of cancer cell proliferation, disease progression, and cancer metastasis.

[0003] Among the receptors of PGE2, there are four subtypes of EP1, EP2, EP3, and EP4, which are widely distributed in various tissues. Among these subtypes, PGE2 intervenes in inflammatory responses (including immune inflammatory responses), relaxation of smooth muscle, pain induction, lymphocyte differentiation, hypertrophy or proliferation of mesangial cells, secretion of gastrointestinal mucus, etc. via the EP4 receptor. Therefore, it can be considered that EP4 receptor antagonists have the potential to be used as anti-inflammatory and / or analgesic drugs for treating diseases related to the PGE2-EP4 pathway, such as inflammatory diseases, diseases accompanied by various pains, etc.

[0004] EP4 is the main receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis (see, e.g., J. Pharmacol. Exp. Ther., 325, 425 (2008)), and its activation leads to the accumulation of the intracellular signaling molecule cAMP. Studies have detected the expression of the EP4 receptor on the peripheral nerve endings of nociceptors, macrophages, and neutrophils, and these cell types have been confirmed to be extremely important for endometriosis. It has been reported that oral administration of an EP4 antagonist can reduce proteinuria in type 2 diabetic mice and inhibit the progression of diabetic nephropathy. Another study reported that the activation of EP4 and the increased production of PGE2 in the bladder mucosa may be an important cause of bladder overactivity caused by prostatitis, and intravesical injection of an EP4 antagonist can effectively improve bladder overactivity after prostatitis. Therefore, selective EP4 antagonists can be used to treat arthritis, including arthritic pain, as well as endometriosis, diabetic nephropathy, and overactive bladder. Current arthritis medications are mainly traditional NSAIDs (non-steroidal anti-inflammatory drugs) or selective COX-2 inhibitors, which can produce cardiovascular and / or gastrointestinal side effects. Selective EP4 antagonists are less likely to produce cardiovascular side effects.

[0005] PGE2 continuously activates EP receptors in the tumor microenvironment (produced in large amounts by tumor cells) (Ochs et al, J Neurochem. 2016, 136, p. 1142-1154; Zelenay, S. et al, Cell 2015, 162, p. 1257-1270), which promotes the accumulation and enhances the activity of various immunosuppressive cells, including type 2 tumor-associated macrophages (TAMS), Treg cells, and myeloid-derived suppressor cells (MDSCs). One of the main features of the immunosuppressive tumor microenvironment is the presence of large numbers of MDSCs and TAM, which in turn are closely associated with a low overall survival rate in patients with gastric cancer, ovarian cancer, breast cancer, bladder cancer, hepatocellular carcinoma (HCC), head and neck cancer, and other types of cancer. In addition, PGE2 has been reported to induce immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DC) in tumors and inhibiting the activation of tumor-infiltrating DC (Wang et al, Trends in Molecular Medicine 2016, 22, p. 1-3). All these PGE2-mediated effects will jointly help tumor cells evade immune surveillance. PGE2 plays a very important role in promoting tumorigenesis and development. Elevated expression levels of PGE2 and its related receptors EP2 and EP4 have been found in various malignant tumors, including colon cancer, lung cancer, breast cancer, and head and neck cancer, and are often closely associated with poor prognosis (Bhooshan, N. et al. Lung Cancer 101, 88-91). Therefore, selective blockade of the EP2 and EP4 signaling pathways can inhibit tumorigenesis and development by altering the tumor microenvironment and regulating tumor immune cells.

[0006] Existing preclinical research data show that EP2 and EP4 specific antagonists can prevent or inhibit tumor growth to varying degrees in animal models of colon cancer, esophageal cancer, lung cancer, breast cancer, etc. Among the PGE2 receptor drugs entering clinical trials, the EP4 antagonist Grapiprant developed by Pfizer has been approved by the FDA for the treatment of arthritis in dogs and entered the anti-tumor clinical phase II study in 2015 for the treatment of various types of solid tumors such as prostate cancer, non-small cell lung cancer, and breast cancer (De Vito, V. et al. J Pharm Biomed Anal 118, 251-258). The EP4 antagonist E7046 developed by Eisai also started related clinical phase I research in 2015 and carried out a phase Ib clinical trial of combined radiotherapy or chemoradiotherapy for the treatment of rectal cancer in 2017. ONO-4578 developed by Ono Pharmaceutical carried out a clinical phase I study of advanced or metastatic solid tumors in 2017 and a phase I / II clinical trial of single-agent or combined with nivolumab for the treatment of advanced solid tumors in 2018.

[0007] At present, certain progress has been made in the treatment of EP4 antagonists in the fields of inflammatory diseases, pain, cancer, etc., but there is still a need to further develop new drugs to improve or replace the current drugs. Summary of the Invention

[0008] The present invention aims to provide a compound that can effectively antagonize EP4, which can be used as an improvement or replacement for current drugs or EP4 antagonists.

[0009] To this end, in the first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula V or a tautomer, stereoisomer, hydrate, solvate, salt or prodrug of the compound represented by formula V:

[0010]

[0011] Wherein, ring A is selected from

[0012] Ring B is selected from

[0013] R 1 is selected from -CH3, -CHF2 and -CF3;

[0014] R 2 is selected from C2-C6 alkyl, C3-C6 cycloalkyl, phenyl, trifluoromethyl, C2-C6 alkyl substituted by halogen, C3-C6 cycloalkyl substituted by halogen, C2-C6 alkyl substituted by hydroxyl, C2-C6 alkyl substituted by cyano, -SF5, -X-R 2a; wherein X is selected from oxygen, sulfur, -CO-, -SO2-, -SO-; R 2a is selected from C1-C6 alkyl, C1-C6 alkyl substituted by halogen;

[0015] R 3 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 alkyl substituted by fluorine, phenyl;

[0016] R 4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by halogen, C1-C6 alkoxy substituted by halogen;

[0017] R 5 is selected from hydrogen, halogen;

[0018] R 6a and R 6b one of them is hydrogen and the other is methyl; or R 6a and R 6b together form a cyclobutyl ring;

[0019] R 7 is selected from -CH3, -CHF2 and -CF3;

[0020] M is selected from oxygen, sulfur, methylene;

[0021] provided that when R 2 is trifluoromethyl, M is oxygen, R 6a and R 6b one of them is hydrogen and the other is methyl, ring A is selected from when R 2 is trifluoromethyl, M is oxygen, and ring A is then R 6a and R 6b together form a cyclobutyl ring.

[0022] According to an embodiment of the present invention, the above compound may further include at least one of the following additional technical features:

[0023] According to an embodiment of the present invention, the above compound is a compound represented by formula III or a tautomer, stereoisomer, hydrate, solvate, salt or prodrug of the compound represented by formula III:

[0024]

[0025] wherein, R 1 is selected from -CH3, -CHF2 and -CF3; R 7 is selected from -CH3, -CHF2 and -CF3; M is selected from oxygen, sulfur, methylene.

[0026] According to an embodiment of the present invention, the compound is a compound represented by Formula II or a tautomer, stereoisomer, hydrate, solvate, salt or prodrug of the compound represented by Formula II,

[0027]

[0028] wherein, R 1 is selected from -CH3, -CHF2 and -CF3; preferably, R 1 is -CHF2; R 2 is selected from ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluoroethyl, fluoropropyl, fluoroisopropyl, fluorobutyl, fluoroisobutyl, hydroxyethyl, hydroxyisopropyl, cyanomethyl, cyanoethyl, phenyl, -SF5, -X-R 2a ; wherein X is selected from oxygen, sulfur, -CO-; R 2a is selected from methyl, ethyl, fluoromethyl, fluoroethyl; R 3 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, fluoromethyl, fluoroethyl, phenyl; R 4 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, fluoromethyl, fluoroethyl; R 5 is selected from hydrogen, fluorine, chlorine; M is selected from oxygen, sulfur, methylene.

[0029] According to an embodiment of the present invention, the compound is a compound represented by Formula I (the compound represented by Formula I is also referred to as Compound I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0030]

[0031] wherein,

[0032] R 1 is selected from -CH3, -CHF2 and -CF3; R 2 is selected from C2-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkyl substituted by halogen, C3-C6 cycloalkyl substituted by halogen; R 3 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 alkyl substituted by fluorine; R 4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by halogen, C1-C6 alkoxy substituted by halogen.

[0033] According to an embodiment of the present invention, the above compound may further include at least one of the following additional technical features:

[0034] According to an embodiment of the present invention, R 2Selected from C2-C3 alkyl, C3-C6 cycloalkyl, fluorine-substituted C2-C3 alkyl, and fluorine-substituted C3-C6 cycloalkyl.

[0035] According to an embodiment of the present invention, preferably, R 2 Selected from -CH2CH3, -CH(CH3)2, cyclopropyl, -CF2CH3, and -CH2CF3.

[0036] According to an embodiment of the present invention, R 3 Selected from hydrogen, fluorine, and chlorine.

[0037] According to an embodiment of the present invention, R 4 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, and halogen-substituted C1-C6 alkoxy.

[0038] According to certain embodiments of the present invention, R 4 Selected from hydrogen, fluorine, chlorine, C1-C4 alkyl, C1-C4 alkoxy, fluorine- or chlorine-substituted C1-C4 alkyl, and fluorine- or chlorine-substituted C1-C4 alkoxy; preferably, R 4 Selected from hydrogen, fluorine, and chlorine.

[0039] According to an embodiment of the present invention, the compound is one of the following compounds or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of one of the following compounds:

[0040]

[0041]

[0042]

[0043]

[0044] According to an embodiment of the present invention, the salt includes a pharmaceutically acceptable salt, selected from at least one of the following: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid. Those skilled in the art can understand that, in addition to pharmaceutically acceptable salts, other salt types can also be used in the present invention, which can be used as intermediates in compound purification or in the preparation of other pharmaceutically acceptable salts, or can be used for the identification, characterization or purification of the compounds of the present invention.

[0045] In a second aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: a pharmaceutically acceptable excipient and the aforementioned compound.

[0046] In a third aspect of the present invention, the present invention provides the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a drug for treating or preventing EP4-related diseases.

[0047] According to an embodiment of the present invention, the use may further include at least one of the following additional technical features:

[0048] According to an embodiment of the present invention, the EP4-related diseases include at least one selected from the following: inflammatory diseases, pain, cancer, metabolic diseases, urinary system diseases.

[0049] According to an embodiment of the present invention, the inflammatory diseases include at least one selected from the following: arthritis, rheumatoid arthritis.

[0050] According to an embodiment of the present invention, the pain includes osteoarthritis pain, pain caused by endometriosis.

[0051] According to an embodiment of the present invention, the compound or the aforementioned pharmaceutical composition can be administered in combination with radiotherapy and / or antibody therapy, wherein the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.

[0052] According to an embodiment of the present invention, the cancer includes solid cancer.

[0053] According to embodiments of the present invention, the cancers include breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, and urinary tract cancer.

[0054] According to embodiments of the present invention, the metabolic diseases include diabetes, and the urinary system diseases include overactive bladder.

[0055] According to embodiments of the present invention, the use of the compounds or pharmaceutical compositions of the present invention can provide better and more effective clinical therapeutic drugs or regimens for patients in need. According to embodiments of the present invention, the present invention provides a series of EP4 antagonists with novel structures, better pharmacokinetic properties, better efficacy, and good drug-likeness, which can effectively treat EP4-related diseases or disorders.

[0056] The present invention also relates to a method for treating diseases related to EP4, which method comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0057] Term Definitions and Explanations

[0058] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of the present application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination shall fall within the scope described in the specification of the present application.

[0059] Unless otherwise defined, all scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise specified, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions for a term herein, the definition in this chapter shall prevail.

[0060] Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy, and pharmacological methods. Unless otherwise specifically defined, the terms employed herein in connection with descriptions of analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation, and delivery, as well as in the treatment of patients. For example, the instructions provided by the manufacturer for the kits can be utilized, or reactions and purifications can be carried out in a manner known in the art or as described in the present application. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in accordance with conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also equally includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0061] For numerical ranges recited in the specification and claims of the present application, when the numerical range is understood as "integers", it should be understood that both endpoints of the range and each integer within the range are recited. For example, "integers from 1 to 6" should be understood as reciting each of the integers 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as "numbers", it should be understood that both endpoints of the range and each integer within the range and each decimal within the range are recited. For example, "numbers from 1 to 10" should be understood as not only reciting each of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers respectively with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

[0062] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0063] The term "pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.

[0064] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization, or purification of the compounds of the present invention.

[0065] The term "stereoisomer" refers to isomers that result from different spatial arrangements of atoms in a molecule. The stereochemical definitions and conventions used in this invention generally follow those defined in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds of this invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0066] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and a mixture of such isomers is commonly called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such a racemic mixture or racemate can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0067] Depending on the choice of starting materials and methods, the compounds of this invention may exist in the form of one or a mixture of the possible isomers, e.g., as pure enantiomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral auxiliaries, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be of the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents on the cycloalkyl may be of the cis- or trans- configuration.

[0068] When depicting the bonds to the chiral carbon in the formula of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and both the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of this general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. Unless otherwise indicated, wedge and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0069] The compounds of the present invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. The resolution of the racemic mixtures of the compounds can be carried out by any one of a number of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional crystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methyl-benzylamine (e.g., the S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl-phenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be employed. The choice of the specific method as well as the elution conditions and the choice of the column can be made by those skilled in the art according to the structure of the compound and the test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can be obtained by stereoselective organic synthesis using optically pure starting materials or reagents of known configuration.

[0070] Many geometric isomers of alkenes, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain an alkene double bond, unless otherwise indicated, such double bonds include the E and Z geometric isomers.

[0071] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound may exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are identical to those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0072] The term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0073] The term "solvate" refers to a stoichiometric or non-stoichiometric amount of a solvent, including water when the solvent is water, that is bound to a compound of the present invention or its salt by intermolecular non-covalent forces.

[0074] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a bioactive compound of the present invention. Prodrugs of the present invention are prepared by modifying a functional group in the compound, and such modification can be carried out by conventional procedures or removed in vivo to yield the parent compound. Prodrugs include compounds formed by attaching a hydroxyl or amino group in the compound of the present invention to any group, and when a prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0075] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms that make up the compound. For example, a compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0076] The term "adjuvant" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents, etc.

[0077] The term "C1-C6 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of said alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, said group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

[0078] The term "C3-C6 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0079] The term "C1-C6 alkoxy" should be understood as -O-(C 1-6 alkyl), where "C 1-6 alkyl" has the above definition.

[0080] The term "halo group" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0081] "Haloalkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group including having a specific number of carbon atoms and being substituted by one or more halogens (such as -CvFw, where v = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl.

[0082] Advantages

[0083] According to an embodiment of the present invention, the compounds and / or their compositions of the present invention can effectively antagonize EP4 receptor activity, have more excellent hepatic metabolic stability and cardiac safety advantages, have better pharmacokinetic properties, have a higher in vivo exposure, a low dosage and better compliance. It has broad application prospects in the preparation of drugs for treating EP4-related diseases.

[0084] Additional aspects and advantages of the present invention will be given in part in the following description, will become apparent in part from the following description, or will be learned through the practice of the present invention. Brief Description of the Drawings

[0085] Figure 1Inhibitory results of the compounds according to the embodiments of the present invention on tumors. Detailed implementation manners

[0086] The solutions of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the embodiments regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. For reagents or instruments whose manufacturers are not indicated, they are all conventional products that can be obtained through commercial purchases.

[0087] Unless otherwise specified, the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0088] The abbreviations of the present invention are defined as follows:

[0089] BAST: Bis(2-methoxyethyl)aminosulfur trifluoride

[0090] m-CPBA: m-Chloroperbenzoic acid

[0091] L-selectride: Lithium tri-sec-butylborohydride

[0092] Pd(dppf)Cl2: 1,1-Bis(diphenylphosphino)ferrocene palladium dichloride

[0093] DCM: Dichloromethane

[0094] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0095] DIPEA: Diisopropylethylamine, namely N,N-Diisopropylethylamine

[0096] DMF: N,N-Dimethylformamide

[0097] N: Normal concentration. For example, 1N hydrochloric acid represents a 1 mol / L hydrochloric acid solution

[0098] THF: Tetrahydrofuran

[0099] DMA: N,N-Dimethylacetamide

[0100] DMSO: Dimethyl sulfoxide

[0101] EA: Ethyl acetate

[0102] IC 50: Half maximal inhibitory concentration, which refers to the concentration when the maximum inhibitory effect reaches half.

[0103] CHO: Chinese hamster ovary cells, Chinese hamster ovary cells

[0104] HBSS: Hank's Balanced Salt Solution, Hank's balanced salt solution

[0105] BSA: Albumin from bovine serum, bovine serum albumin

[0106] HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0107] IBMX: 3-isobutyl-1-methyl-7H-xanthine, 3-isobutyl-1-methyl-7H-xanthine

[0108] FLIPR: Fluorescence Imaging Plate Reader, real-time fluorescence imaging analysis system

[0109] EC 80 : concentration for 80%of maximal effect, the concentration that can cause 80%of the maximum effect

[0110] Unless otherwise indicated, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

[0111] Control Example 1: Preparation of the control compound

[0112]

[0113] The control compound was synthesized with reference to Patent Application WO2012039972A1.

[0114] The control compounds in the following test examples all refer to the compounds described in Control Example 1.

[0115] Preparation Example 1: Preparation of Intermediate A

[0116] (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide)ethyl)benzoic acid methyl ester (Intermediate A)

[0117] methyl(S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(Intermediate A)

[0118]

[0119] The synthetic route of Intermediate A is as follows:

[0120]

[0121] At room temperature, the raw material 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (5 g, 23.8 mmol) (synthesized with reference to patent application WO2011151369A1) was added to DCM (200 mL), then methyl (S)-4-(1-aminoethyl)benzoate (5.1 g, 28.6 mmol), HATU (10.9 g, 28.6 mmol), and DIPEA (4.6 g, 35.7 mmol) were added. The mixture was stirred at room temperature for 16 h, then water (200 mL) was added. The mixture was extracted with DCM (50 mL×3), the layers were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain white solid methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (5.6 g, yield 63.3%).

[0122] LCMS(ESI) m / z: 372.5 [M+H] +

[0123] Preparation Example 2: Acidic Preparation Method A

[0124] This example is a product purification example. During this purification process, high performance liquid chromatography was used for purification, and the purification conditions are as follows:

[0125] Welch, Ultimate C18 column, 10 μm, 21.2 mm×250 mm.

