GPR84 antagonist as well as preparation method and application thereof

Abstract

The invention discloses a compound and application of the compound in medicine, and particularly relates to a novel compound and a medicine composition containing the compound. The invention further relates to a preparation method of the compound and application of the compound or the pharmaceutical composition in preparation of drugs for treating GPR84 antagonist mediated diseases and / or symptoms, in particular to application of the compound or the pharmaceutical composition in preparation of drugs for treating non-alcoholic fatty liver diseases, inflammatory bowel diseases, idiopathic pulmonary fibrosis and diabetic neuralgia.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and particularly relates to a GPR84 antagonist, a preparation method thereof and an application thereof. Background Art

[0002] G protein-coupled receptor 84 (GPR84) belongs to fatty acid receptors and can be activated by medium-chain fatty acids. It can inhibit the adenylate cyclase activity of the downstream signaling pathway through G αi protein, thereby down-regulating the level of cAMP.

[0003] GPR84 is mainly expressed in innate immune cells. Up-regulated expression will promote the inflammation of such cells. Research shows that the activation of GPR84 will lead to chemotactic responses, enhance the release of cytokines (IL-8, IL-12) and tumor necrosis factor α [TNF-α], thereby amplifying the macrophage inflammatory response at the inflammatory site, exacerbating the occurrence of inflammation, and triggering various inflammatory diseases (Carlota Recio et al, 2018). Research shows that GPR84 plays an important role in the occurrence of endometriosis (Sacher F et al, 2018), inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver diseases, etc. (Puengel et al. 2018; Thibodeau J.F. et al. 2018).

[0004] The activation of this receptor in neutrophils and macrophages will trigger the release of reactive oxygen species, suggesting that this receptor has an immunomodulatory effect. Research shows that GPR84 plays an important role in the occurrence of inflammatory bowel disease (Arijs et al, 2011; Planell et al, 2017; Labeguere F.et al, 2020), multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus or primary and secondary autoimmune uveitis and other diseases.

[0005] The regulation of GPR84 on neutrophil activity and systemic inflammation is closely related to lung diseases (such as asthma, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, etc.) (Nguyen et al, 2018; Saniere L.et al, 2019; Edward Jenner et al, 2020).

[0006] Normalization of GPR84 adipose tissue inflammation indicates that GPR84 is closely related to metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, obesity, and polycystic ovary syndrome (PCOS). Inflammatory changes in adipose tissue enhance the expression of GPR84 in adipocytes, and the regulation of GPR84 modulates the immune response capacity of adipocytes (Muredda et al, 2017; Recio et al, 2018; Simard, J.C. et al, 2020).

[0007] In addition, GPR84 signaling has a peripheral drive in neuropathic pain (Nicol et al, 2015). Studies have shown that GPR84 and TREM-1 signaling pathways are involved in the pathogenesis of reflux esophagitis (Abdel-Aziz, H, 2015).

[0008] Currently, researchers have conducted some studies to find drugs that can prevent and / or treat diseases related to GPR84. PCT applications WO2013092791, WO2014095798, WO2015197550, WO2016169911, WO2018161831, WO2018210822, WO2019096944, WO2020007342, WO2021122415, WO2022179940, WO2022194267, and WO2022218372 disclose many small molecule compounds, which are used as GPR84 antagonists to prevent or treat diseases related to GPR84. However, there is still an urgent clinical need for more and better GPR84 antagonists. Summary of the Invention

[0009] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a GPR84 antagonist. The present invention further relates to the use of the compound or its pharmaceutical composition for preparing a drug, which treats a disease and / or disorder by antagonizing GPR84 with the compound. The present invention further describes the synthesis method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

[0010] Specifically:

[0011] On the one hand, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

[0012]

[0013] Wherein:

[0014] L1 is -O-, -S-, -CR 9 R 10 -, -O-CR 11 R 12 - or -S-CR 13 R 14 -;

[0015] L2 is -C(=O)NR 15 - or

[0016] L3 is a bond or -CR 17 R 18 -;

[0017] R 3 and R 4 are each independently C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, and the C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 10-membered heteroaryl may each independently be optionally substituted by 1, 2 or 3 R a wherein the R a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group;

[0018] R 1 、R 2 、R 5 、R 6 、R 7 、R 8 and R 16 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-6 cycloalkyl, and the phenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino and C 3-6The cycloalkyl group may independently and optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 alkoxy, C 1-6 alkylamino and C 3-6 cycloalkyl;

[0019] R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 17 and R 18 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro or C 1-6 alkyl, and the C 1-6 alkyl may independently and optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl,

[0020] amino and nitro;

[0021] R 15 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and the 3- to 6-membered heterocyclic group may independently and optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro.