[0126] Mobile phase A is a pure aqueous solution of 1‰ trifluoroacetic acid, and mobile phase B is an acetonitrile solution. Gradient conditions: 0 - 3 minutes, mobile phase A is maintained at 90%, gradient elution from 3 - 18 minutes, mobile phase A changes from 90% to 5%, and mobile phase A is maintained at 5% from 18 - 22 minutes).

[0127] In the following examples, the "Acidic Preparation Method A" mentioned refers to the Acidic Preparation Method A of this Preparation Example 2.

[0128] Example 1: Preparation of Compound I-1

[0129] (S)-4-(1-(3-(Difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-1)

[0130] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-1)

[0131]

[0132] The synthetic route of Compound I-1 is as follows:

[0133]

[0134] First step: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-1B)

[0135] methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-1B)

[0136]

[0137] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (370 mg, 1.0 mmol) was added to DMF (10 mL), 3-ethylphenol (I-1A) (183 mg, 1.5 mmol) and KOH (168 mg, 3.0 mmol) were added, and the mixture was heated to 120 °C and stirred for 6 h. After cooling to room temperature, water (40 mL) was added for dilution, the pH was adjusted to 7 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude colorless liquid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-1B) (220 mg, yield 48.1%).

[0138] LCMS(ESI) m / z: 458.1 [M+H] +

[0139] Step 2: (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-1)

[0140] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-1)

[0141]

[0142] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-1B) (220 mg, 0.48 mmol) was added to THF (4 mL), water (2 mL) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain the white solid (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-1) (80 mg, yield 37.5%).

[0143] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 7.90 (d, 1H), 7.71 (d, 2H), 7.32 (t, 1H), 7.25 (t, 1H), 7.12 (d, 2H), 7.07 (d, 1H), 6.90 (s, 1H), 6.76 (dd, 1H), 4.90 (t, 1H), 3.72 (s, 3H), 2.61 (q, 2H), 1.22 (d, 3H), 1.14 (t, 3H).

[0144] LCMS(ESI) m / z: 444.1 [M+H] +

[0145] Example 2: Preparation of Compound I-2

[0146] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-2)

[0147] (S)-4-(1-(3-(Difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-2)

[0148]

[0149] The synthetic route of Compound I-2 is as follows:

[0150]

[0151] The first step: 1-fluoro-4-methoxy-2-vinylbenzene (Compound I-2B)

[0152] 1-fluoro-4-methoxy-2-vinylbenzene (Compound I-2B)

[0153]

[0154] At room temperature, 2-bromo-1-fluoro-4-methoxybenzene (Compound I-2A) (1.02 g, 5.0 mmol) was added to 1,4-dioxane (20 mL), then potassium vinyltrifluoroborate (740 mg, 5.52 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (430 mg, 0.50 mmol), and potassium carbonate (1.52 g, 11.0 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 14 h. After cooling to room temperature, water (200 mL) was added for dilution, and the mixture was extracted with DCM (80 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (pure petroleum ether) to obtain crude 1-fluoro-4-methoxy-2-vinylbenzene (Compound I-2B) as a colorless liquid (680 mg, yield 89.9%).

[0155] The second step: 2-ethyl-1-fluoro-4-methoxybenzene (Compound I-2C)

[0156] 2-ethyl-1-fluoro-4-methoxybenzene (Compound I-2C)

[0157]

[0158] At room temperature, 1-fluoro-4-methoxy-2-vinylbenzene (3.60 g, 23.7 mmol) was added to methanol (50 mL), 10% palladium on carbon (200 mg) was added, H2 was introduced, and the mixture was stirred at room temperature for 16 h. It was filtered and washed with methanol (30 mL × 3), the organic phases were combined, concentrated, and the crude product of colorless liquid 2-ethyl-1-fluoro-4-methoxybenzene (Compound I-2C) (2.90 g, yield 79.5%) was obtained.

[0159] Step 3: 3-Ethyl-4-fluorophenol (Compound I-2D)

[0160] 3-ethyl-4-fluorophenol (Compound I-2D)

[0161]

[0162] At room temperature, 2-ethyl-1-fluoro-4-methoxybenzene (100 mg, 0.65 mmol) was added to DCM (3 mL), cooled to -60 °C, 1 mol / L BBr3 DCM solution (2 mL) was added, and it was allowed to warm to room temperature naturally and stirred at room temperature for 4 h. Water (3 mL) was added to quench the reaction, it was extracted with DCM (5 mL × 3), the layers were separated, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the colorless liquid 3-ethyl-4-fluorophenol (Compound I-2D) (60 mg, yield 89.9%).

[0163] Step 4: 3-(Difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-2E)

[0164] 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-2E)

[0165]

[0166] At room temperature, 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg, 1.18 mmol) was added to DMF (5 mL), then 3-ethyl-4-fluorophenol (379 mg, 2.70 mmol) and potassium carbonate (546 mg, 3.95 mmol) were added. The mixture was heated to 100 °C and stirred for 1.5 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=4:1) to obtain crude 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-2E) as a colorless liquid (600 mg, yield 100%).

[0167] LCMS(ESI) m / z: 299.1 [M+H] +

[0168] Step 5: 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-2F)

[0169] 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-2F)

[0170]

[0171] At room temperature, 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg, 1.80 mmol) was added to tert-butanol (10 mL) and water (2 mL), then 2-methyl-2-butene (246 mg, 3.52 mmol), sodium chlorite (316 mg, 3.52 mmol) and sodium dihydrogen phosphate (281 mg, 2.34 mmol) were added. The mixture was stirred at room temperature for 4 h. Water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, to obtain crude 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-2F) as a colorless liquid (350 mg, yield 94.9%).

[0172] LCMS(ESI) m / z: 315.1 [M+H] +

[0173] Step 6: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-2G)

[0174] methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-2G)

[0175]

[0176] At room temperature, 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (350 mg, 1.11 mmol) was added to DMF (5 mL), then methyl (S)-4-(1-aminoethyl)benzoate (220 mg, 1.23 mmol), HATU (467 mg, 1.23 mmol), and DIPEA (301 mg, 2.33 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (20 mL), extracted with ethyl acetate (10 mL×3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=4:1) to obtain colorless liquid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-2G) (400 mg, yield 75.5%).

[0177] LCMS(ESI) m / z: 476.2 [M+H] +

[0178] Step 7: (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-2)

[0179] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-2)

[0180]

[0181] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (400 mg, 0.84 mmol) was added to THF (5 mL), water (5 mL) and methanol (5 mL), and lithium hydroxide monohydrate (141 mg, 3.36 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain white solid (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (300 mg, yield 77.2%).

[0182] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.17 (t, 1H), 7.14 - 7.10 (m, 3H), 7.01 - 6.97 (m, 1H), 6.82 - 6.79 (m, 1H), 4.92 (t, 1H), 3.73 (s, 3H), 2.59 (q, 2H), 1.25 (d, 3H), 1.11 (t, 3H).

[0183] LCMS (ESI) m / z: 462.2 [M + H] +

[0184] Example 3: Preparation of Compound I-3

[0185] (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-3)

[0186] (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-3)

[0187]

[0188] The synthetic route of Compound I-3 is as follows:

[0189]

[0190] The first step: Methyl (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-3B)

[0191] methyl (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-3B)

[0192]

[0193] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (145 mg, 0.39 mmol) was added to DMA (2 mL), 3-cyclopropylphenol (80 mg, 0.59 mmol) and KOH (34 mg, 0.61 mmol) were added, and the mixture was heated to 120 °C and stirred for 2 h. After cooling to room temperature, water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude colorless liquid methyl (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-3B) (20 mg, yield 10.9%).

[0194] LCMS (ESI) m / z: 470.6 [M+H] +

[0195] Step 2: (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-3)

[0196] (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-3)

[0197]

[0198] At room temperature, methyl (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-3B) (20 mg, 0.04 mmol) was added to THF (1 mL), water (1 mL) and lithium hydroxide monohydrate (2 mg, 0.048 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a white solid, (S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-3) (1.5 mg, yield 7.7%).

[0199] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.27 (t, 1H), 7.11 (t, 1H), 7.10 (d, 2H), 6.90 (d, 1H), 6.80 (t, 1H), 6.70 (dd, 1H), 4.90 (t, 1H), 3.72 (s, 3H), 1.92 - 1.98 (m, 1H), 1.23 (d, 3H), 0.96 - 0.92 (m, 2H), 0.66 - 0.27 (m, 2H).

[0200] LCMS (ESI) m / z: 456.6 [M + H] +

[0201] Example 4: Preparation of Compound I-4

[0202] (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-4)

[0203] (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-4)

[0204]

[0205] The synthetic route of Compound I-4 is as follows:

[0206]

[0207] The first step: 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-4B)

[0208] 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-4B)

[0209]

[0210] At room temperature, 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 2.57 mmol) was added to DMF (5 mL), then 3-isopropylphenol (386 mg, 2.80 mmol) and KOH (216 mg, 3.85 mmol) were added. The mixture was heated to 150 °C and stirred for 4 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain crude 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-4B) as a pale yellow liquid (750 mg, yield 98.9%).

[0211] LCMS(ESI) m / z: 295.1 [M+H] +

[0212] Step 2: 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-4C)

[0213] 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-4C)

[0214]

[0215] At room temperature, 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde (750 mg, 2.55 mmol) was added to tert-butanol (6 mL) and water (7 mL). 2-Methyl-2-butene (355 mg, 5.07 mmol), sodium chlorite (456 mg, 5.07 mmol), and sodium dihydrogen phosphate (669 mg, 5.57 mmol) were added, and the mixture was stirred at room temperature for 14 h. Water (15 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-4C), a pale yellow solid (800 mg, yield 100%).

[0216] LCMS(ESI) m / z: 311.1 [M+H] +

[0217] Step 3: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-4D)

[0218] methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-4D)

[0219]

[0220] At room temperature, 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (800 mg, 2.58 mmol) was added to DCM (20 mL). Methyl (S)-4-(1-aminoethyl)benzoate (459 mg, 2.56 mmol), HATU (1.40 g, 3.68 mmol), and DIPEA (991 mg, 7.68 mmol) were added, and the mixture was stirred at room temperature for 16 h. DCM (40 mL) was added for dilution, and the mixture was washed with water (20 mL×3). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=4:1) to obtain methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-4D), a pale yellow liquid (720 mg, yield 59.2%).

[0221] LCMS(ESI) m / z: 472.2 [M+H] +

[0222] Step 4: (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-4)

[0223] (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-4)

[0224]

[0225] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-4D) (440 mg, 0.93 mmol) was added to methanol (10 mL) and water (1 mL), and sodium hydroxide (93 mg, 2.32 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a white solid, (S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (93 mg, yield 21.7%).

[0226] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 7.89 (d, 1H), 7.70 (d, 2H), 7.32 (t, 1H), 7.12 (t, 1H), 7.10 (s, 1H), 7.06 (d, 2H), 6.99 (s, 1H), 6.72 - 6.70 (m, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.91 - 2.85 (m, 1H), 1.21 (d, 3H), 1.17 (d, 6H).

[0227] LCMS(ESI) m / z: 458.3 [M+H] +

[0228] Example 5: Preparation of Compound I-5

[0229] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-5)

[0230] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-5)

[0231]

[0232] The synthetic route of Compound I-5 is as follows:

[0233]

[0234] The first step: 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound I-5B)

[0235] 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound I-5B)

[0236]

[0237] At room temperature, 1-bromo-3-(1,1-difluoroethyl)benzene (800 mg, 3.62 mmol) was added to 1,4-dioxane (30 mL), followed by addition of bis(pinacolato)diboron (17.0 g, 156.3 mmol), copper(I) iodide (2.5 g, 13.0 mmol), L-proline (2.76 g, 10.86 mmol), potassium acetate (710 mg, 7.24 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (295 mg, 0.36 mmol). The mixture was heated to 90 °C under nitrogen protection and stirred for 16 h. After cooling to room temperature, water (200 mL) was added for dilution, and the mixture was extracted with dichloromethane (80 mL × 3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (pure petroleum ether) to obtain crude 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound I-5B) as a colorless liquid (900 mg, yield 92.7%).

[0238] The second step: 3-(1,1-difluoroethyl)phenol (Compound I-5C)

[0239] 3-(1,1-difluoroethyl)phenol (Compound I-5C)

[0240]

[0241] At room temperature, 2-(3-(1,1-difluoroethyl)phenyl)pinacol borate (Compound I-5B) (900 mg, 3.36 mmol) was added to THF (15 mL) and water (15 mL). Sodium perborate monohydrate (1.01 g, 10.07 mmol) was added, and the mixture was stirred at room temperature for 16 h. Water (200 mL) was added for dilution, and the mixture was extracted with DCM (50 mL×3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=8:1) to obtain colorless liquid 3-(1,1-difluoroethyl)phenol (Compound I-5C) (280 mg, yield 52.7%).

[0242] Step 3: methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-5D)

[0243] methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-5D)

[0244]

[0245] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (650 mg, 1.75 mmol) was added to DMF (12 mL). 3-(1,1-Difluoroethyl)phenol (360 mg, 2.27 mmol) and potassium hydroxide (147 mg, 2.62 mmol) were added, and the mixture was heated to 120 °C and stirred for 2 h. After cooling to room temperature, water (200 mL) was added for dilution, and the mixture was extracted with ethyl acetate (80 mL×3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, to obtain crude colorless liquid methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-5D) (1.2 g, crude product).

[0246] LCMS(ESI) m / z: 494.6 [M+H] + 。

[0247] Step 4: (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-5)

[0248] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-5)

[0249]

[0250] At room temperature, methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-5D) (1.0 g, 2.03 mmol) was added to THF (5 mL), water (4 mL) and lithium hydroxide monohydrate (340 mg, 8.11 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a white solid (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-5) (88 mg, yield 7.9%)

[0251] LCMS(ESI) m / z: 480.5 [M+H] +

[0252] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.10 (d, 1H), 7.71 (d, 2H), 7.53 (t, 1H), 7.47 (d, 1H), 7.27 (d, 1H), 7.11 (t, 1H), 7.11 (d, 2H), 7.07 (dd, 1H), 4.88 (t, 1H), 3.74 (s, 3H), 1.96 (t, 3H), 1.96 (d, 3H).

[0253] Example 6: Preparation of Compound I-6

[0254] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-6)

[0255] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-6)

[0256]

[0257] The synthetic route of Compound I-6 is as follows:

[0258]

[0259] The first step: methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6B)

[0260] methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6B)

[0261]

[0262] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (371 mg, 1.0 mmol) was added to DMSO (5 mL), 3-hydroxybenzaldehyde (122 mg, 1.0 mmol), K2CO3 (270 mg, 2.0 mmol), copper(I) iodide (76 mg, 0.4 mmol), and phenanthroline (72 mg, 0.4 mmol) were added. Under nitrogen protection, the mixture was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (20 ml) was added for dilution, and the mixture was extracted with ethyl acetate (10 ml × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 8:1) to obtain the title compound, colorless liquid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6B) (180 mg, yield 39.3%).

[0263] LCMS(ESI) m / z: 458.1 [M+H] +

[0264] Step 2: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6C)

[0265] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-6C)

[0266]

[0267] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6B) (41.4 mg, 0.09 mmol) was added to DMF (2 mL), and triphenylphosphonium difluoroacetate (64 mg, 0.18 mmol) was added. The mixture was heated to 60 °C and stirred for 2 h. A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.3 mL, 0.30 mmol) was added, and stirring was continued for 4 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 8:1) to obtain colorless solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6C) (40 mg, yield 91.2%).

[0268] LCMS(ESI) m / z: 512.1 [M+H] +

[0269] Step 3: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-6)

[0270] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-6)

[0271]

[0272] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-6C) (40 mg, 0.082 mmol) was added to methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (12 mg, 0.3 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain a white solid, (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-6) (4.8 mg, yield 12.3%).

[0273] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 7.95 (d, 1H), 7.73 (d, 2H), 7.43 (t, 1H), 7.22 (d, 1H), 7.13 (t, 1H), 7.12 (d, 2H), 7.10 (s, 1H), 6.97 (dd, 1H), 4.89 (t, 1H), 3.74 (s, 3H), 3.72 - 3.63 (m, 2H), 1.24 (d, 3H).

[0274] LCMS (ESI) m / z: 498.5 [M+H] +

[0275] Example 7: Preparation of Compound I-7

[0276] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-7)

[0277] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-7)

[0278]

[0279] The synthetic route of Compound I-7 is as follows:

[0280]

[0281] Step 1: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-7B)

[0282] 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(Compound I-7B)

[0283]

[0284] At room temperature, 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (700 mg, 3.30 mmol) was added to tert-butanol (20 mL) and water (5 mL). 2-Methyl-2-butene (1.80 g, 25.7 mmol), sodium chlorite (1.48 g, 16.4 mmol), and sodium dihydrogen phosphate (3.10 g, 25.8 mmol) were added, and the mixture was stirred at room temperature for 14 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude residue as a colorless liquid. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to obtain 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as a colorless solid (Compound I-7B) (680 mg, yield 90.3%).

[0285] LCMS(ESI) m / z: 229.6 [M+H] +

[0286] Step 2: Methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7C)

[0287] methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-7C)

[0288]

[0289] At room temperature, 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-7B) (680 mg, 2.98 mmol) was added to DMF (20 mL), then (S)-methyl 4-(1-aminoethyl)benzoate (537 mg, 3.00 mmol), HATU (1.70 g, 4.47 mmol), and DIPEA (1.90 g, 14.7 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (200 mL), extracted with ethyl acetate (30 mL×3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to obtain the colorless solid methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7C) (700 mg, yield 60.3%).

[0290] LCMS(ESI) m / z: 390.5 [M+H] +

[0291] Step 3: Methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7D)

[0292] methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7D)

[0293]

[0294] At room temperature, methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7C) (700 mg, 1.00 mmol) was added to DMF (10 mL), 3-(1,1-difluoroethyl)phenol (284 mg, 1.00 mmol) and KOH (264 mg, 4.63 mmol) were added, and the mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude colorless liquid methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7D) (100 mg, yield 10.8%).

[0295] LCMS(ESI) m / z: 512.3 [M+H] +

[0296] Step 4: (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-7)

[0297] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-7)

[0298]

[0299] At room temperature, methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-7D) (100 mg, 0.19 mmol) was added to THF (5 mL), water (4 mL) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to prepare white solid (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-7) (47.2 mg, yield 48.5%)

[0300] 11H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.58 (d, 1H), 7.73 (d, 2H), 7.53 (t, 1H), 7.40 (d, 1H), 7.27 (s, 1H), 7.15 (d, 2H), 7.11 (d, 1H), 4.85 (t, 1H), 3.29 (s, 3H), 1.96 (t, 3H), 1.17 (d, 3H).

[0301] LCMS (ESI) m / z: 498.3 [M+H] +

[0302] Example 8: Preparation of Compound I-8

[0303] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-8)

[0304] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-8)

[0305]

[0306] The synthetic route of Compound I-8 is as follows:

[0307]

[0308] The first step: 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (Compound I-8B)

[0309] 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (Compound I-8B)

[0310]

[0311] At room temperature, 1,3-dimethyl-5-hydroxypyrazole (5.5 g, 49.1 mmol) was added to DMF (10.9 g). It was cooled to 0 °C, and POCl3 (53.0 g, 346.4 mmol) was added. It was allowed to warm to room temperature naturally and then heated to 120 °C and stirred for 1 h. After cooling to room temperature, it was diluted with water (200 mL), extracted with EA (200 mL×3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to obtain the colorless liquid 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (Compound I-8B) (4.3 g, yield 55.4%).

[0312] LCMS(ESI) m / z: 159.6 [M+H] +

[0313] Step 2: 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (Compound I-8C)

[0314] 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (Compound I-8C)

[0315]

[0316] At room temperature, Compound 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (Compound I-8B) (3.20 g, 20.2 mmol) was added to tert-butanol (50 mL) and water (15 mL). 2-Methyl-2-butene (11.3 g, 161.4 mmol), sodium chlorite (9.10 g, 101.1 mmol), and sodium dihydrogen phosphate (19.4 g, 161.6 mmol) were added, and it was stirred at room temperature for 14 h. It was diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude residue of the title compound as a colorless liquid was obtained. It was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:1) to obtain the colorless solid 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (Compound I-8C) (3.10 g, yield 87.9%).

[0317] LCMS(ESI) m / z: 175.6 [M+H] +

[0318] Step 3: Methyl (S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8D) methyl (S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8D)

[0319]

[0320] At room temperature, compound 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (Compound I-8C) (1.20 g, 6.89 mmol) was added to DMF (30 mL), then methyl (S)-4-(1-aminoethyl)benzoate (1.23 g, 6.87 mmol), HATU (3.90 g, 10.1 mmol), and DIPEA (4.50 g, 34.8 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain colorless solid methyl (S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8D) (1.90 g, yield 82.2%).

[0321] LCMS(ESI) m / z: 336.6 [M+H] +

[0322] Step 4: Methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8E)

[0323] methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8E)

[0324]

[0325] At room temperature, methyl (S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8D) (335 mg, 1.00 mmol) was added to DMF (10 mL), 3-(1,1-difluoroethyl)phenol (158 mg, 1.00 mmol) and KOH (150 mg, 2.67 mmol) were added, and the mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of the title compound, colorless liquid, methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8E) (170 mg, yield 37.1%).

[0326] LCMS(ESI) m / z: 458.5 [M+H] +

[0327] Step 5: (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-8)

[0328] (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-8)

[0329]

[0330] At room temperature, methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8E) (500 mg, 1.09 mmol) was added to THF (5 mL), water (4 mL) and lithium hydroxide monohydrate (340 mg, 8.11 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to prepare the white solid (S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-8) (53 mg, yield 10.9%).

[0331] 11H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 7.73 (d, 2H), 7.71 (d, 1H), 7.52 (t, 1H), 7.37 (d, 1H), 7.21 (s, 1H), 7.14 (d, 2H), 7.01 (dd, 1H), 4.91 (t, 1H), 3.59 (s, 3H), 2.27 (s, 3H), 1.96 (t, 3H), 1.22 (d, 3H).

[0332] LCMS (ESI) m / z: 444.5 [M+H] +

[0333] Example 9: Preparation of Compound I-9

[0334] (S)-4-(1-(5-(3-Ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-9)

[0335] (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-9)

[0336] The synthetic route of Compound I-9 is as follows:

[0337]

[0338] The synthetic route of Compound I-9 is as follows:

[0339]

[0340] First step: Methyl (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-9B)

[0341] methyl (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-9B)

[0342]

[0343] At room temperature, methyl (S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-8D) (100 mg, 0.30 mmol) was added to DMF (3 mL), 3-ethylphenol (36 mg, 0.30 mmol) and KOH (49 mg, 0.86 mmol) were added, and the mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product of colorless liquid methyl (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-9B) (60 mg, yield 47.7%).

[0344] LCMS(ESI) m / z: 422.6 [M+H] +

[0345] Step 2: (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-9)

[0346] (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-9)

[0347]

[0348] At room temperature, methyl (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-9B) (60 mg, 0.14 mmol) was added to THF (2 mL), water (2 mL) and lithium hydroxide monohydrate (6 mg, 0.14 mmol) were added, and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to prepare white solid (S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-9) (10 mg, yield 17.2%).

[0349] 11H NMR (400 mHz, DMSO-d6) δ 12.6 (s, 1H), 7.72 (d, 2H), 7.50 (d, 1H), 7.31 (t, 1H), 7.12 (d, 2H), 7.04 (d, 1H), 6.85 (s, 1H), 6.71 (dd, 1H), 4.92 (t, 1H), 3.56 (s, 3H), 2.67 (q, 2H), 2.27 (s, 3H), 1.24 (d, 3H), 1.14 (t, 3H).

[0350] LCMS (ESI) m / z: 408.6 [M+H] +

[0351] Example 10: Preparation of Compound I-10

[0352] (S)-4-(1-(5-(3-(1,1-Difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-10)

[0353] (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-10)

[0354]

[0355] The synthetic route of Compound I-10 is as follows:

[0356]

[0357] First step: Methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10B)

[0358] methyl

[0359] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10B)

[0360]

[0361] At room temperature, 1-(2-fluoro-5-hydroxyphenyl)ethan-1-one (1.58 g, 10.8 mmol) was added to N,N-dimethylformamide (30 mL). Methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (2.0 g, 5.4 mmol) and potassium hydroxide (450 mg, 8.1 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (30 mL) was added, and it was extracted with ethyl acetate (30 mL × 3). The layers were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain white solid methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10B) (346 mg, yield 13%).

[0362] LC-MS, M / Z(ESI): 490.2[M+H] +

[0363] Step 2: Methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10C)

[0364] methyl

[0365] (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10C)

[0366]

[0367] At room temperature, methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10B) (346 mg, 0.71 mmol) was added to sulfur trioxide bis(diethylamide) (10 mL), and the mixture was heated to 50 °C and stirred for 16 h. After cooling to 0 °C, water (50 mL) was added for dilution, and the mixture was extracted with EA (100 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude white methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10C) (390 mg, yield 100%).

[0368] LC-MS, M / Z(ESI): 512.2 [M+H] +

[0369] Step 3: (S)-4-(1-(5-(3-(1,1-Difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-10)

[0370] (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-10)

[0371]

[0372] At room temperature, methyl (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-10C) (390 mg, 0.76 mmol) was added to tetrahydrofuran (10 mL), methanol (10 mL) and water (3 mL), and lithium hydroxide (64 mg, 1.52 mmol) was added. The mixture was stirred at room temperature for 36 h. The pH was adjusted to 7 with 1N hydrochloric acid, and the mixture was concentrated. The title compound was prepared by acidic preparative method A to obtain white solid (S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-10) (116 mg, yield 31%).

[0373] LC-MS, M / Z(ESI): 498.1 [M+H] +

[0374] 1 H NMR(400 mHz, DMSO-d6) δ 12.10(s, 1H), 8.19(d, 1H), 7.75(d, 2H), 7.39(t, 1H), 7.26(t, 1H), 7.15(d, 2H), 7.13(d, 1H), 7.12(t, 1H), 4.90(t, 1H), 3.75(s, 3H), 2.01(t, 3H), 1.22(d, 3H).

[0375] Example 11: Preparation of Compound I-11

[0376] (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11)

[0377] (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11)

[0378]

[0379] The synthetic route of Compound I-11 is as follows:

[0380]

[0381] The first step: methyl (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-11B)

[0382] methyl

[0383] (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-11B)

[0384]

[0385] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (371 mg, 1.00 mmol) was added to dimethyl sulfoxide (3 mL). 4-Chloro-3-ethylphenol (156 mg, 1.00 mmol) and potassium hydroxide (112 mg, 2.00 mmol) were added. The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The layers were separated, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid methyl ester (Compound I-11B) as a colorless liquid (80 mg, yield 16%).

[0386] LC-MS, M / Z (ESI): 492.3 (M+1).

[0387] Step 2: (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11)

[0388] (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11)

[0389]

[0390] At room temperature, (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11B) (80 mg, 0.16 mmol) was added to tetrahydrofuran (1 mL). Water (1 mL) and lithium hydroxide monohydrate (21 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to prepare (S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-11) as a white solid (13.3 mg, yield 17%).

[0391] 11H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.04 (d, 1H), 7.73 (d, 2H), 7.41 (d, 1H), 7.11 (t, 1H), 7.10 (d, 2H), 7.08 (d, 1H), 6.82 (d, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.67 (q, 2H), 1.24 (d, 3H), 1.11 (t, 3H).

[0392] LC-MS, M / Z (ESI): 478.3 (M+1)

[0393] Example 12: Preparation of Compound I-12

[0394] (S)-4-(1-(3-(Difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-12)

[0395] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-12)

[0396]

[0397] The synthetic route of Compound I-12 is as follows:

[0398]

[0399] The first step: 1-fluoro-3-methoxy-5-vinylbenzene (Compound I-12B)

[0400] 1-fluoro-3-methoxy-5-vinylbenzene (Compound I-12B)

[0401]

[0402] At room temperature, 1-bromo-3-fluoro-5-methoxybenzene (2.0 g, 9.7 mmol) was added to 1,4-dioxane (50 mL), then potassium vinyltrifluoroborate (1.6 g, 11.7 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (1.4 g, 1.96 mmol), and potassium carbonate (2.7 g, 19.6 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 16 h. After cooling to room temperature, water (200 mL) was added for dilution, and the mixture was extracted with dichloromethane (80 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (pure petroleum ether) to obtain colorless liquid 1-fluoro-3-methoxy-5-vinylbenzene (Compound I-12B) (600 mg, yield 40%).

[0403] Step 2: 1-ethyl-3-fluoro-5-methoxybenzene (Compound I-12C)

[0404] 1-ethyl-3-fluoro-5-methoxybenzene(Compound I-12C)

[0405]

[0406] At room temperature, 1-fluoro-3-methoxy-5-vinylbenzene (300 mg, 1.97 mmol) was added to methanol (20 mL), then 10% palladium on carbon (200 mg) was added, and H2 was introduced. The mixture was stirred at room temperature for 16 h. After filtration, it was washed with methanol (30 mL × 3), the organic phases were combined, and concentrated to obtain crude colorless liquid 1-ethyl-3-fluoro-5-methoxybenzene (Compound I-12C) (200 mg, yield 66%).

[0407] Step 3: 3-ethyl-5-fluorophenol (Compound I-12D)

[0408] 3-ethyl-5-fluorophenol(Compound I-12D)

[0409]

[0410] At room temperature, 1-ethyl-3-fluoro-5-methoxybenzene (200 mg, 1.3 mmol) was added to dichloromethane (2 mL), and the mixture was cooled to 0 °C. Then BBr3 (2 mL of 1 mol / L dichloromethane solution) was added, and the temperature was allowed to rise to room temperature naturally. The mixture was stirred at room temperature for 4 h. Water (3 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (5 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude colorless liquid 3-ethyl-5-fluorophenol (Compound I-12D) (180 mg, yield 99%).

[0411] Step 4: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-12E)

[0412] methyl

[0413] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-12E)

[0414]

[0415] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (250 mg, 0.67 mmol) was added to N,N-dimethylformamide (15 mL). 3-Ethyl-5-fluorophenol (180 mg, 1.28 mmol), potassium carbonate (270 mg, 1.96 mmol), copper(I) iodide (50 mg, 0.26 mmol), and 1,10-phenanthroline (90 mg, 0.50 mmol) were added, and the mixture was heated to 120 °C and stirred for 1 h. After cooling to room temperature, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), separated, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-12E) as a colorless liquid (200 mg, yield 62%).

[0416] LC-MS, M / Z (ESI): 476.2 (M+1).

[0417] Step 5: (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-12)

[0418] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-12)

[0419]

[0420] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (200 mg, 0.42 mmol) was added to tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (53 mg, 1.26 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated to obtain the title compound, (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid, as a white solid (130 mg, yield 67%).

[0421] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.10 (d, 1H), 7.74 (d, 2H), 7.16 (d, 2H), 7.11 (t, 1H), 6.93 (d, 1H), 6.72 (s, 1H), 6.69 (d, 1H), 4.92 (t, 1H), 3.73 (s, 3H), 2.58 - 2.54 (m, 2H), 1.25 (d, 3H), 1.13 (t, 3H).

[0422] LC-MS, M / Z (ESI): 462.1 (M + 1)

[0423] Example 13: Preparation of Compound I-13

[0424] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-13)

[0425] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-13)

[0426]

[0427] The synthetic route of Compound I-13 is as follows:

[0428]

[0429] The first step: 3-vinylphenol (Compound I-13B)

[0430] 3-vinylphenol (Compound I-13B)

[0431]

[0432] At 0 °C, methyltriphenylphosphonium bromide (7.30 g, 20.5 mmol) was added to anhydrous tetrahydrofuran (40 mL), potassium tert-butoxide (2.3 g, 20.5 mmol) was added, and the mixture was stirred at low temperature for 2 h. A solution of 3-hydroxybenzaldehyde (1.0 g, 8.20 mmol) and tetrahydrofuran (15 mL) was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature naturally and stirred for 16 h. Water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain 3-vinylphenol (Compound I-13B) as a yellow liquid (500 mg, yield 49%).

[0433] Step 2: methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13C)

[0434] methyl

[0435] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13C)

[0436]

[0437] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (600 mg, 1.62 mmol) was added to N,N-dimethylformamide (18 mL), then 3-vinylphenol (Compound I-13B) (388 mg, 3.23 mmol) and potassium hydroxide (181 mg, 3.23 mmol) were added. The mixture was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (60 mL) was added for dilution, and the mixture was extracted with ethyl acetate (60 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=10:1) to obtain white solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13C) (200 mg, yield 27%).

[0438] LC-MS, M / Z (ESI): 456.2 (M+1).

[0439] Step 3: Methyl 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13D)

[0440] methyl 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13D)

[0441]

[0442] At room temperature, the raw material methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13C) (100 mg, 0.22 mmol) was added to acetonitrile (25 mL), and a selective fluorination reagent (233 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.02 mmol), and triethylsilane (40.0 mg, 0.33 mmol) were added. The mixture was stirred at room temperature for 16 h under nitrogen protection. Water (60 mL) was added for dilution, and the mixture was extracted with ethyl acetate (60 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain white solid methyl 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13D) (65.0 mg, yield 62%).

[0443] LC-MS, M / Z(ESI): 476.3(M+1)

[0444] Step 4: 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-13)

[0445] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-13)

[0446]

[0447] At room temperature, the raw material methyl 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-13D) (150 mg, 0.19 mmol) was added to tetrahydrofuran (24 mL), water (12 mL) and methanol (12 mL) were added, and lithium hydroxide (15.0 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction solution was concentrated and prepared by acidic method A to obtain white solid 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-13) (50.0 mg, yield 32%).

[0448] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.03 (d, 1H), 7.72 (d, 2H), 7.45 (t, 1H), 7.25 (t, 1H), 7.11 (d, 2H), 6.98 (t, 1H), 6.94 (t, 1H), 5.78 (dd, 1H), 4.89 (m, 1H), 3.73 (s, 3H), 3.60 (s, 1H), 1.55 (dd, 3H), 1.24 (d, 3H).

[0449] LC-MS, M / Z (ESI): 462.3 (M+1)

[0450] Example 14: Preparation of Compound I-14

[0451] (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-14)

[0452] (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-14)

[0453]

[0454] The synthetic route of Compound I-14 is as follows:

[0455]

[0456] First step: Methyl (S)-4-(1-(3-(difluoromethyl)-(5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14B)

[0457] methyl

[0458] (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14B)

[0459]

[0460] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (574 mg, 1.54 mmol) was added to N,N-dimethylformamide (15 mL), then 3-hydroxybenzaldehyde (378 mg, 3.09 mmol), copper(I) iodide (60 mg, 0.31 mmol), 1,10-phenanthroline (114 mg, 0.62 mmol), and cesium carbonate (1.50 g, 4.62 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (50 mL) was added for dilution, and the pH was adjusted to 4 with 1 N hydrochloric acid. It was extracted with ethyl acetate (50 mL × 3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain pale yellow solid methyl (S)-4-(1-(3-(difluoromethyl)-(5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14B) (280 mg, yield 40%).

[0461] LC-MS, M / Z(ESI): 458.3[M+H] + 。

[0462] Step 2: methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-(2,2-difluorovinyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14C)

[0463] methyl

[0464] (S)-4-(1-(3-(difluoromethyl)-5-(3-(2,2-difluorovinyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14C)

[0465]

[0466] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14B) (280 mg, 0.61 mmol) was added to N,N-dimethylformamide (15 mL). Triphenylphosphine (200 mg, 0.76 mmol) and sodium difluorochloroacetate (140 mg, 0.92 mmol) were added. Under nitrogen protection, it was microwave-heated to 100 °C and stirred for 1 h. It was cooled to room temperature, diluted with water (50 mL), the pH was adjusted to 4 with 1 N hydrochloric acid, extracted with ethyl acetate (50 mL × 3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain pale yellow solid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-(2,2-difluorovinyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14C) (120 mg, yield 40%).

[0467] LC-MS, M / Z(ESI): 492.4[M+H] + 。

[0468] Step 3: methyl (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14D)

[0469] methyl

[0470] (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14D)

[0471]

[0472] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-(2,2-difluorovinyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14C) (120 mg, 0.24 mmol) was added to methanol (20 mL), 10% palladium on carbon (20 mg) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 16 h. It was filtered and concentrated to obtain crude light yellow solid methyl (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14D) (120 mg, yield 99%).

[0473] LC-MS, M / Z(ESI): 494.4[M+H] + 。

[0474] Step 4: (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-14)

[0475] (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-14)

[0476]

[0477] At room temperature, methyl (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-14D) (120 mg, 0.24 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (31 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1N hydrochloric acid, the reaction solution was concentrated, and white solid (S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-14) (90 mg, yield 77%) was prepared by acidic preparation method A.

[0478] 11H NMR(400 mHz, DMSO-d6) δ 12.8 (s, 1H), 7.95 (d, 1H), 7.74 (d, 2H), 7.39 (t, 1H), 7.25 (t, 1H), 7.16 (d, 2H), 7.13 (d, 1H), 7.04 (d, 1H), 6.91 (t, 1H), 6.34 (dt, 1H), 4.91 (t, 1H), 3.71 (s, 3H), 3.22 (q, 2H), 1.22 (d, 3H).