[0022] In some embodiments, R 3 and R 4 are each independently C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, phenyl or a 5- to 10-membered heteroaryl, wherein the C 3-6 cycloalkyl, the 3- to 6-membered heterocyclic group, phenyl and the 5- to 10-membered heteroaryl may independently and optionally be substituted by 1, 2 or 3 R a substituents, and the R a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl or a 5- to 6-membered heterocyclic group.

[0023] In some embodiments, R 3 and R 4 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,

[0024]

[0025] wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,

[0026] may each independently optionally be substituted with 1, 2 or 3 R a groups, where the R a group is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

[0027] In some embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 16 are each independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, phenyl, C 2-3 alkynyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylamino or C 3-6 cycloalkyl, where the phenyl, C 2-3 alkynyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylamino and C 3-6 cycloalkyl may each independently optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 alkoxy, C 1-3 alkylamino and C3-6 substituted by a substituent of a cycloalkyl group;

[0028] R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 17 and R 18 are each independently H, D, F, Cl, Br, I, CN, a hydroxyl group, oxo, an amino group, a nitro group or a C 1-3 alkyl group, and the C 1-3 alkyl group may independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, a hydroxyl group, an amino group and a nitro group;

[0029] R 15 is H, a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group, and the C 1-3 alkyl group, the C 2-3 alkenyl group, the C 2-3 alkynyl group, the C 3-6 cycloalkyl group and the 3- to 6-membered heterocyclic group may independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, a hydroxyl group, an amino group and a nitro group.

[0030] In some embodiments, R 1 、R 2 、R 5 、R 6 、R 7 、R 8 and R 16Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, phenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the phenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. , -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0031] R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro;

[0032] R 15 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0033] In some embodiments, the compounds of the present invention are compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:

[0034]

[0035]

[0036] On the one hand, the present invention relates to a pharmaceutical composition comprising the compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.

[0037] On the one hand, the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating a disease mediated by a GPR84 antagonist in a patient.

[0038] Some of these embodiments are that the diseases mediated by the GPR84 antagonist of the present invention are inflammatory diseases, autoimmune diseases, lung diseases, metabolic disorders and metabolic endocrine disorders.

[0039] Some of these embodiments are that the inflammatory diseases of the present invention are endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic or alcoholic and toxic fatty liver diseases.

[0040] Some of these embodiments are that the autoimmune diseases of the present invention are inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus or primary and secondary autoimmune uveitis.

[0041] Some of these embodiments are that the lung diseases of the present invention are asthma, idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease.

[0042] Some of these embodiments are that the metabolic disorders and metabolic endocrine disorders of the present invention are metabolic syndrome, insulin resistance, type I and type II diabetes, diabetic neuropathy, obesity or polycystic ovary syndrome.

[0043] On the other hand, the present invention relates to methods for preparing, isolating and purifying the compounds contained in formula (I).

[0044] The foregoing merely outlines certain aspects of the present invention and is not limiting thereof. The content of these and other aspects will be described in more specific and complete detail below.

[0045] Definitions and General Terms

[0046] The present invention will list in detail the documents corresponding to the defined and specific content, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is expected to cover all alternatives, variations, and equivalents, which may be included in the existing field of invention as defined by the claims. Those skilled in the art will recognize many methods and substances similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and substances. There are many documents and similar substances that are different from or conflict with the present invention application, including but not limited to the definition of terms, the usage of terms, the techniques described, or the scope controlled by the present invention application.

[0047] The present invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed., 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, and thus all content incorporates the references.

[0048] The term "comprising" is an open-ended expression, i.e., it includes the content specified in the present invention but does not exclude other aspects.

[0049] The compounds described herein may optionally be substituted by one or more substituents, such as the general formula compounds in the present invention, or like the specific examples, subclasses, and a class of compounds included in the present invention in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "optionally", whether before or after the term "substituted", means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be the same or different at each position.The substituents described above can be, but are not limited to, hydrogen, deuterium (D), F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclic group, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C(=O)O-alkyl, -alkylene-S(=O)2-alkyl, -alkylene-S(=O)2-amino, -S(=O)2-alkyl, -S(=O)2-amino, -S(=O)2OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S(=O)2-alkyl, -O-alkylene-S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, -N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and so on.