[0479] LC-MS, M / Z(ESI): 480.4 [M + H] +

[0480] Example 15: Preparation of Compound I-15

[0481] 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-15)

[0482] 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-15)

[0483]

[0484] The synthetic route of Compound I-15 is as follows:

[0485]

[0486] The first step: 3-(1,1,1-trifluoropropan-2-yl)phenol (Compound I-15B)

[0487] 3-(1,1,1-trifluoropropan-2-yl)phenol (Compound I-15B)

[0488]

[0489] At room temperature, compound 1-methoxy-3-(1,1,1-trifluoropropan-2-yl)benzene (800 mg, 0.72 mmol) was added to dichloromethane (1 mL), cooled to -78 °C, boron tribromide (1.50 g, 5.88 mmol) was added, and the mixture was stirred at room temperature for 4 h. Water (50 mL) was added for dilution, and the mixture was extracted with dichloromethane (50 mL×3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain pale yellow liquid 3-(1,1,1-trifluoropropan-2-yl)phenol (Compound I-15B) (640 mg, yield 86%).

[0490] Step 2: 3-(Difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-15C)

[0491] 3-(Difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-15C)

[0492]

[0493] At room temperature, compound 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (660 mg, 3.37 mmol) was added to N,N-dimethylformamide (6 mL), 3-(1,1,1-trifluoropropan-2-yl)phenol (640 mg, 3.37 mmol) and potassium carbonate (930 mg, 6.72 mmol) were added, and the mixture was heated to 100 °C under nitrogen protection and stirred for 8 h. After cooling to room temperature, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL×3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=5:1) to obtain pale yellow liquid 3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-15C) (1.0 g, yield 18%).

[0494] LC-MS, M / Z(ESI): 349.2 [M+H] + 。

[0495] Step 3: 3-(Difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-15D)

[0496] 3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-15D)

[0497]

[0498] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carbaldehyde (800 mg, 2.30 mmol) was added to tert-butanol (8 mL) and water (8 mL). 2-Methyl-2-butene (322 mg, 4.60 mmol), sodium chlorite (414 mg, 4.60 mmol), and sodium dihydrogen phosphate (617 mg, 5.06 mmol) were added, and the mixture was stirred at room temperature for 8 h. Water (15 mL) was added for dilution, and the pH was adjusted to 4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL×3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-15D) as a pale yellow solid (850 mg, yield 100%).

[0499] LC-MS, M / Z(ESI): 365.1 [M+H] + 。

[0500] Step 4: Methyl 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-15E)

[0501] methyl 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-15E)

[0502]

[0503] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (850 mg, 2.34 mmol) was added to N,N-dimethylformamide (10 mL). Methyl (S)-4-(1-aminoethyl)benzoate (418 mg, 2.34 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.3 g, 3.50 mmol), and N,N-diisopropylethylamine (900 mg, 7.0 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (40 mL), extracted with ethyl acetate (40 mL × 3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain methyl 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-15E) (1.0 g, yield 81%).

[0504] LC-MS, M / Z(ESI): 526.3[M+H] + 。

[0505] Step 5: 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-15)

[0506] 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-15)

[0507]

[0508] At room temperature, methyl 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-15E) (1.0 g, 1.90 mmol) was added to tetrahydrofuran (10 mL) and water (2 mL), and lithium hydroxide (200 mg, 4.76 mmol) was added. The mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. White solid 4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-15) (356 mg, yield 37%) was prepared by acidic preparation method A.

[0509] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 7.97 (dd, 1H), 7.73 (d, 2H), 7.43 (dd, 1H), 7.28 (d, 1H), 7.25 (t, 1H), 7.13 (d, 2H), 7.11 (d, 1H), 6.99 (t, 1H), 4.90 (t, 1H), 3.89 - 3.85 (m, 1H), 3.73 (s, 3H), 1.41 (d, 3H), 1.21 (t, 3H).

[0510] LC-MS, M / Z (ESI): 512.3 [M + H] +

[0511] Example 16: Preparation of Compound I-16

[0512] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-16)

[0513] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-16)

[0514]

[0515] The synthetic route of Compound I-16 is shown as follows:

[0516]

[0517] Step 1: 1-(benzyloxy)-2,3-difluoro-5-methoxybenzene (Compound I-16B)

[0518] 1-(benzyloxy)-2,3-difluoro-5-methoxybenzene(Compound I-16B)

[0519]

[0520] At room temperature, 1,2,3-trifluoro-5-methoxybenzene (8.5 g, 52.4 mmol) was added to toluene (100 mL), then benzyl alcohol (11.3 g, 104 mmol) and potassium hydroxide (5.86 g, 104 mmol) were added. The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, water (500 mL) was added for dilution, and the pH was adjusted to 7 - 8 with 1N hydrochloric acid. The mixture was extracted with dichloromethane (100 mL × 3), the layers were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V), 20:1) to obtain colorless liquid 1-(benzyloxy)-2,3-difluoro-5-methoxybenzene (Compound I-16B) (5.2 g, yield 40%).

[0521] Step 2: 2,3-difluoro-5-methoxyphenol (Compound I-16C)

[0522] 2,3-difluoro-5-methoxyphenol(Compound I-16C)

[0523]

[0524] At room temperature, 1-(benzyloxy)-2,3-difluoro-5-methoxybenzene (5.2 g, 20.8 mmol) was added to tetrahydrofuran (100 mL), then 10% palladium on carbon (520 mg) was added, and hydrogen was introduced. The mixture was stirred at room temperature for 16 h. After filtration and concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain crude colorless liquid 2,3-difluoro-5-methoxyphenol (Compound I-16C) (3.8 g, yield 100%).

[0525] Step 3: 2,3-difluoro-5-methoxyphenyl trifluoromethanesulfonate (Compound I-16D)

[0526] 2,3-difluoro-5-methoxyphenyl trifluoromethanesulfonate(Compound I-16D)

[0527]

[0528] At room temperature, 2,3-difluoro-5-methoxyphenol (500 mg, 3.12 mmol) was added to dichloromethane (20 mL), and then trifluoromethanesulfonic anhydride (881 mg, 3.12 mmol) and pyridine (493 mg, 6.25 mmol) were added. The mixture was stirred at room temperature for 4 h. Saturated sodium bicarbonate (20 mL) was added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product of 2,3-difluoro-5-methoxyphenyl trifluoromethanesulfonate (Compound I-16D), a colorless liquid, was obtained (600 mg, yield 66%).

[0529] Step 4: 1,2-Difluoro-5-methoxy-3-vinylbenzene (Compound I-16E)

[0530] 1,2-difluoro-5-methoxy-3-vinylbenzene (Compound I-16E)

[0531]

[0532] At room temperature, 2,3-difluoro-5-methoxyphenyl trifluoromethanesulfonate (600 mg, 2.05 mmol) was added to 1,4-dioxane (50 mL), and then potassium vinyltrifluoroborate (1.25 g, 9.37 mmol), potassium carbonate (1.30 g, 9.37 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (254 mg, 0.31 mmol) were added. The mixture was heated to 90 °C under nitrogen protection and stirred for 16 h. After cooling to room temperature, water (200 mL) was added for dilution, and the mixture was extracted with dichloromethane (50 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1) to obtain the title compound, 1,2-difluoro-5-methoxy-3-vinylbenzene (Compound I-16E), a pale yellow liquid (200 mg, yield 57%).

[0533] Step 5: 1-Ethyl-2,3-difluoro-5-methoxybenzene (Compound I-16F)

[0534] 1-ethyl-2,3-difluoro-5-methoxybenzene (Compound I-16F)

[0535]

[0536] At room temperature, 1,2-difluoro-5-methoxy-3-vinylbenzene (130 mg, 0.82 mmol) was added to methanol (15 mL), 10% palladium on carbon (20 mg) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 16 h. It was filtered and concentrated to obtain a pale yellow liquid, 1-ethyl-2,3-difluoro-5-methoxybenzene (Compound I-16F) (100 mg, yield 76%).

[0537] Step 6: 3-Ethyl-4,5-difluorophenol (Compound I-16G)

[0538] 3-ethyl-4,5-difluorophenol(Compound I-16G)

[0539]

[0540] At room temperature, 1-ethyl-2,3-difluoro-5-methoxybenzene (100 mg, 0.58 mmol) was added to dichloromethane (10 mL), boron tribromide (726 mg, 2.90 mmol) was added at 0 °C, and the mixture was stirred for 3 h. Water (20 mL) was added for dilution, and it was extracted with dichloromethane (30 mL × 3), the layers were separated, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude pale yellow liquid, 3-ethyl-4,5-difluorophenol (Compound I-16G) (60 mg, yield 66%).

[0541] Step 7: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-16H)

[0542] methyl

[0543] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-16H)

[0544]

[0545] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (600 mg, 1.61 mmol) was added to N,N-dimethylformamide (15 mL), 3-ethyl-4,5-difluorophenol (450 mg, 3.0 mmol) and potassium hydroxide (210 mg, 3.9 mmol) were added, and the mixture was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (50 mL) was added for dilution, the pH was adjusted to 4 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (60 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain pale yellow solid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-16H) (350 mg, yield 44%).

[0546] LC-MS, M / Z (ESI): 494.4 [M+H] + 。

[0547] Step 8: (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-16)

[0548] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-16)

[0549]

[0550] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (325 mg, 0.66 mmol) was added to tetrahydrofuran (15 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (32 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, the reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (170 mg, yield 54%) was prepared by acidic preparation method A.

[0551] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.15 (d, 1H), 7.76 (d, 2H), 7.24 (t, 1H), 7.18 (d, 2H), 7.01 (t, 1H), 6.80 (d, 1H), 4.94 (t, 1H), 3.74 (s, 3H), 2.62 (q, 2H), 1.27 (d, 3H), 1.11 (t, 3H).

[0552] LC-MS, M / Z (ESI): 480.4 [M+H] +

[0553] Example 17: Preparation of Compound I-17

[0554] (S)-4-(1-(3-(Difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-17)

[0555] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-17)

[0556]

[0557] The synthetic route of Compound I-17 is as follows:

[0558]

[0559] First step: Methyl (S)-4-(1-(5-(3-bromo-4-methylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17B)

[0560] methyl

[0561] (S)-4-(1-(5-(3-bromo-4-methylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17B)

[0562]

[0563] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (500 mg, 1.35 mmol) was added to N,N-dimethylformamide (10 mL), then 3-bromo-4-methylphenol (380 mg, 2.02 mmol), copper(I) iodide (100 mg, 0.52 mmol), 1,10-phenanthroline (180 mg, 1.0 mmol), and cesium carbonate (1.30 g, 4.05 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, it was diluted with water (50 mL), the pH was adjusted to 4 with 1 N hydrochloric acid, and it was extracted with ethyl acetate (50 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain pale yellow solid methyl (S)-4-(1-(5-(3-bromo-4-methylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17B) (270 mg, yield 38%).

[0564] LC-MS, M / Z(ESI): 522.3[M+H] + 。

[0565] Step 2: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-methyl-3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17C)

[0566] methyl

[0567] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-methyl-3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17C)

[0568]

[0569] At room temperature, methyl (S)-4-(1-(5-(3-bromo-4-methylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17B) (260 mg, 0.50 mmol) was added to 1,4-dioxane (5 mL). Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (73 mg, 0.10 mmol), potassium vinyltrifluoroborate (100 mg, 0.75 mmol), and potassium carbonate (140 mg, 1.0 mmol) were added. The mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After cooling to room temperature, water (50 mL) was added for dilution, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain a pale yellow solid, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-methyl-3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17C) (160 mg, yield 68%).

[0570] LC-MS, M / Z(ESI): 470.3[M+H] + 。

[0571] Step 3: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17D)

[0572] methyl

[0573] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17D)

[0574]

[0575] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-methyl-3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (160 mg, 0.34 mmol) was added to methanol (10 mL), 10% palladium on carbon (20 mg) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 16 h. It was filtered and concentrated to obtain crude light yellow solid methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17D) (150 mg, yield 93%).

[0576] LC-MS, M / Z (ESI): 472.3 [M+H] + 。

[0577] Step 4: (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-17)

[0578] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-17)

[0579]

[0580] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-17D) (150 mg, 0.32 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (24 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, the reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (85 mg, yield 58%) was prepared by acidic preparation method A.

[0581] 11H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 7.90 (d, 1H), 7.69 (d, 2H), 7.25 (t, 1H), 7.13 (d, 1H), 7.11 (d, 2H), 6.85 (d, 1H), 6.64 (dd, 1H), 4.93 (t, 1H), 3.71 (s, 3H), 2.55 (q, 2H), 2.23 (s, 3H), 1.24 (d, 3H), 1.07 (t, 3H).

[0582] LC-MS, M / Z (ESI): 458.3 [M+H] +

[0583] Example 18: Preparation of Compound I-18

[0584] (S)-4-(1-(3-(Difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-18)

[0585] (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-18)

[0586]

[0587] The synthetic route of Compound I-18 is as follows:

[0588]

[0589] First step: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-18B)

[0590] methyl

[0591] (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-18B)

[0592]

[0593] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (371 mg, 1.0 mmol) was added to dimethyl sulfoxide (3 mL), 4-ethylphenol (122 mg, 1.0 mmol) and potassium hydroxide (114 mg, 2.0 mmol) were added, and the mixture was heated to 120 °C by microwave and stirred for 20 min. After cooling to room temperature, water (20 mL) was added for dilution, the pH was adjusted to 4 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product of white solid methyl (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-18B) (175 mg, yield 38%) was obtained.

[0594] LC-MS, M / Z (ESI): 458.3 [M+H] + 。

[0595] Step 2: (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-18)

[0596] (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-18)

[0597]

[0598] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-18B) (175 mg, 0.38 mmol) was added to tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL), lithium hydroxide (3 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 12 h. The pH was adjusted to 4 with 1 N hydrochloric acid, the reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-18) (40 mg, yield 24%) was obtained by acidic preparation method A.

[0599] 11H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 7.95 (d, 1H), 7.71 (d, 2H), 7.24 (d, 2H), 7.21 (t, 1H), 7.11 (d, 2H), 6.92 (d, 2H), 4.91 (t, 1H), 3.72 (s, 3H), 2.62 (q, 2H), 1.24 (d, 3H), 1.19 (t, 3H).

[0600] LC-MS, M / Z (ESI): 444.3 [M+H] +

[0601] Example 19: Preparation of Compound I-19

[0602] (S)-4-(1-(5-(4-(1,1-Difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-19)

[0603] (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-19)

[0604]

[0605] The synthetic route of Compound I-19 is as follows:

[0606]

[0607] The first step: 5-(4-Acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-19B)

[0608] 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-19B)

[0609]

[0610] At room temperature, 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (1.0 g, 5.15 mmol) was added to N,N-dimethylformamide (15 mL). 4-Acetylphenol (1.05 g, 7.73 mmol), copper(I) iodide (918 mg, 5.15 mmol), 1,10-phenanthroline (1.05 g, 7.73 mmol), and potassium carbonate (1.42 g, 10.3 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 2 h. After cooling to room temperature, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the crude product of 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-19B) as a pale yellow liquid (270 mg, yield 18%).

[0611] LC-MS, M / Z(ESI): 295.1 [M+H] + 。

[0612] Step 2: 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-19C)

[0613] 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-19C)

[0614]

[0615] At room temperature, 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (Compound I-19B) (400 mg, 1.36 mmol) was added to tert-butanol (9 mL) and water (3 mL). 2-Methyl-2-butene (476 mg, 6.80 mmol), sodium chlorite (369 mg, 4.08 mmol), and sodium dihydrogen phosphate (408 mg, 3.40 mmol) were added. The mixture was stirred at room temperature for 14 h. Water (15 mL) was added for dilution, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of 5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-19C) as a pale yellow solid (350 mg, yield 100%).

[0616] LC-MS, M / Z(ESI): 311.1 [M+H] + 。

[0617] Step 3: methyl (S)-4-(1-(5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19D)

[0618] methyl

[0619] (S)-4-(1-(5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19D)

[0620]

[0621] At room temperature, 3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (350 mg, 1.13 mmol) was added to N,N-dimethylformamide (7 mL), then (S)-methyl 4-(1-aminoethyl)benzoate (242 mg, 1.36 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (650 mg, 1.71 mmol), and N,N-diisopropylethylamine (437 mg, 3.67 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (40 mL), and extracted with ethyl acetate (40 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=4:1) to obtain a pale yellow liquid, methyl (S)-4-(1-(5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19D) (500 mg, yield 94%).

[0622] LC-MS, M / Z(ESI): 472.2 [M+H] + 。

[0623] Step 4: methyl (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19E)

[0624] methyl

[0625] (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19E)

[0626]

[0627] At room temperature, methyl (S)-4-(1-(5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19D) (50 mg, 0.53 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (5 mL), and the mixture was heated to 50 °C and stirred for 48 h. After cooling to room temperature, the reaction solution was added dropwise to a saturated sodium bicarbonate (50 mL) solution, extracted with ethyl acetate (40 mL × 3), separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19E) as a pale yellow solid (250 mg, yield 96%).

[0628] LC-MS, M / Z (ESI): 494.5 [M+H] + 。

[0629] Step 5: (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-19)

[0630] (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-19)

[0631]

[0632] At room temperature, methyl (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-19E) (250 mg, 0.51 mmol) was added to tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL). Lithium hydroxide (61 mg, 2.55 mmol) was added and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. (S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-19) (19 mg, yield 8%) was obtained as a white solid by acidic preparative method A.

[0633] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.11 (d, 1H), 7.71 (d, 2H), 7.60 (d, 2H), 7.25 (t, 1H), 7.12 (d, 2H), 7.08 (d, 2H), 4.90 (t, 1H), 3.73 (s, 3H), 2.01 (t, 3H), 1.23 (d, 3H).

[0634] LC-MS, M / Z (ESI): 480.5 [M+H] +

[0635] Example 20: Preparation of Compound I-20

[0636] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-20)

[0637] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-20)

[0638]

[0639] The synthetic route of Compound I-20 is shown below:

[0640]

[0641] Step 1: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-20B)

[0642] methyl

[0643] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-20B)

[0644]

[0645] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (370 mg, 1.0 mmol) was added to N,N-dimethylformamide (10 mL), 3,4,5-trifluorophenol (222 mg, 1.5 mmol) and potassium hydroxide (168 mg, 3.0 mmol) were added, and the mixture was heated to 120 °C and stirred for 6 h. After cooling to room temperature, water (50 mL) was added for dilution, the pH was adjusted to 4 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (60 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude white solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-20B) (80 mg, yield 17%).

[0646] LC-MS, M / Z (ESI): 484.1 [M+H] + 。

[0647] Step 2: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-20)

[0648] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-20)

[0649]

[0650] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (80 mg, 0.16 mmol) was added to tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide (17 mg, 0.40 mmol) was added, and the mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the pH was adjusted to 4 with 1 N hydrochloric acid. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-20) (7 mg, yield 9.0%) was prepared by acidic preparation method A.

[0651] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.24 (d, 1H), 7.78 (d, 2H), 7.24 (d, 2H), 7.22 (t, 1H), 7.09 (d, 1H), 7.02 (d, 1H), 4.96 (t, 1H), 3.73 (s, 3H), 1.30 (d, 3H).

[0652] LC-MS, M / Z (ESI): 470.1 [M+H] +

[0653] Example 21: Preparation of Compound I-21

[0654] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-21)

[0655] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-21)

[0656]

[0657] The synthetic route of Compound I-21 is shown below:

[0658]

[0659] The first step: Methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-21B)

[0660] methyl

[0661] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-21B)

[0662]

[0663] At room temperature, 1-(2-fluoro-5-hydroxyphenyl)ethan-1-one (1.58 g, 10.8 mmol) was added to N,N-dimethylformamide (30 mL), and methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (2.0 g, 5.4 mmol) and potassium hydroxide (450 mg, 8.1 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 4 with 1N hydrochloric acid. It was extracted with ethyl acetate (30 mL × 3), the liquid was separated, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain white solid methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-21B) (346 mg, yield 13%).

[0664] LC-MS, M / Z (ESI): 490.2 [M+H]+

[0665] Step 2: (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-21)

[0666] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-21)

[0667]

[0668] At room temperature, methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-21B) (65 mg, 0.13 mmol) was added to tetrahydrofuran (5 mL), methanol (5 mL) and water (1 mL). Lithium hydroxide (20 mg, 0.47 mmol) was added and the mixture was stirred at room temperature for 5 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction mixture was concentrated. (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-21) (30 mg, yield 66%) was obtained as a white solid by acidic preparative method A.

[0669] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.18 (d, 1H), 7.72 (d, 2H), 7.38 - 7.32 (m, 2H), 7.29 - 7.24 (m, 1H), 7.26 (t, 1H), 7.16 (d, 2H), 4.91 (t, 1H), 3.73 (s, 3H), 2.54 (d, 3H), 1.24 (d, 3H).

[0670] LC-MS, M / Z (ESI): 476.1 [M+H] +

[0671] Example 22: Preparation of Compound I-22

[0672] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22)

[0673] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22)

[0674]

[0675] The synthetic route of Compound I-22 is shown below:

[0676]

[0677] Step 1: Methyl (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-22B)

[0678] methyl

[0679] (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-22B)

[0680]

[0681] At room temperature, 1-(3-hydroxyphenyl)ethan-1-one (275 mg, 2.02 mmol) was added to N,N-dimethylformamide (6 mL), and methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (500 mg, 1.35 mmol), copper(I) iodide (100 mg, 0.52 mmol), 1,10-phenanthroline (180 mg, 1.0 mmol), and cesium carbonate (1.30 g, 4.05 mmol) were added. Under nitrogen protection, the mixture was microwave-heated to 120 °C and stirred for 2 h. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), the layers were separated, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain white solid methyl (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-22B) (300 mg, yield 47%).

[0682] LC-MS, M / Z (ESI): 472.3 [M+H]+

[0683] Step 2: (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22C)

[0684] (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-22C)

[0685]

[0686] At room temperature, methyl (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-22B) (290 mg, 0.62 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (45 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22C), a white solid, was obtained by acidic preparative method A (180 mg, yield 64%).

[0687] LC-MS, M / Z(ESI): 458.3 [M+H] + 。

[0688] Step 3: 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22)

[0689] 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22)

[0690]

[0691] At room temperature, (S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22C) (170 mg, 0.37 mmol) was added to methanol (15 mL) and water (15 mL), and sodium borohydride (15 mg, 0.39 mmol) was added. The mixture was stirred at room temperature for 2 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the solution was concentrated. 4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-22), a white solid, was obtained by acidic preparative method A (168 mg, yield 98%).

[0692] LC-MS, M / Z(ESI): 460.3 [M+H]+ 。

[0693] 1 1H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 7.92 (d, 1H), 7.73 (d, 2H), 7.36 (t, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 7.13 (d, 2H), 7.11 (t, 1H), 6.83 (dd, 1H), 5.26 (d, 1H), 4.92 (t, 1H), 4.71 (s, 1H), 3.72 (s, 3H), 1.28 (dd, 3H), 1.22 (d, 3H).

[0694] LC-MS, M / Z (ESI): 478.1 [M + H] +

[0695] Example 23: Preparation of Compound I-23

[0696] 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-23)

[0697] 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-23)

[0698]

[0699] The synthetic route of Compound I-23 is shown below:

[0700]

[0701] The first step: Methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23B)

[0702] methyl

[0703] (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23B)

[0704]

[0705] At room temperature, 1-(2-fluoro-5-hydroxyphenyl)ethan-1-one (1.58 g, 10.8 mmol) was added to N,N-dimethylformamide (30 mL), and methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (2.0 g, 5.4 mmol) and potassium hydroxide (450 mg, 8.1 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 4 with 1 N hydrochloric acid. It was extracted with ethyl acetate (30 mL × 3), the liquid was separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain white solid methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23B) (346 mg, yield 13%).

[0706] LC-MS, M / Z(ESI): 490.2[M+H] +

[0707] Step 2: methyl 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23C)

[0708] methyl 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23C)

[0709]

[0710] At room temperature, methyl (S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23B) (100 mg, 0.20 mmol) was added to tetrahydrofuran (10 mL), cooled to 0 °C, sodium borohydride (23 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature for 3 h. Water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (80 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain crude white solid methyl 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23C) (75 mg, yield 75%).

[0711] LC-MS, M / Z (ESI): 492.1 [M+H] + 。

[0712] Step 3: 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-23)

[0713] 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-23)

[0714]

[0715] At room temperature, methyl 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-23C) (75 mg, 0.15 mmol) was added to tetrahydrofuran (5 mL), methanol (5 mL) and water (1 mL), lithium hydroxide monohydrate (20 mg, 0.47 mmol) was added, and the mixture was stirred at room temperature for 5 h. The pH was adjusted to 4 with 1N hydrochloric acid, the reaction solution was concentrated, and white solid 4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-23) (48 mg, yield 66%) was obtained by acidic preparation method A.

[0716] 1 1H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.02 (d, 1H), 7.74 (d, 2H), 7.25 (t, 1H), 7.21 - 7.10 (m, 4H), 6.90 - 6.81 (m, 1H), 4.96 - 4.86 (m, 2H), 3.72 (s, 3H), 3.67 (s, 1H), 1.28 (d, 3H), 1.24 (d, 3H).

[0717] LC-MS, M / Z (ESI): 478.1 [M + H] +

[0718] Example 24: Preparation of Compound I-24

[0719] (S)-4-(1-(3-(Difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-24)

[0720] (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-24)

[0721]

[0722] The synthetic route of Compound I-24 is as follows:

[0723]

[0724] The first step: 4-fluoro-3-(2-hydroxypropan-2-yl)phenol (Compound I-24B)

[0725] 4-fluoro-3-(2-hydroxypropan-2-yl)phenol (Compound I-24B)

[0726]

[0727] At room temperature, methyl 2-fluoro-5-hydroxybenzoate (340 mg, 2.0 mmol) was added to a solution of methylmagnesium bromide (5 mL, 1 mol / L) in tetrahydrofuran, and the mixture was stirred for 16 h. Saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 4-fluoro-3-(2-hydroxypropan-2-yl)phenol (Compound I-24B) as a colorless liquid (340 mg, yield 100%).

[0728] Step 2: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-24C)

[0729] methyl

[0730] (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-24C)

[0731]

[0732] At room temperature, 4-fluoro-3-(2-hydroxypropan-2-yl)phenol (Compound I-24B) (340 mg, 2.0 mmol) was added to N,N-dimethylformamide (9 mL), and methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (495 mg, 1.34 mmol), copper(I) iodide (100 mg, 0.52 mmol), 1,10-phenanthroline (180 mg, 1.0 mmol), and cesium carbonate (1.30 g, 4.05 mmol) were added. The mixture was heated to 120 °C by microwave irradiation under nitrogen protection and stirred for 2 h. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give methyl (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-24C) as a white solid (120 mg, yield 32%).

[0733] LC-MS, M / Z(ESI):506.3[M+1] + .

[0734] Step 3: (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropane-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamide)ethyl)benzoic acid (Compound I-24)

[0735] (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-24)

[0736]

[0737] The raw material (S)-methyl 4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropane-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamide)ethyl)benzoate (Compound I-24C) (120 mg, 0.24 mmol) was added to tetrahydrofuran (5 mL) and water (1 mL) at room temperature, and lithium hydroxide (20 mg, 0.47 mmol) was added and stirred at room temperature for 16 hours. The pH was adjusted to 4 with 1N hydrochloric acid, and the reaction solution was concentrated. A white solid (S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropane-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamide)ethyl)benzoic acid (Compound I-24) (22 mg, yield 19%) was prepared by acidic preparation method A.

[0738] 1 H NMR(400mHz,DMSO-d6)δ12.8(s,1H),7.96(d,1H),7.73(d,2H),7.33(t,1H),7.26(t,1H),7.17(d ,2H),7.14(t,1H),6.85(t,1H),4.92(t,1H),3.73(s,3H),3.72(s,1H),1.44(s,6H),1.25(d,3H).

[0739] LC-MS, M / Z(ESI):492.3[M+1] +

[0740] Example 25: Preparation of Compound I-25

[0741] (S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-25)

[0742] (S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-25)

[0743]

[0744] The synthetic route of Compound I-25 is as follows:

[0745]

[0746] The first step: (S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-25)

[0747] (S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-25)

[0748]

[0749] At room temperature, add 2-(3-hydroxyphenyl)acetonitrile (72 mg, 0.40 mmol) to N,N-dimethylformamide (2 mL), add methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (100 mg, 0.27 mmol), potassium hydroxide (30 mg, 0.53 mmol), and heat to 170 °C under nitrogen protection by microwave irradiation, stir for 5 min. Cool to room temperature, add water (5 mL), and stir for 0.5 h. Adjust the pH to 4 with 1N hydrochloric acid, concentrate the reaction solution, and prepare a white solid (S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (10 mg, yield 8%) by acidic preparation method A.

[0750] 11H NMR (400 mHz, CDCl3) δ 12.7 (s, 1H), 7.93 (d, 2H), 7.38 (t, 1H), 7.25 (t, 1H), 7.19 (d, 1H), 7.16 (d, 2H), 6.94 (s, 1H), 6.82 (t, 1H), 6.35 (d, 1H), 5.18 (t, 1H), 3.73 (s, 2H), 3.70 (s, 3H), 1.41 (d, 3H).

[0751] LC-MS, M / Z (ESI): 455.5 [M+H] +

[0752] Example 26: Preparation of Compound I-26

[0753] (S)-4-(1-(5-([1,1'-Diphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-26)

[0754] (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-26)

[0755]

[0756] The synthetic route of Compound I-26 is as follows:

[0757]

[0758] First step: Methyl (S)-4-(1-(5-([1,1'-diphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-26B)

[0759] methyl

[0760] (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-26B)

[0761]

[0762] At room temperature, add compound [1,1'-biphenyl]-4-ol (458 mg, 2.70 mmol) to N,N-dimethylformamide (10 mL), then add methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (500 mg, 1.35 mmol) and potassium hydroxide (227 mg, 4.05 mmol). Under nitrogen protection, heat to 120 °C by microwave and stir for 1 h. Cool to room temperature, add water (30 mL), adjust the pH to 4 with 1 N hydrochloric acid, extract with ethyl acetate (30 mL × 3), separate the layers, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the crude white solid methyl (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-26B) (500 mg, yield 73%).

[0763] LC-MS, M / Z(ESI): 506.4 [M+H]+

[0764] Step 2: (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-26)

[0765] (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-26)

[0766]

[0767] At room temperature, methyl (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-26B) (450 mg, 0.89 mmol) was added to tetrahydrofuran (10 mL), methanol (5 mL) and water (4 mL). Lithium hydroxide (108 mg, 4.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. White solid (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-26) (70 mg, yield 16%) was prepared by acidic preparation method A.

[0768] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.08 (d, 1H), 7.71 (d, 2H), 7.69 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.38 (t, 1H), 7.26 (t, 1H), 7.15 (d, 2H), 7.12 (d, 2H), 4.92 (t, 1H), 3.76 (s, 3H), 1.25 (d, 3H).

[0769] LC-MS, M / Z (ESI): 492.4 [M+H] +

[0770] Example 27: Preparation of Compound I-27

[0771] (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-27)

[0772] (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-27)

[0773]

[0774] The synthetic route of Compound I-27 is as follows:

[0775]

[0776] Step 1: Methyl (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-27B)

[0777] methyl

[0778] (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-27B)

[0779]

[0780] At room temperature, [1,1'-biphenyl]-3-ol (458 mg, 2.70 mmol) was added to N,N-dimethylformamide (10 mL), then methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (500 mg, 1.35 mmol) and potassium hydroxide (227 mg, 4.05 mmol) were added. Under nitrogen protection, it was heated to 120 °C by microwave and stirred for 1 h. After cooling to room temperature, water (30 mL) was added, and the pH was adjusted to 4 with 1 N hydrochloric acid. It was extracted with ethyl acetate (30 mL × 3), the liquid was separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain crude white solid methyl (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-27B) (450 mg, yield 66%).

[0781] LC-MS, M / Z(ESI): 506.4 [M+H] +

[0782] Step 2: (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-27)

[0783] (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-27)

[0784]

[0785] At room temperature, methyl (S)-4-(1-(5-([1,1'-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-27B) (400 mg, 0.79 mmol) was added to tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL). Lithium hydroxide (96 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1N hydrochloric acid, and the reaction solution was concentrated. White solid (S)-4-(1-(5-([1,1'-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-27) (115 mg, yield 30%) was obtained by acidic preparative method A.

[0786] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.07 (d, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 7.50 - 7.44 (m, 4H), 7.41 (d, 1H), 7.31 (s, 1H), 7.25 - 6.96 (m, 4H), 4.89 (t, 1H), 3.77 (s, 3H), 1.19 (d, 3H).

[0787] LC-MS, M / Z (ESI): 492.4 [M + H] +

[0788] Example 28: Preparation of Compound I-28

[0789] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-28)

[0790] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-28)

[0791]

[0792] The synthetic route of Compound I-28 is shown below:

[0793]

[0794] Step 1: 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-28B)

[0795] 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-28B)

[0796]

[0797] At room temperature, 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 2.57 mmol) was added to N,N-dimethylformamide (5 mL), and 3-(pentafluoro-λ 6 -sulfanyl)phenol (386 mg, 2.80 mmol) and potassium hydroxide (216 mg, 3.85 mmol) were added. The mixture was heated to 150 °C and stirred for 4 h. After cooling to room temperature, water (20 mL) was added for dilution, and the pH was adjusted to 4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (15 mL × 3), the layers were separated, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain a crude light yellow liquid of 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-28B) (750 mg, yield 98%).

[0798] LC-MS, M / Z (ESI): 379.1 [M+H] + .

[0799] Step 2: 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-28C)

[0800] 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-28C)

[0801]

[0802] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde (Compound I-28B) (750 mg, 2.55 mmol) was added to tert-butanol (6 mL) and water (7 mL). 2-Methyl-2-butene (355 mg, 5.07 mmol), sodium chlorite (456 mg, 5.07 mmol), and sodium dihydrogen phosphate (669 mg, 5.57 mmol) were added, and the mixture was stirred at room temperature for 14 h. Water (15 mL) was added for dilution, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-28C) as a pale yellow solid (800 mg, yield 100%).

[0803] LC-MS, M / Z (ESI): 395.1 [M+H] + 。

[0804] Step 3: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-28D)

[0805] methyl

[0806] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-28D)

[0807]

[0808] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6((3-(Difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ-sulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid (Compound I-28C) (800 mg, 2.58 mmol) was added to dichloromethane (20 mL). Methyl (S)-4-(1-aminoethyl)benzoate (459 mg, 2.56 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.40 g, 3.68 mmol), and N,N-diisopropylethylamine (991 mg, 7.68 mmol) were added, and the mixture was stirred at room temperature for 16 h. Dichloromethane (40 mL) was added for dilution, and the mixture was washed with water (20 mL × 3). After liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain a pale yellow liquid, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-28D) (720 mg, yield 59%).

[0809] LC-MS, M / Z (ESI): 556.1 [M+H] + .

[0810] Step 4: (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-28)

[0811] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-28)

[0812]

[0813] At room temperature, the starting material, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ 6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-28D) (440 mg, 0.93 mmol) was added to methanol (10 mL) and water (1 mL). Sodium hydroxide (93 mg, 2.32 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated to prepare a white solid, (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6 -sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-28) (93 mg, yield 22%).

[0814] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 8.18 (d, 1H), 7.74 (d, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.65 (t, 1H), 7.26 (d, 1H), 7.23 (t, 1H), 7.21 (d, 2H), 4.89 (t, 1H), 3.78 (s, 3H), 1.11 (d, 3H).

[0815] LC-MS, M / Z (ESI): 542.1 [M+H] +

[0816] Example 29: Preparation of Compound I-29

[0817] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-29)

[0818] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-29)

[0819]

[0820] The synthetic route of Compound I-29 is shown below:

[0821]

[0822] First step: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-29B)

[0823] methyl

[0824] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-29B)

[0825]

[0826] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (186 mg, 0.50 mmol) was added to N,N-dimethylformamide (5 mL). 3-((Trifluoromethyl)thio)phenol (120 mg, 0.60 mmol) and potassium hydroxide (45 mg, 0.80 mmol) were added, and the mixture was heated to 120 °C and stirred for 12 h. After cooling to room temperature, water (20 mL) was added for dilution, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain white solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-29B) (20 mg, yield 7.5%).

[0827] LC-MS, M / Z (ESI): 530.2 [M+H] + 。

[0828] Step 2: (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-29)

[0829] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-29)

[0830]

[0831] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-29B) (20 mg, 0.04 mmol) was added to tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL). Lithium hydroxide (3 mg, 0.16 mmol) was added, and the mixture was heated to 50 °C and stirred for 4 h. After cooling to room temperature, the pH was adjusted to 4 with 1 N hydrochloric acid. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-29) (14 mg, yield 72%) was obtained by acidic preparative method A.