[0050] The term "alkyl" as used in the present invention includes saturated straight-chain or branched-chain monovalent hydrocarbon groups having 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group may independently and optionally be substituted by one or more substituents described in the present invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alk-" as used herein include both straight-chain and branched-chain saturated carbon chains. The term "alkylene" or "sub-alkyl" as used herein refers to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon, and examples of such groups include, but are not limited to, methylene, ethylene, and isopropylidene, and the like.

[0051] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1 to 12 carbon atoms. In some embodiments, the alkylene radical contains 1 to 6 carbon atoms; in other embodiments, the alkylene radical contains 1 to 4 carbon atoms; in still other embodiments, the alkylene radical contains 1 to 3 carbon atoms; and in yet other embodiments, the alkylene radical contains 1 to 2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-), and the like.

[0052] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C is a sp 2 double bond, and the alkenyl radical can be independently and optionally substituted by one or more substituents described in the present invention, including groups with "trans", "cis" or "E", "Z" orientations. Specific examples of the alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0053] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C is a sp triple bond, and the alkynyl radical can be independently and optionally substituted by one or more substituents described in the present invention. Specific examples of the alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0054] The term "heteroatom" refers to one or more of O, S, N, P, and Si, including any oxidized form of C, N, S, and P; the forms of primary, secondary, tertiary amines, and quaternary ammonium salts; or the form in which the hydrogen on the nitrogen atom in a heterocycle is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NR (such as NR in N-substituted pyrrolidinyl); or the -CH2- in a heterocycle is oxidized to form -C(=O)-.

[0055] The term "halogen" refers to F, Cl, Br, or I.

[0056] The term "deuterium" refers to heavy hydrogen, D.

[0057] The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.

[0058] The term "alkoxy" or "alkyloxy" as used in the present invention refers to an alkyl group, as defined in the present invention, which is attached to other parts of the compound molecule through an oxygen atom. In some embodiments, the alkoxy group is C 1-4 alkoxy; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may independently be unsubstituted or substituted by one or more substituents described in the present invention.

[0059] The term "alkylthio" or "alkylsulfanyl" as used in the present invention refers to an alkyl group, as defined in the present invention, which is attached to other parts of the compound molecule through a sulfur atom. In some embodiments, the alkylthio group is C 1-4 alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like. And the alkylthio group may independently be unsubstituted or substituted by one or more substituents described in the present invention.

[0060] The term "alkylamino" as used in the present invention refers to an alkyl group, as defined in the present invention, which is attached to other parts of the compound molecule through an N atom. In some embodiments, the alkylamino group is C 1-4 alkylamino; such examples include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, and the like. And the alkylamino group may independently be unsubstituted or substituted by one or more substituents described in the present invention.

[0061] The term "cycloalkyl" or "cycloalkane" means a monocyclic, bicyclic or tricyclic carbocyclic system containing 3 - 12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but does not contain an aromatic ring at all. In one embodiment, the cycloalkyl group contains 3 - 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 - 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 - 6 carbon atoms. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. The cycloalkyl group may independently be unsubstituted or substituted by one or more substituents described in the present invention.

[0062] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 3-12 ring atoms, and in no case containing an aromatic ring, wherein at least one ring atom is a heteroatom. In one embodiment, the "heterocyclic group" or "heterocycle" contains 3-10 ring atoms; in one embodiment, the "heterocyclic group" or "heterocycle" contains 3-8 ring atoms; in another embodiment, the "heterocyclic group" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" contains 3-6 ring atoms; in still one embodiment, the "heterocyclic group" or "heterocycle" contains 5-6 ring atoms; in yet one more embodiment, the "heterocyclic group" or "heterocycle" contains 4-6 ring atoms; unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the heteroatom has the meaning as described in the present invention. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxaazepinyl, diazepinyl, thiaazepinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and 1,2,3,6-tetrahydropyridinyl. Examples of the -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, pyrimidinedione, and 5,6-dihydropyridin-2(1H)-one. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolanyl and 1,1-dioxothiomorpholinyl. The described heterocyclic group can be optionally substituted by one or more substituents described in the present invention. yl yl yl, and 1,2,3,6-tetrahydropyridinyl. Examples of the -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, pyrimidinedione, and 5,6-dihydropyridin-2(1H)-one. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolanyl and 1,1-dioxothiomorpholinyl. The described heterocyclic group can be optionally substituted by one or more substituents described in the present invention.

[0063] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbocyclic system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, each ring contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl, and anthracenyl. The described aryl group can be independently optionally substituted by one or more substituents described in the present invention.