[0832] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.16 (d, 1H), 7.74 (d, 2H), 7.57 (t, 2H), 7.39 (s, 1H), 7.22 - 6.69 (m, 4H), 4.91 - 4.84 (m, 1H), 3.74 (s, 3H), 1.21 (d, 3H).

[0833] LC-MS, M / Z (ESI): 516.2 [M + H] +

[0834] Example 30: Preparation of Compound I-30

[0835] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30)

[0836] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30)

[0837]

[0838] The synthetic route of Compound I-30 is as follows:

[0839]

[0840] The first step: 3-(methylthio)phenol (Compound I-30B)

[0841] 3-(methylthio)phenol (Compound I-30B)

[0842]

[0843] At room temperature, add (3-methoxyphenyl)(methyl)sulfide (4.0 g, 26 mmol) to 30% hydrobromic acid acetic acid solution (12 mL) and 48% aqueous hydrobromic acid solution (3 mL). Heat under reflux with N2 protection and stir for 6 h. Cool to room temperature, add water (100 mL) for dilution, extract with ether (100 mL × 3), separate the layers, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain crude 3-(methylthio)phenol (Compound I-30B) as a colorless liquid (3.8 g, yield 100%).

[0844] Step 2: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-30C)

[0845] methyl

[0846] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-30C)

[0847]

[0848] At room temperature, add methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (700 mg, 1.89 mmol) to N,N-dimethylformamide (5 mL), add 3-(methylthio)phenol (528 mg, 3.77 mmol), potassium hydroxide (318 mg, 5.67 mmol), heat to 150 °C by microwave irradiation and stir for 2 h. Cool to room temperature, add water (20 mL) for dilution, adjust the pH to 4 with 1N hydrochloric acid, extract with ethyl acetate (30 mL × 3), separate the layers, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain crude methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-30C) as a white solid (800 mg, yield 89%).

[0849] LC-MS, M / Z (ESI): 476.5 [M+H]+ 。

[0850] Step 3: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30)

[0851] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-30)

[0852]

[0853] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-30C) (800 mg, 1.68 mmol) was added to tetrahydrofuran (10 mL), methanol (10 mL) and water (2 mL). Lithium hydroxide (121 mg, 5.0 mmol) was added, and the mixture was heated to 50 °C and stirred for 4 h. After cooling to room temperature, the pH was adjusted to 4 with 1N hydrochloric acid. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30) (165 mg, yield 21%) was obtained by acidic preparative method A.

[0854] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.34 (t, 2H), 7.14 (d, 2H), 7.11 (t, 1H), 6.97 (t, 1H), 6.70 (d, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.45 (s, 3H), 1.24 (d, 3H).

[0855] LC-MS, M / Z (ESI): 462.5 [M+H] +

[0856] Example 31: Preparation of Compound I-31

[0857] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylsulfonyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-31)

[0858] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(methylsulfonyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-31)

[0859]

[0860] The synthetic route of Compound I-31 is as follows:

[0861]

[0862] At room temperature, the raw material (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30) (80 mg, 0.17 mmol) was added to dichloromethane (5 mL), and m-chloroperoxybenzoic acid (83 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, and the white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylsulfonyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-31) (64 mg, yield 75%) was prepared by acidic preparation method A.

[0863] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.21 (d, 1H), 7.77 (d, 2H), 7.75 (d, 1H), 7.70 (t, 1H), 7.59 (t, 1H), 7.37 (d, 1H), 7.25 (t, 1H), 7.15 (d, 2H), 4.87 (t, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 1.19 (d, 3H).

[0864] LC-MS, M / Z (ESI): 494.1 [M+H] +

[0865] Example 32: Preparation of Compound I-32

[0866] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(methylsulfinyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-32)

[0867] 4-((1S)-1-(3-(Difluoromethyl)-1-methyl-5-(3-(methylsulfinyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-32)

[0868]

[0869] The synthetic route of Compound I-32 is as follows:

[0870]

[0871] At room temperature, the raw material (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-30) (60 mg, 0.13 mmol) was added to tetrahydrofuran (5 mL), 30% hydrogen peroxide (1 mL) was added, and the mixture was heated to 60 °C and stirred for 7 h. After cooling to room temperature, the reaction solution was concentrated, and the white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylsulfinyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-32) (35 mg, yield 75%) was prepared by acidic preparation method A.

[0872] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.15 (d, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.50 (t, 1H), 7.36 (s, 1H), 7.25 (t, 1H), 7.15 (d, 1H), 7.13 (d, 2H), 4.87 (t, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.20 (d, 3H).

[0873] LC-MS, M / Z (ESI): 478.2 [M+H] +

[0874] Example 33: Preparation of Compound I-33

[0875] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-33)

[0876] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-33)

[0877]

[0878] The synthetic route of Compound I-33 is as follows:

[0879]

[0880] The first step: 1-(Benzyloxy)-3-(2,2,2-trifluoroethoxy)benzene (Compound I-33B)

[0881] 1-(benzyloxy)-3-(2,2,2-trifluoroethoxy)benzene (Compound I-33B)

[0882]

[0883] At room temperature, 3-(benzyloxy)phenol (600 mg, 3.0 mmol) was added to N,N-dimethylformamide (10 mL), then 2,2,2-trifluoroethane-1-sulfonic acid trifluoride (840 mg, 3.6 mmol) and potassium carbonate (1.24 g, 9.0 mmol) were added. The mixture was heated to 60 °C and stirred for 16 h. After cooling to room temperature, water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The layers were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain colorless liquid 1-(benzyloxy)-3-(2,2,2-trifluoroethoxy)benzene (Compound I-33B) (380 mg, yield 45%).

[0884] The second step: 3-(2,2,2-trifluoroethoxy)phenol (Compound I-33C)

[0885] 3-(2,2,2-trifluoroethoxy)phenol (Compound I-33C)

[0886]

[0887] At room temperature, 1-(benzyloxy)-3-(2,2,2-trifluoroethoxy)benzene (Compound I-33B) (520 mg, 1.84 mmol) was added to ethanol (10 mL), 10% palladium on carbon (50 mg) was added, a drop of formic acid was added, hydrogen gas was introduced, and the mixture was stirred for 12 h. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the title compound, 3-(2,2,2-trifluoroethoxy)phenol (Compound I-33C), as a white solid (210 mg, yield 59%).

[0888] Step 3: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-33D)

[0889] methyl

[0890] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-33D)

[0891]

[0892] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (371 mg, 1.0 mmol) was added to N,N-dimethylformamide (5 mL), 3-(2,2,2-trifluoroethoxy)phenol (Compound I-33C) (210 mg, 1.1 mmol), copper(I) iodide (191 mg, 1.0 mmol), cesium carbonate (1.0 g, 3.1 mmol), and 1,10-phenanthroline (72 mg, 0.40 mmol) were added, and the mixture was heated to 120 °C by microwave and stirred for 2 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-33D) as a white solid (120 mg, yield 8%).

[0893] LC-MS, M / Z(ESI):528.2[M+H] + .

[0894] Step 4: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamide)ethyl)benzoic acid (Compound I-33)

[0895] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-33)

[0896]

[0897] The raw material (S)-methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamide)ethyl)benzoate (Compound I-33D) (120 mg, 0.23 mmol) was added to tetrahydrofuran (5 mL), methanol (5 mL) and water (1 mL) at room temperature, and lithium hydroxide (20 mg, 0.83 mmol) was added and stirred at room temperature for 16 hours. The pH was adjusted to 4 with 1N hydrochloric acid, and the reaction solution was concentrated. A white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamide)ethyl)benzoic acid (Compound I-33) (45 mg, yield 72%) was prepared by acidic preparation method A.

[0898] 1 H NMR(400mHz,DMSO-d6)δ12.8(s,1H),8.02(d,1H),7.74(d,2H),7.38(t,1H),7.16(t,1H),7.14(d, 2H),6.93(d,1H),6.76(t,1H),6.65(d,1H),4.92(t,1H),4.78(dd,2H),3.72(s,3H),1.25(d,3H).

[0899] LC-MS, M / Z(ESI):514.2[M+H] +

[0900] Example 34: Preparation of Compound I-34

[0901] (S)-4-(1-(3-(Difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-34)

[0902] (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-34)

[0903]

[0904] The synthetic route of Compound I-34 is as follows:

[0905]

[0906] The first step: Methyl (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-34B)

[0907] methyl

[0908] (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-34B)

[0909]

[0910] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (370 mg, 1.0 mmol) was added to N,N-dimethylformamide (10 mL), 2,4-difluorophenol (195 mg, 1.5 mmol) and potassium hydroxide (168 mg, 3.0 mmol) were added, and the mixture was heated to 120 °C and stirred for 6 h. After cooling to room temperature, water (50 mL) was added for dilution, the pH was adjusted to 4 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (60 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude white solid methyl (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-34B) (160 mg, yield 34%).

[0911] LC-MS, M / Z (ESI): 466.1 [M+H] + 。

[0912] Step 2: (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-34)

[0913] (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(Compound I-34)

[0914]

[0915] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-34B) (160 mg, 0.34 mmol) was added to tetrahydrofuran (4 mL) and water (2 mL). Lithium hydroxide (32 mg, 0.76 mmol) was added, and the mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the pH was adjusted to 4 with 1N hydrochloric acid. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-34) (11 mg, yield 7.0%) was obtained by acidic preparative method A.

[0916] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 8.28 (d, 1H), 7.78 (d, 2H), 7.45 (t, 1H), 7.21 (d, 2H), 7.17 (t, 1H), 7.04 (d, 1H), 7.02 (d, 1H), 4.88 (t, 1H), 3.76 (s, 3H), 1.26 (d, 3H).

[0917] LC-MS, M / Z (ESI): 452.1 [M+H] +

[0918] Example 35: Preparation of Compound I-35

[0919] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid methyl ester (Compound I-35)

[0920] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-35)

[0921]

[0922] The synthetic route of Compound I-35 is as follows:

[0923]

[0924] The first step: methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-35B)

[0925] methyl

[0926] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-35B)

[0927]

[0928] At room temperature, 3-(trifluoromethyl)benzenethiol (215 mg, 1.20 mmol) was added to N,N-dimethylformamide (20 mL), and sodium hydride (80 mg, 2.00 mmol) was added. The mixture was stirred for 0.5 h. Methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (375 mg, 1.00 mmol) was added, and the mixture was heated to 120 °C and stirred for 8 h. After cooling to room temperature, water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL × 3). The layers were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain white solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-35B) (350 mg, yield 67%).

[0929] LC-MS, M / Z (ESI): 514.2 (M+1).

[0930] Step 2: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-35)

[0931] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-35)

[0932]

[0933] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-35B) (220 mg, 0.43 mmol) was added to tetrahydrofuran (5 mL), water (5 mL) and methanol (5 mL) were added, and lithium hydroxide (30 mg, 1.25 mmol). The mixture was heated to 50 °C and stirred for 18 h. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-35) (105 mg, yield 49%) was obtained by acidic preparative method A.

[0934] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.68 (d, 1H), 7.79 (d, 2H), 7.63 (d, 1H), 7.58 (t, 2H), 7.39 (d, 2H), 7.27 (t, 1H), 7.14 (t, 1H), 5.10 - 5.03 (m, 1H), 3.89 (s, 3H), 1.38 (d, 3H).

[0935] LC-MS, M / Z (ESI): 500.2 (M+1)

[0936] Example 36: Preparation of Compound I-36

[0937] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-36)

[0938] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-36)

[0939]

[0940] The synthetic route of Compound I-36 is as follows:

[0941]

[0942] The first step: (4-(trifluoromethyl)benzyl)zinc(II) bromide (Compound I-36B)

[0943] (4-(trifluoromethyl)benzyl)zinc(II)bromide(Compound I-36B)

[0944]

[0945] At room temperature, zinc powder (2.60 g, 40.0 mmol) was added to anhydrous tetrahydrofuran (15 mL). Under nitrogen protection, 1,2-dibromoethane (0.02 mL) was heated to 60 °C, trimethylchlorosilane (0.02 mL) was added, and stirring was continued for 15 min. After cooling to 0 °C, a solution of compound 4-(trifluoromethyl)benzyl bromide (4.80 g, 20.0 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition was complete, the mixture was heated to 60 °C and stirred for 1 h. After cooling to room temperature, a 1 mol / L tetrahydrofuran solution of (4-(trifluoromethyl)benzyl)zinc(II) bromide (20 mL) (Compound I-36B) was obtained.

[0946] The second step: methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-36C)

[0947] methyl

[0948] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(Compound I-36C)

[0949]

[0950] At room temperature, a solution of zinc (4-(trifluoromethyl)benzyl) bromide in tetrahydrofuran (Compound I-36B) (2.70 mL, 2.70 mmol) was added to N,N-dimethylformamide (15 mL). Methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (500 mg, 1.35 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (35 mg, 0.13 mmol), and nickel(II) chloride dimethoxyethane complex (30 mg, 0.13 mmol) were added. Under nitrogen protection, the mixture was heated to 100 °C by microwave irradiation and stirred for 1 h. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-36C) as a white solid (180 mg, yield 27%).

[0951] LC-MS, M / Z (ESI): 496.3 [M+1]+.

[0952] Step 3: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-36)

[0953] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-36)

[0954]

[0955] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-36C) (150 mg, 0.30 mmol) was added to 48% hydrobromic acid in acetic acid solution (3 mL), and the mixture was heated to 65 °C and stirred for 16 h. After cooling to room temperature, the reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-36) (90 mg, yield 62%) was obtained by acidic preparation method A.

[0956] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.47 (d, 1H), 7.86 (d, 2H), 7.62 (d, 2H), 7.41 (d, 2H), 7.33 (d, 2H), 7.23 (t, 1H), 5.12 (t, 1H), 4.37 (dd, 2H), 3.77 (s, 3H), 1.41 (s, 3H).

[0957] LC-MS, M / Z (ESI): 482.3 [M+1] +

[0958] Example 37: Preparation of Compound I-37

[0959] (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid (Compound I-37)

[0960] (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid (Compound I-37)

[0961]

[0962] The synthetic route of Compound I-37 is as follows:

[0963]

[0964] The first step: (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (Compound I-37B)

[0965] (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (Compound I-37B)

[0966]

[0967] At room temperature, 1-(5-bromothiophen-2-yl)ethan-1-one (2.05 g, 10.0 mmol) was added to dichloromethane (50 mL). (R)-tert-Butanesulfinamide (1.8 g, 15.0 mmol) and tetraethyl titanate (5.70 g, 25.0 mmol) were added. The mixture was heated to 50 °C and stirred for 20 h. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the white solid (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (Compound I-37B) (500 mg, yield 16%).

[0968] Step 2: (R)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound I-37C)

[0969] (R)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound I-37C)

[0970]

[0971] At room temperature, the compound (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (Compound I-37B) (500 mg, 1.62 mmol) was added to tetrahydrofuran (10 mL). The mixture was cooled to -78 °C, and 1 mol / L lithium tri-sec-butylborohydride in tetrahydrofuran solution (2.4 mL, 2.4 mmol) was added. The mixture was allowed to warm to room temperature naturally and stirred for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the white solid (R)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound I-37C) (320 mg, yield 64%).

[0972] LC-MS, M / Z (ESI): 310.2 [M+H] + 。

[0973] Step 3: (S)-1-(5-bromothiophen-2-yl)ethane-1-amine hydrochloride (Compound I-37D)

[0974] (S)-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride (Compound I-37D)

[0975]

[0976] At room temperature, the raw material (R)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound I-37C) (310 mg, 1.0 mmol) was added to methanol (10 mL), and 4 mol / L hydrochloric acid in dioxane solution (0.5 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated, ether (10 mL) was added, and the white solid (S)-1-(5-bromothiophen-2-yl)ethane-1-amine hydrochloride (60097D) (190 mg, yield 78%) was obtained by filtration.

[0977] Step 4: (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamide (Compound I-37E)

[0978] (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamide (Compound I-37E)

[0979]

[0980] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxylic acid (140 mg, 0.41 mmol) was added to dichloromethane (5 mL) and N,N-dimethylformamide (5 mL). (S)-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride (Compound I-37D) (118 mg, 0.49 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (239 mg, 0.63 mmol) and N,N-diisopropylethylamine (135 mg, 1.05 mmol). The mixture was stirred at room temperature for 16 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the crude product of white solid (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamide (Compound I-37E) (170 mg, yield 78%).

[0981] LC-MS, M / Z (ESI): 524.2 [M+H] + 。

[0982] Step 5: Methyl (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylate (Compound I-37F)

[0983] methyl

[0984] (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylate (Compound I-37F)

[0985]

[0986] At room temperature, (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamide (Compound I-37E) (170 mg, 0.32 mmol) was added to methanol (5 mL), and triethylamine (320 mg, 3.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (53 mg, 0.06 mmol) were added. Carbon monoxide was introduced, and the mixture was heated to 120 °C and stirred for 48 h. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain white solid methyl (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylate (Compound I-37F) (140 mg, yield 86%).

[0987] LC-MS, M / Z(ESI): 504.5[M+H] + 。

[0988] Step 6: (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid (Compound I-37)

[0989] (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid (Compound I-37)

[0990]

[0991] At room temperature, methyl (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylate (Compound I-37F) (140 mg, 0.28 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (20 mg, 0.47 mmol) was added. The mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. (S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid (Compound I-37) (110 mg, yield 81%) was obtained as a white solid by acidic preparative method A.

[0992] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 8.32 (d, 1H), 7.62 (t, 1H), 7.54 (t, 1H), 7.42 (d, 2H), 7.28 (t, 1H), 7.23 (t, 1H), 6.75 (d, 1H), 5.51 - 5.04 (m, 1H), 3.76 (s, 3H), 1.27 (d, 3H).

[0993] LC-MS, M / Z (ESI): 490.5 [M + H] +

[0994] Example 38: Preparation of Compound I-38

[0995] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid (Compound I-38)

[0996] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid (Compound I-38)

[0997]

[0998] The synthetic route of Compound I-38 is as follows:

[0999]

[1000] Step 1: tert-butyl (S)-(1-(3,5-difluorophenyl)ethyl)carbamate (Compound I-38B)

[1001] tert-butyl (S)-(1-(3,5-difluorophenyl)ethyl)carbamate (Compound I-38B)

[1002]

[1003] At room temperature, (S)-1-(3,5-difluorophenyl)ethane-1-amine hydrochloride (2.0 g, 10.3 mmol) was added to dichloromethane (50 mL), followed by di-tert-butyl dicarbonate (4.5 g, 20.7 mmol) and triethylamine (3.1 g, 31.0 mmol). The mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain white solid tert-butyl (S)-(1-(3,5-difluorophenyl)ethyl)carbamate (Compound I-38B) (2.2 g, yield 72%).

[1004] Step 2: (S)-4-(1-((tert-butoxycarbonyl)amino)ethyl)-2,6-difluorobenzoic acid (Compound I-38C)

[1005] (S)-4-(1-((tert-butoxycarbonyl)amino)ethyl)-2,6-difluorobenzoic acid (Compound I-38C)

[1006]

[1007] At room temperature, tert-butyl (S)-(1-(3,5-difluorophenyl)ethyl)carbamate (500 mg, 2.50 mmol) was added to tetrahydrofuran (10 mL). The mixture was cooled to -78 °C, and 2.5 mol / L butyllithium in THF solution (2.0 mL, 5.0 mmol) was added. The mixture was stirred for 2 h. Carbon dioxide was introduced at low temperature, and the mixture was allowed to warm to room temperature naturally and stirred for 16 h. The pH was adjusted to 2 with 1 N hydrochloric acid, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude white solid (S)-4-(1-((tert-butoxycarbonyl)amino)ethyl)-2,6-difluorobenzoic acid (Compound I-38C) (550 mg, yield 90%).

[1008] Step 3: Methyl (S)-4-(1-aminoethyl)-2,6-difluorobenzoate (Compound I-38D)

[1009] methyl(S)-4-(1-aminoethyl)-2,6-difluorobenzoate (Compound I-38D)

[1010]

[1011] At room temperature, the raw material (S)-4-(1-(tert-butoxycarbonyl)amino)ethyl)-2,6-difluorobenzoic acid (Compound I-38C) (500 mg, 2.0 mmol) was added to methanol (100 mL), concentrated sulfuric acid (20 mL) was added, and the mixture was heated to 80 °C and stirred for 6 h. Water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of white solid methyl (S)-4-(1-aminoethyl)-2,6-difluorobenzoate (Compound I-38D) (1.2 g, yield 100%).

[1012] Step 4: methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoate (Compound I-38E)

[1013] methyl

[1014] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoate (Compound I-38E)

[1015]

[1016] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxylic acid (100 mg, 0.30 mmol) was added to dichloromethane (8 mL) and N,N-dimethylformamide (2 mL). (S)-Methyl 4-(1-aminoethyl)-2,6-difluorobenzoate (Compound I-38D) (78 mg, 0.36 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol), and N,N-diisopropylethylamine (58 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature for 16 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel thin-layer chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the white solid (S)-methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoate (Compound I-38E) (82 mg, yield 52%).

[1017] LC-MS, M / Z (ESI): 534.3 [M+H] + 。

[1018] Step 5: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid (Compound I-38)

[1019] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid (Compound I-38)

[1020]

[1021] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoate (82 mg, 0.15 mmol) was added to tetrahydrofuran (2 mL) and water (4 mL), and lithium hydroxide (18.9 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 16 h. The pH was adjusted to 4 with 1 N hydrochloric acid, and the reaction solution was concentrated. (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid (Compound I-38), a white solid, was prepared by acidic preparative method A (16 mg, yield 20%).

[1022] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.12 (d, 1H), 7.61 (t, 1H), 7.56 (t, 1H), 7.45 (s, 1H), 7.27 (t, 1H), 7.25 (t, 1H), 6.62 (d, 2H), 4.76 (t, 1H), 3.76 (s, 3H), 1.13 (d, 3H).

[1023] LC-MS, M / Z (ESI): 520.3 [M + H] +

[1024] Example 39: Preparation of Compound I-39

[1025] (S)-4-(1-(3-(Difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid (Compound I-39)

[1026] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid (Compound I-39)

[1027]

[1028] The synthetic route of Compound I-39 is as follows:

[1029]

[1030] The first step: Synthesis of methyl 4-formyl-2-methylbenzoate (Compound I-39B)

[1031] methyl 4-formyl-2-methylbenzoate (Compound I-39B)

[1032]

[1033] 4-Bromo-3-methylbenzaldehyde (Compound I-39A) (10.0 g, 50.2 mmol) and triethylamine (15.3 g, 151 mmol) were added to methanol (200 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (2.94 g, 4.02 mmol) was added at room temperature. Then, it was purged with carbon monoxide three times, and then reacted at 65 °C under a pressure of 50 Psi for 15 h. After cooling to room temperature, it was filtered through diatomaceous earth, and the filter cake was washed three times with ethyl acetate. The filtrate was concentrated to obtain the crude product, and the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 - 5:1) to obtain methyl 4-formyl-2-methylbenzoate (Compound I-39B) (8.0 g, yield 89%).

[1034] Step 2: Synthesis of methyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)-2-methylbenzoate (Compound I-39C)

[1035] methyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)-2-methylbenzoate (Compound I-39C)

[1036]

[1037] Methyl 4-formyl-2-methylbenzoate (Compound I-39B) (8.0 g, 44.9 mmol), R-(+)-tert-butylsulfinamide (6.53 g, 53.9 mmol), and cesium carbonate (17.6 g, 53.9 mmol) were added to dichloromethane (200 mL), and the reaction solution was reacted at 50 °C for 15 h. Water (200 mL) and dichloromethane (200 mL) were added to the reaction solution, and the aqueous phase was extracted with dichloromethane (200 mL × 3). The combined extracts were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 - 1:1) to obtain methyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)-2-methylbenzoate (Compound I-39C) (10.0 g, yield 79%).

[1038] Step 3: Synthesis of methyl 4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-2-methylbenzoate (Compound I-39D)

[1039] methyl 4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-2-methylbenzoate(Compound I-39D)

[1040]

[1041] Methyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)-2-methylbenzoate (Compound I-39C) (1.0 g, 3.55 mmol) was added to tetrahydrofuran (20 mL). The reaction solution was cooled to -10 °C, and methylmagnesium chloride (7.1 mL, 21.3 mmol, 3 mol / L) was slowly added dropwise. The reaction solution was reacted at room temperature for 15 h. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined extraction solutions were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 - 1:1) to obtain methyl 4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-2-methylbenzoate (Compound I-39D) (0.7 g, yield 66%).

[1042] Step 4: Synthesis of methyl (S)-4-(1-aminoethyl)-2-methylbenzoate (Compound I-39E)

[1043] methyl(S)-4-(1-aminoethyl)-2-methylbenzoate(Compound I-39E)

[1044]

[1045] Methyl 4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-2-methylbenzoate (Compound I-39D) (0.7 g, 2.35 mmol) was added to ethyl acetate (10 mL). Ethyl acetate / hydrogen chloride solution (10 mL) was added at room temperature, and the reaction solution was reacted at room temperature for 2 h. The reaction solution was concentrated to obtain methyl (S)-4-(1-aminoethyl)-2-methylbenzoate (Compound I-39E) (0.4 g, yield 88%).

[1046] Step 5: Synthesis of (S)-methyl 4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoate (Compound I-39F)

[1047] methyl methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoate (Compound I-39F)

[1048]

[1049] (S)-4-(1-aminoethyl)-2-methylbenzoic acid methyl ester (Compound I-39E) (0.1 g, 0.52 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (0.24 g, 0.62 mmol) and N,N-diisopropylethylamine (0.20 g, 1.55 mmol), 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (0.20 g, 0.62 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at room temperature for 12 h. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and ethyl acetate (100 mL×4) was used for extraction. The combined extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and spin-dried to obtain a crude product, which was separated and purified using a silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-1:1) to obtain (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid methyl ester (Compound I-39F) (0.15 g, yield 59%).

[1050] Step 6: Synthesis of (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid (Compound I-39)

[1051] (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid (Compound I-39)

[1052]

[1053] Methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoate (Compound I-39F) (0.15 g, 0.31 mmol) was added to tetrahydrofuran (5 mL), methanol (5 mL) and water (1 mL). Lithium hydroxide (0.03 g, 1.23 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. Water (50 mL) and ethyl acetate (100 mL) were added to the crude product, and the pH was adjusted to 7 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give a white solid, (S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid (Compound I-39) (83 mg, yield 57%).

[1054] 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 7.6, 6.4 Hz, 2H), 6.99–6.94 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.80–6.75 (m, 1H), 4.84–4.79 (m, 1H), 3.69 (s, 3H), 2.36 (s, 3H), 2.53 (dd, J = 14.8, 7.4 Hz, 2H) 1.19 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.6 Hz, 3H).

[1055] LC-MS, M / Z (ESI): 476.3 [M+H] + 。

[1056] Example 40: Preparation of Compound I-40

[1057] 4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid (Compound I-40)

[1058] 4-(1-(3-(Difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid (Compound I-40)

[1059]

[1060] The synthetic route of Compound I-40 is as follows:

[1061]

[1062] The first step: N-cyclobutylidene-2-methylpropane-2-sulfinamide (Compound I-40B)

[1063] N-cyclobutylidene-2-methylpropane-2-sulfinamide (Compound I-40B)

[1064]

[1065] At room temperature, cyclobutanone (5.0 g, 71.4 mmol) was added to dichloromethane (100 mL), followed by tert-butylsulfinamide (10.3 g, 85.6 mmol) and tetraethyl titanate (32.6 g, 143 mmol). The mixture was heated to 40 °C and stirred for 24 h. After cooling to room temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain a pale yellow liquid, N-cyclobutylidene-2-methylpropane-2-sulfinamide (Compound I-40B) (6.5 g, yield 53%).

[1066] The second step: N-(1-(4-bromophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (Compound I-40C)

[1067] N-(1-(4-bromophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (Compound I-40C)

[1068]

[1069] At room temperature, 1,4-dibromobenzene (14.0 g, 59.8 mmol) was added to tetrahydrofuran (150 mL). The mixture was cooled to -78 °C, and 2.5 mol / L butyllithium in tetrahydrofuran solution (24.0 mL, 60.0 mmol) was added. After stirring for 40 min, a solution of N-cyclobuten-2-yl-2-methylpropan-2-sulfinamide (Compound I-40B) (7.0 g, 40.4 mmol) in tetrahydrofuran (150 mL) was added dropwise under nitrogen protection. The mixture was allowed to warm to room temperature naturally and stirred for 2.5 h. Saturated aqueous ammonium chloride solution (200 mL) was added for dilution, and the mixture was extracted with ethyl acetate (200 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain yellow solid N-(1-(4-bromophenyl)cyclobutyl)-2-methylpropan-2-sulfinamide (Compound I-40C) (1.8 g, yield 64%).

[1070] LC-MS, M / Z(ESI): 330.0[M+H] + 。

[1071] Step 3: Methyl 4-(1-((tert-butylsulfinyl)amino)cyclobutyl)benzoate (Compound I-40D)

[1072] methyl 4-(1-((tert-butylsulfinyl)amino)cyclobutyl)benzoate(Compound I-40D)

[1073]

[1074] At room temperature, the starting material N-(1-(4-bromophenyl)cyclobutyl)-2-methylpropan-2-sulfinamide (Compound I-40C) (1.80 g, 5.47 mmol) was added to methanol (30 mL). Triethylamine (2.76 g, 27.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (450 mg, 0.55 mmol) were added. Carbon monoxide was introduced, and the mixture was heated to 85 °C and stirred for 24 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain yellow liquid methyl 4-(1-((tert-butylsulfinyl)amino)cyclobutyl)benzoate (Compound I-40D) (1.30 g, yield 77%).

[1075] Step 4: Methyl 4-(1-aminocyclobutyl)benzoate (Compound I-40E)

[1076] methyl 4-(1-aminocyclobutyl)benzoate (Compound I-40E)

[1077]

[1078] At room temperature, methyl 4-(1-((tert-butylsulfinyl)amino)cyclobutyl)benzoate (Compound I-40D) (600 mg, 1.94 mmol) was added to dichloromethane (10 mL). 4 mol / L dioxane hydrochloride solution (2.0 mL, 8.0 mmol) was added, and the mixture was stirred at room temperature for 4 h. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The layers were separated, and the organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, separated, the organic phases were combined again, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude colorless liquid methyl 4-(1-aminocyclobutyl)benzoate (Compound I-40E) (350 mg, yield 88%).

[1079] LC-MS, M / Z (ESI): 206.5 [M+H] + 。

[1080] Step 5: methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoate (Compound I-40F)

[1081] methyl

[1082] 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoate (Compound I-40F)

[1083]

[1084] At room temperature, 3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxylic acid (100 mg, 0.30 mmol) was added to N,N-dimethylformamide (3 mL), then methyl 4-(1-aminocyclobutyl)benzoate (Compound I-40E) (74 mg, 0.36 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 16 h. Then water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL×3). After liquid separation, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V)=1:1) to obtain white solid methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoate (Compound I-40F) (60 mg, yield 39%).

[1085] LC-MS, M / Z(ESI): 524.5[M+H] + 。

[1086] Step 6: 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid (Compound I-40)

[1087] 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid (Compound I-40)

[1088]

[1089] At room temperature, methyl 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoate (Compound I-40F) (60 mg, 0.12 mmol) was added to tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide (20 mg, 0.47 mmol) was added. The mixture was stirred at room temperature for 16 h. The pH was adjusted to 2 with 1 N hydrochloric acid, and the reaction solution was concentrated. White solid 4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid (Compound I-40) (16 mg, yield 27%) was obtained by acidic preparation method A.

[1090] 1 H NMR (400 mHz, DMSO-d6) δ 12.7 (s, 1H), 8.52 (s, 1H), 7.74 (d, 2H), 7.68 (d, 1H), 7.62 (d, 1H), 7.50 (s, 1H), 7.34 (t, 1H), 7.25 (d, 2H), 7.18 (t, 1H), 3.78 (s, 3H), 2.33 - 2.28 (m, 2H), 2.16 - 2.13 (m, 2H), 1.70 - 1.65 (m, 1H), 1.59 - 1.54 (m, 1H).

[1091] LC-MS, M / Z (ESI): 510.5 [M + H] +

[1092] Example 41: Preparation of Compound I-41

[1093] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-41)

[1094] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-41)

[1095]

[1096] The synthetic route of Compound I-41 is shown as follows:

[1097]

[1098] Step 1: methyl 3-((3-(difluoromethyl)-4-formyl-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41B)

[1099] methyl

[1100] 3-((3-(difluoromethyl)-4-formyl-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate(Compound I-41B)

[1101]

[1102] At room temperature, 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (120 mg, 0.62 mmol) was added to N,N-dimethylformamide (5 mL), then methyl 3-hydroxy-5-methylthiophene-2-carboxylate (143 mg, 0.74 mmol), cesium carbonate (403 mg, 1.24 mmol), copper(I) iodide (24.0 mg, 0.12 mmol), and 1,10-phenanthroline (45.0 mg, 0.25 mmol) were added. The mixture was heated to 130 °C under microwave irradiation and stirred for 1 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain methyl 3-((3-(difluoromethyl)-4-formyl-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41B) as a colorless liquid (32.0 mg, yield 16%).

[1103] LC-MS, M / Z (ESI): 331.4 (M+1).

[1104] Step 2: 3-(difluoromethyl)-5-((2-(methoxycarbonyl)-5-methylthiophen-3-yl)oxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-41C)

[1105] 3-(difluoromethyl)-5-((2-(methoxycarbonyl)-5-methylthiophen-3-yl)oxy)-1-methyl-1H-pyrazole-4-carboxylic acid(Compound I-41C)

[1106]

[1107] At room temperature, methyl 3-((3-(difluoromethyl)-4-formyl-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41B) (30.0 mg, 0.09 mmol) was added to tert-butanol (6 mL) and water (3 mL). 2-Methyl-2-butene (18.9 mg, 0.27 mmol), sodium chlorite (24.0 mg, 0.27 mmol), and sodium dihydrogen phosphate (27.0 mg, 2.34 mmol) were added, and the mixture was stirred at room temperature for 16 h. Water (5 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid, 3-(difluoromethyl)-5-((2-(methoxycarbonyl)-5-methylthiophen-3-yl)oxy)-1-methyl-1H-pyrazole-4-carboxylic acid (Compound I-41C) (32.0 mg, yield 100%).

[1108] LC-MS, M / Z (ESI): 347.4 (M+1).

[1109] Step 3: (S)-3-((3-(difluoromethyl)-4-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41D)

[1110] methyl

[1111] (S)-3-((3-(difluoromethyl)-4-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41D)

[1112]

[1113] At room temperature, 3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid (24.0 mg, 0.07 mmol) was added to dichloromethane (5 mL), then methyl (S)-4-(1-aminoethyl)benzoate (15.0 mg, 0.08 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (40.0 mg, 0.10 mmol), and N,N-diisopropylethylamine (14.0 mg, 0.10 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (20 mL), extracted with ethyl acetate (10 mL×3), the layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain colorless liquid methyl (S)-3-((3-(difluoromethyl)-4-(((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (Compound I-41D) (25.0 mg, yield 71.0%).

[1114] LC-MS, M / Z (ESI): 508.6 (M+1).

[1115] Step 4: (S)-3-((4-((1-(4-carboxyphenyl)ethyl)carbamoyl)-3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylic acid (Compound I-41E)

[1116] (S)-3-((4-((1-(4-carboxyphenyl)ethyl)carbamoyl)-3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylic acid (Compound I-41E)

[1117]

[1118] At room temperature, the raw material methyl (S)-3-((3-(difluoromethyl)-4-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate (38.0 mg, 0.08 mmol) was added to tetrahydrofuran (5 mL) and water (3 mL), lithium hydroxide (10.0 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 3 h. The pH was adjusted to 6 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product as a white solid, (S)-3-((4-((1-(4-carboxyphenyl)ethyl)carbamoyl)-3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylic acid (Compound I-41E) (33.0 mg, yield 92%).

[1119] LC-MS, M / Z (ESI): 480.3 (M+1)

[1120] Step 5: (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-41)

[1121] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-41)

[1122]

[1123] At room temperature, the raw material (S)-3-((4-((1-(4-carboxyphenyl)ethyl)carbamoyl)-3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylic acid (30.0 mg, 0.06 mmol) was added to N-methylpyrrolidone (6 mL), silver acetate (10.2 mg, 0.06 mmol) was added, and the mixture was heated to 100 °C under nitrogen protection and stirred for 0.5 h. The reaction mixture was filtered and the white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-41) (6.7 mg, yield 25%) was prepared by acidic preparative method A.

[1124] 11H NMR (400 mHz, CDCl3) δ 12.8 (s, 1H), 7.99 (d, 2H), 7.20 (t, 1H), 7.20 (d, 2H), 6.51 (s, 1H), 6.39 (d, 1H), 6.20 (s, 1H), 5.22 (t, 1H), 3.75 (s, 3H), 2.45 (s, 3H), 1.43 (d, 3H).