[0064] The term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic system containing 5 - 12 ring atoms, or 5 - 10 ring atoms, or 5 - 6 ring atoms, wherein at least one ring system is an aromatic ring and at least one ring system contains one or more heteroatoms, and each ring contains a ring composed of 5 - 7 atoms and has one or more attachment points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, the heteroaryl composed of 5 - 10 atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0065] Examples of heteroaryl groups include, but are not limited to: furyl, imidazolyl (such as N - imidazolyl, 2 - imidazolyl, 4 - imidazolyl, 5 - imidazolyl), isoxazolyl, oxazolyl (such as 2 - oxazolyl, 4 - oxazolyl, 5 - oxazolyl), pyrrolyl (such as N - pyrrolyl, 2 - pyrrolyl, 3 - pyrrolyl), pyridyl, pyrimidinyl (such as 2 - pyrimidinyl, 4 - pyrimidinyl, 5 - pyrimidinyl), pyridazinyl, thiazolyl (such as 2 - thiazolyl, 4 - thiazolyl, 5 - thiazolyl), tetrazolyl (such as 5 - tetrazolyl), triazolyl, thiophenyl (such as 2 - thiophenyl, 3 - thiophenyl), pyrazolyl, isothiazolyl, 1,2,3 - oxadiazolyl, 1,2,5 - oxadiazolyl, 1,2,4 - oxadiazolyl, 1,2,3 - triazolyl, 1,2,3 - thiadiazolyl, 1,3,4 - thiadiazolyl, 1,2,5 - thiadiazolyl, pyrazinyl, 1,3,5 - triazinyl; also include the following bicyclics, but are by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (such as 2 - indolyl), purinyl, quinolinyl (such as 2 - quinolinyl, 3 - quinolinyl, 4 - quinolinyl), 1,2,3,4 - tetrahydroisoquinolinyl, 1,3 - benzodioxolyl, indolinyl, isoquinolinyl (such as 1 - isoquinolinyl, 3 - isoquinolinyl or 4 - isoquinolinyl), imidazo[1,2 - a]pyridinyl, pyrazolo[1,5 - a]pyridinyl, pyrazolo[1,5 - a]pyrimidinyl, imidazo[1,2 - b]pyridazinyl, [1,2,4]triazolo[4,3 - b]pyridazinyl, [1,2,4]triazolo[1,5 - a]pyrimidinyl and [1,2,4]triazolo[1,5 - a]pyridinyl, and so on.

[0066] As described in the present invention, the ring system formed by a substituent drawing a bond to the ring represents that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that the substituent R can be mono - substituted or poly - substituted at any possible substitutable position on the pyridine ring.

[0067]

[0068] As described in the present invention, a linking bond is connected to a ring system formed on a ring (as shown in formula b), which means that the linking bond can be connected to the rest of the molecule at any connectable position on the ring system. Formula b represents that any possible connectable position on the octahydrocyclopenta[c]pyrrole ring can be connected to the rest of the molecule.

[0069]

[0070] As described in the present invention, the group “-O-(CR m R n ) p -” has two connection sites that can be connected to the rest of the molecule, and the connection modes of the two connection sites can be interchanged. For example, formula f represents that the group -O-(CR m R n ) p - can be connected to the rest of the molecule through the E end or the E' end. For example, E-O-(CR m R n ) p -E' or E'-O-(CR m R n ) p -E.

[0071]

[0072] In addition, it should be noted that, unless otherwise explicitly indicated, the description methods “each... and... independently is”, “... and... are each independently” and “... and... are respectively independent” used throughout this article can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0073] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds, and the conformational isomers of (Z) and (E). Therefore, the individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, geometric isomers or conformational isomers all fall within the scope of the present invention.

[0074] Unless otherwise indicated, the structural formulas and the compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Accordingly, the individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described in the present invention include one or more enriched isotopes of different atoms.

[0075] "Metabolite" means a product obtained by metabolic action in vivo of a specific compound or its pharmaceutically acceptable salt, analogue or derivative described in the present invention, which exhibits similar activity to the compound of formula (I) in vivo or in vitro. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, or enzymatic cleavage of the administered compound. Accordingly, the present invention includes the metabolites of the compounds, including the metabolites produced by contacting the compounds of the present invention with a mammal for a sufficient period of time.

[0076] In the present invention, the definitions and conventions of stereochemistry are generally referred to the following documents: 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. The compounds of the present invention may contain asymmetric or chiral centers, and thus there are different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral centers of the molecule. The prefixes d, l or (+), (-) are used to name the sign of the rotation of plane-polarized light by the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their stereostructures are different. A specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

[0077] The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can interconvert via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine tautomerizations. Valence (or valency) tautomers include interconversions that reconstitute bonding electrons.