[1125] LC-MS, M / Z (ESI): 436.1 (M+1)

[1126] Example 42: Preparation of Compound I-42

[1127] (S)-4-(1-(3-(Difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-42)

[1128] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-42)

[1129]

[1130] The synthetic route of Compound I-42 is as follows:

[1131]

[1132] First step: Methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-42B)

[1133] methyl

[1134] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-42B)

[1135]

[1136] At room temperature, methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate (Intermediate A) (1.0 g, 2.69 mmol) was added to dimethyl sulfoxide (5 mL), then 5-(trifluoromethyl)thiophen-3-ol (908 mg, 5.40 mmol), potassium carbonate (1.13 g, 8.18 mmol), copper(I) iodide (206 mg, 1.08 mmol), and 1,10-phenanthroline (388 mg, 2.16 mmol) were added. The mixture was heated to 120 °C by microwave and stirred for 4 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL×3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=1:3) to obtain white solid methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-42B) (980 mg, yield 72%).

[1137] LC-MS, M / Z(ESI): 504.2(M+1).

[1138] Step 2: (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-42)

[1139] (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-42)

[1140]

[1141] At room temperature, methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-42B) (980 mg, 1.89 mmol) was added to tetrahydrofuran (5 mL), water (3 mL) and lithium hydroxide (238 mg, 5.67 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, and white solid (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-42) (345 mg, yield 36%) was prepared by acidic preparation method A.

[1142] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.20 (d, 1H), 7.79 (d, 2H), 7.67 (s, 1H), 7.25 (d, 2H), 7.23 (d, 1H), 7.09 (t, 1H), 4.99 - 4.92 (m, 1H), 3.77 (s, 3H), 1.29 (d, 3H).

[1143] LC-MS, M / Z (ESI): 490.2 (M + 1)

[1144] Example 43: Preparation of Compound I-43

[1145] (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-43)

[1146] (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-43)

[1147]

[1148] The synthetic route of Compound I-43 is shown as follows:

[1149]

[1150] The first step: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-43B)

[1151] 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-43B)

[1152]

[1153] At room temperature, 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (700 mg, 3.30 mmol) was added to tert-butanol (20 mL) and water (5 mL). 2-Methyl-2-butene (1.80 g, 25.7 mmol), sodium chlorite (1.48 g, 16.4 mmol), and sodium dihydrogen phosphate (3.10 g, 25.8 mmol) were added, and the mixture was stirred at room temperature for 14 h. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude residue of the title compound as a colorless liquid. The crude residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-43B) as a colorless solid (680 mg, yield 90%).

[1154] LC-MS, M / Z (ESI): 229.6 (M+1).

[1155] Step 2: Methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43C)

[1156] methyl

[1157] (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43C)

[1158]

[1159] At room temperature, 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-43B) (680 mg, 2.98 mmol) was added to N,N-dimethylformamide (20 mL). Methyl (S)-4-(1-aminoethyl)benzoate (537 mg, 3.00 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.70 g, 4.47 mmol), and N,N-diisopropylethylamine (1.90 g, 14.7 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water (200 mL), extracted with ethyl acetate (30 mL × 3), separated, and the organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43C) as a colorless solid (700 mg, yield 60%).

[1160] LC-MS, M / Z (ESI): 390.5 (M+1).

[1161] Step 3: Methyl (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43D)

[1162] methyl

[1163] (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43D)

[1164]

[1165] At room temperature, methyl (S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate (500 mg, 1.3 mmol) was added to dimethyl sulfoxide (10 mL), and 5-(trifluoromethyl)thiophen-3-ol (216 mg, 1.3 mmol), potassium carbonate (360 mg, 2.6 mmol), copper(I) iodide (100 mg, 0.5 mmol), and 1,10-phenanthroline (100 mg, 0.5 mmol) were added. The mixture was heated to 95 °C by microwave and stirred for 5 h. After cooling to room temperature, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The layers were separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain yellow solid methyl (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43D) (200 mg, yield 30%).

[1166] LC-MS, M / Z (ESI): 522.1 (M+1).

[1167] Step 4: (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-43)

[1168] (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-43)

[1169]

[1170] At room temperature, methyl (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate (Compound I-43D) (100 mg, 0.19 mmol) was added to tetrahydrofuran (30 mL), water (10 mL), and lithium hydroxide (24 mg, 0.57 mmol) were added, and the mixture was heated to 50 °C and stirred for 2 h. The reaction solution was concentrated, and yellow solid (S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid (Compound I-43) (54 mg, yield 56%) was obtained by acidic preparation method A.

[1171] 1 H NMR (400 mHz, DMSO-d6) δ 12.8 (s, 1H), 8.64 (d, 1H), 7.80 (d, 2H), 7.68 (s, 1H), 7.31 (d, 1H), 7.24 (d, 2H), 4.92 (t, 1H), 3.80 (s, 3H), 1.26 (d, 3H).

[1172] LC-MS, M / Z (ESI): 508.1 (M+1)

[1173] Test Examples of Biological Activity and Related Properties

[1174] Test Example 1: Determination Experiment of EP4 Antagonism

[1175] The antagonistic effects of the control compound and the compounds prepared in Examples 1-43 on EP4 were tested separately, and the determination was carried out in a CHO stable cell line highly expressing the human EP4 receptor.

[1176] After the cells were digested with trypsin, they were resuspended in a buffer (1×HBSS, 0.1% BSA, 20 mM HEPES, and 500 μM IBMX), and 8000 cells were seeded in each well of a 384-well plate with an inoculation volume of 15 μL. A working solution of the compound at 8X concentration was prepared with the experimental buffer, and then 2.5 μL of the 8X compound working solution was added to the above 384-well plate and incubated at 37 °C for 30 min. A working solution of the agonist PGE2 at 8X concentration (4 nM) was prepared with the experimental buffer, and 2.5 μL was added to each well of the above 384-well plate (the final concentration of PGE2 was 0.5 nM), and incubated at 37 °C for 30 min. After the reaction was completed, the content of cAMP in the cells was quantified according to the method in the instruction manual of the cAMP test kit (PerkinElmer, Cat#TRF0263). Calculate the antagonistic effect (IC 50 value) of the test compound.

[1177] Table 1 Antagonistic effect of test compounds on EP4

[1178] Test Compound <![CDATA[IC 50 (nM)]]> Control Compound 44 Compound I-1 3.7 Compound I-2 1.9 Compound I-3 2.8 Compound I-5 2.2 Compound I-6 8.2 Compound I-9 29 Compound I-28 5.7 Compound I-29 14 Compound I-30 12 Compound I-35 6.6 Compound I-42 8.6

[1179] The experimental results show that the compounds of the present invention have good antagonistic effects on EP4. Compared with the control compounds, the antagonistic effects of most compounds are more than 5 times that of the control compounds, and the compounds of the invention show more excellent antagonistic effects on the EP4 receptor.

[1180] Test Example 2: Determination of the inhibitory effect of EP4 receptor calcium influx

[1181] The inhibitory effects of the control compounds and the compounds prepared in Examples 1-43 on EP4 calcium influx were respectively tested, and the determination was carried out in 293 cells overexpressing the human EP4 receptor.

[1182] The cells were quickly thawed in a 37 °C water bath, centrifuged, resuspended, and counted. The cell suspension was inoculated into 2 384-well plates (20,000 cells / well) at 20 μL / well, and placed in a 37 °C, 5% CO2 incubator overnight. Prepare 2X Fluo-4 Direct TM (Invitrogen, Cat#F10471) loading buffer: Add 77 mg probenecid to 1 mL of FLIPR buffer, with a concentration of 250 mM. Add 10 mL of FLIPR buffer and 0.2 mL of 250 mM probenecid to each tube of Fluo-4 Direct TM crystals (F10471).

[1183] Take out one cell plate from the incubator, remove the culture medium, add 20 μL of assay buffer and 2X Fluo-4Direct TM wash-free loading buffer to the 384-well cell culture plate, with a final volume of 40 μL. Incubate in a 37 °C, 5% CO2 incubator for 50 minutes, incubate at room temperature for 10 minutes, and place in FLIPR. Transfer 10 μL of buffer to the cell plate and read the fluorescence signal. Prepare a 10 mM stock solution of the agonist PGE2 in DMSO solvent, and use the buffer to gradient dilute it to 6X working solutions at 10 concentration points. Transfer 10 μL of the agonist PGE2 to the cell plate, read the fluorescence signal, and calculate the EC 80 value.

[1184] Prepare 6X EC 80 concentration of the agonist PGE2, and prepare a 10 mM stock solution of the test compound in DMSO solvent, and use the buffer to gradient dilute it to 6X compound working solutions at 10 concentration points.

[1185] Take another cell plate, remove the culture medium, and add 20 μL of assay buffer and 2X Fluo-4 Direct TM non-washing loading buffer. Incubate in a 37 °C, 5% CO2 incubator for 50 minutes, then incubate at room temperature for 10 minutes, and place it in the FLIPR. Transfer 10 μL of the compound working solution, DMSO, and the EP4 complete antagonist to the cell plate, and read the fluorescence signal. Transfer 10 μL of the agonist PGE2 at 6X EC 80 concentration to the cell plate, read the fluorescence signal, and calculate the inhibition rate:

[1186] Inhibition rate (%) = 100 - (test group - EP4 complete antagonist group) / (DMSO group - EP4 complete antagonist group) * 100. Calculate the IC 50 value of the compound's inhibition of EP4 calcium influx based on the inhibition rates at different concentrations of the compound.

[1187] Table 2 Inhibitory effect of the test compounds on EP4 calcium influx

[1188]

[1189]

[1190] The experimental results show that the compounds of the present invention exhibit good inhibitory effects on EP4 calcium influx and are superior to the control compounds. In particular, for compound I-4, its inhibitory effect on EP4 calcium influx is more than 5 times higher than that of the control compound; the compounds of the present invention show more excellent inhibitory effects on EP4 calcium influx.

[1191] Test Example 3: Radioactive ligand EP4 receptor binding assay

[1192] Test the binding of the control compounds and the compounds prepared in Examples 1-43 to the radioactive ligand EP4 using recombinant human EP4 receptor membrane protein (prepared from 293 cells overexpressing human EP4 receptor). Prepare a 10 mM stock solution of the test compound and PGE2 in DMSO solvent, and then use a buffer (50 mM HBSS, 0.1% BSA, 500 mM NaCl) to serially dilute to 8 concentration points of 4× working solution. Add 1 μL of the compound working solution, DMSO, and PGE2 working solution to the assay plate respectively, add 100 μL of EP4 receptor membrane protein (20 μg / well) and 100 μL of radioactive ligand 3H]-PGE2 (PerkinElmer, Cat: NET428250UC, Lot: 2469552) (final concentration 1.5 nM), incubate for 1 hour at room temperature with sealing. At room temperature, soak the Unifilter-96 GF / C filter plate (Perkin Elmer) with 0.5% BSA, 50 μL / well for at least 30 min. After the binding is completed, filter the reaction mixture through the GF / C plate using the Perkin Elmer Filtermate Harvester, then wash the filter plate and dry it at 50 °C for 1 hour. After drying, seal the bottom of the filter plate holes with the Perkin Elmer Unifilter-96 sealing tape, and add 50 μL of MicroScint TM -20 cocktail (Perkin Elmer), and seal the top of the filter plate. Read the 3 H counts captured on the filter using the PerkinElmer MicroBeta2 Reader.

[1193] Analyze the data using GraphPad Prism 5, and calculate the inhibition rate according to the following formula:

[1194] Inhibition rate (%) = 100 - (test group - PGE2 group) / (DMSO group - PGE2 group) * 100

[1195] Based on the inhibition rates of different concentrations of the compound, calculate the IC 50 and Ki values of the compound through the radioligand EP4 binding assay.

[1196] Table 3 IC 50 and Ki values of the test compounds through the radioligand EP4 binding assay

[1197]

[1198]

[1199] The experimental results show that compared with the control compound, the compounds of the present invention have better affinity for the EP4 receptor and are superior to the control compound. In particular, for compounds I-2 and I-5, their affinity for the EP4 receptor is increased by more than 5 times compared with the control compound; the compounds of the present invention show more excellent affinity for the EP4 receptor.

[1200] Test Example 4: Pharmacokinetic experiment

[1201] In this experiment, the pharmacokinetic parameters of the control compound and the compounds prepared in Examples 1-43 were tested on mice, rats and dogs respectively.

[1202] Mouse pharmacokinetic study: Male ICR mice weighing 20 - 25 g were fasted overnight. Three mice were given a 5 mg / kg oral gavage dose. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. Another three mice were given a 1 mg / kg intravenous injection dose, and blood samples were collected at the same time points as above. Blood samples were centrifuged at 6800 g for 6 minutes at 2 - 8 °C, and the plasma was collected and stored at -80 °C. Plasma samples at each time point were mixed with 3 - 5 volumes of acetonitrile solution containing internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4 °C, the supernatant was mixed with 3 volumes of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[1203] Rat pharmacokinetic study: Male SD rats weighing 180 - 240 g were fasted overnight. Three rats were given a 5 mg / kg oral gavage dose. Another three rats were given a 1 mg / kg intravenous injection dose. The remaining procedures were the same as those in the mouse pharmacokinetic study.

[1204] Dog pharmacokinetic study: Male Beagle dogs weighing 8 - 10 kg were fasted overnight. Three Beagle dogs were given a 3 mg / kg oral gavage dose. Another three Beagle dogs were given a 1 mg / kg intravenous injection dose. The remaining procedures were the same as those in the mouse pharmacokinetic study.

[1205] Table 4-1 Results of the mouse intravenous injection pharmacokinetic study

[1206]

[1207]

[1208] Table 4-2 Results of the mouse oral gavage pharmacokinetic study

[1209]

[1210] Table 5-1 Results of the rat intravenous injection pharmacokinetic study

[1211]

[1212] Table 5-2 Results of the rat oral gavage pharmacokinetic study

[1213]

[1214] Table 6-1 Results of the dog intravenous injection pharmacokinetic study

[1215]

[1216] Table 6-2 Pharmacokinetic test results of oral gavage administration in dogs

[1217]

[1218] The experimental results show that, compared with the control compound, the intravenous clearance rate of the compound of the present invention is lower, and the oral exposure is higher. Especially for compound I-5, the exposure after oral administration in rats and dogs is about twice that of the control compound. The compounds of the present invention exhibit more excellent pharmacokinetic properties and good drug-likeness.

[1219] Test Example 5: Anti-tumor effect of the test compound combined with radiotherapy in a CT-26 murine colon cancer tumor model

[1220] In this experiment, the anti-tumor effects of the control compound and the compounds prepared in Examples 1-43 combined with radiotherapy were tested in a CT-26 murine colon cancer tumor model.

[1221] After one week of adaptive feeding of the mice, CT-26 cells in the logarithmic phase were resuspended in PBS, and 5x10 5 CT-26 cells were inoculated subcutaneously at the right posterior part at a dose of 100 μL / mouse. The tumor growth was observed regularly. When the tumor grew to an average volume of 60-80 mm 3 , the tumor-bearing mice were randomly divided into 5 groups with 10 mice in each group according to the tumor volume. The experiment was divided into groups of the control compound (150 mg / kg), compound I-2 (150 mg / kg), and compound I-5 (150 mg / kg) combined with radiotherapy group (3 Gy), radiotherapy group (3 Gy) alone treatment group, and vehicle control group. Oral gavage administration was performed once a day for a total of 23 days; radiotherapy was used once on the first day of administration. The tumor volume and mouse body weight were measured twice a week, and the tumor weight was weighed at the end of the experiment. The efficacy was evaluated according to the relative tumor inhibition rate (TGI), and the safety was evaluated according to the changes in animal body weight and death. The calculation formulas for tumor volume and relative tumor inhibition rate are as follows:

[1222] Tumor volume (TV) = 1 / 2 × a × b 2 , where a and b are the length and width of the tumor measurement, respectively.

[1223] Relative tumor inhibition rate TGI (%) = ((TWc - TWt) / TWc) × 100%, where TWc is the average tumor weight of the vehicle control group and TWt is the average tumor weight of the treatment group.

[1224] The experimental results are as Figure 1As shown, it indicates that the control compound, test compound I-2, and I-5 combined with radiotherapy showed significant tumor inhibitory effects on the 23rd day after the start of drug administration. The relative tumor inhibition rates TGI(%) were 54%, 63%, and 79% respectively, and there were significant differences statistically compared with the vehicle control group (p mean < 0.05). There was a significant difference statistically between the group of compound I-5 combined with radiotherapy and the group of radiotherapy alone (p < 0.05), and it was superior to the group of the control compound combined with radiotherapy. There were no animal deaths in the groups of radiotherapy combined with drug administration, no obvious drug toxicity was shown, and they were well tolerated during the treatment period.

Claims

1. A compound which is a compound represented by Formula II or a salt of the compound represented by Formula II: Wherein, R 1 selected from -CHF2; R 2 selected from ethyl, fluoroethyl; R 3 selected from hydrogen, fluorine, chlorine; R 4 selected from hydrogen; R 5 selected from hydrogen; M is selected from oxygen.

2. A compound which is a compound represented by Formula I or a salt of the compound represented by Formula I: Wherein, R 1 selected from -CHF2; R 2 selected from C2 alkyl, C3 cycloalkyl, C2 alkyl substituted with fluorine; R 3 selected from hydrogen, fluorine and chlorine; R 4 selected from hydrogen.

3. The compound according to claim 2, characterized in that, R 2 Selected from -CH2CH3, cyclopropyl, -CF2CH3, and -CH2CF3.

4. A compound which is a compound shown below or a pharmaceutically acceptable salt of the compound shown below:

5. A pharmaceutical composition, characterized in that Comprising a pharmaceutically acceptable excipient and any compound described in any one of Claims 1 to 4.

6. Use of the compound described in any one of Claims 1 to 4 or the pharmaceutical composition of Claim 5 in the preparation of a medicament for treating or preventing EP4-related diseases.

7. Use of the compound described in any one of Claims 1 to 4 or the pharmaceutical composition of Claim 5 in the preparation of a medicament for treating or preventing at least one selected from the following: inflammatory diseases, pain, cancer, metabolic diseases, urinary system diseases.

8. The use according to Claim 7, wherein the inflammatory disease is selected from arthritis, rheumatoid arthritis.

9. The use according to Claim 7, wherein the pain is selected from osteoarthritis pain, pain caused by endometriosis.

10. The use according to Claim 7, wherein the medicament is administered in combination with radiotherapy and / or antibody therapy, and the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.

11. The use according to Claim 7, wherein the cancer is selected from solid cancers.

12. The use according to Claim 7, wherein the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer.

13. The use according to Claim 7, wherein the metabolic disease is diabetes, and the urinary system disease is selected from overactive bladder.

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