[0078] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. The salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to: inorganic acid salts formed by reacting with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or these salts are obtained by other methods described in books and literature, such as ion exchange method. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N+(C 1-4 alkyl)4. The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. The alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0079] The "hydrate" of the present invention refers to the association formed by solvent molecules being water.

[0080] The "solvate" of the present invention refers to the association formed by one or more solvent molecules and the compounds of the present invention. The solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0081] The "ester" of the present invention refers to an in vivo hydrolyzable ester formed by a compound of formula (I) containing a hydroxyl group. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in a human or animal body to produce the parent alcohol. The groups of in vivo hydrolyzable esters of the compound of formula (I) containing a hydroxyl group include, but are not limited to: phosphate group, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl group, benzoyl group, phenylacetyl group, alkoxycarbonyl group, dialkylcarbamoyl group, and N-(dialkylaminoethyl)-N-alkylcarbamoyl group, etc.

[0082] The "nitroxide" of the present invention refers to when a compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (such as peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (such as dichloromethane), reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0083] The term "prodrug" used in the present invention represents a compound that is converted in vivo into a compound represented by formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or its enzymatic conversion in the blood or tissues into the parent structure. The prodrug compounds of the present invention can be esters. In the existing inventions, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24)Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, and it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl groups on the parent compound. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255 - 270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 - 2345.

[0084] Unless otherwise specified herein or the context clearly dictates the contrary, the terms "a", "an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) can be construed to include both the singular and the plural.

[0085] The term "GPR84 antagonist" as used herein refers to a substance that can antagonize GPR84.

[0086] General synthesis process

[0087] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, but only provides methods for practicing the present invention.

[0088] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definitions of the substituents are as described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0089] Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to suitably prepare other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriately protecting interfering groups, by using other known reagents in addition to those described in the present invention, or making some conventional modifications to the reaction conditions. Additionally, the reactions or known reaction conditions disclosed in the present invention are also generally recognized as applicable to the preparation of other compounds of the present invention.

[0090] In the following examples described below, unless otherwise indicated, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Merck Chemical Technology Co., Ltd., and Shanghai Macklin Biochemical Technology Co., Ltd., and were used without further purification. Unless otherwise indicated, general reagents were obtained from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., Hubei Xingchi Technology Co., Ltd., and Qingdao Ocean Chemical Factory.

[0091] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Ultra-dry dichloromethane was dried over calcium hydride and redistilled. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, and methanol were of analytical grade.

[0092] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube placed over an anhydrous solvent (unless otherwise indicated), the reaction flasks were stoppered with appropriate rubber stoppers, and the substrates were injected via syringe. The glassware was dried.

[0093] The silica gel column used was a Flash silica gel column purchased from Tianjin Agela Technologies Co., Ltd. Silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0094] 1H NMR spectra were recorded using a Bruker 500 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were measured in CDCl3, DMSO-d6, CD3OD or acetone-d6 as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiple peaks appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J was expressed in Hertz (Hz).

[0095] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate 1 mL / min. Mobile phase: 0% - 95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI) was used, detected by DAD at 210 nm / 254 nm.

[0096] Compound purification was performed using a Cheetah Pro medium-pressure rapid purification preparative chromatograph from Tianjin Bonna Ager Technology Co., Ltd., detected by UV at 210 nm / 254 nm.

[0097] The following abbreviations were used throughout the present invention:

[0098] PE petroleum ether EtOAc / EA ethyl acetate

[0099] mg milligram mmol millimole

[0100] mL milliliter g gram

[0101] M mole per liter DMSO-d6 deuterated dimethyl sulfoxide

[0102] DMF N,N-dimethylformamide MeOH methanol

[0103] DCM dichloromethane CDCl3 deuterated chloroform

[0104] HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate Detailed implementation manners

[0105] The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0106] Synthesis of Example 1 1 - (((S)-1,4 - dioxan - 2 - yl)methyl)-4-(4-(1 - (((S)-1,4 - dioxan - 2 - yl)methyl)-1H - pyrazol - 3 - yl)-3-(trifluoromethyl)phenyl)-1H - 1,2,3 - triazole (Compound 1)

[0107]

[0108] Step 1: Synthesis of (S)-1 - ((1,4 - dioxan - 2 - yl)methyl)-3-(2-(trifluoromethyl)-4-((trimethylsilyl)ethynyl)phenyl)-1H - pyrazole

[0109] Under a nitrogen atmosphere, (S)-1 - ((1,4 - dioxan - 2 - yl)methyl)-3-(4 - bromo - 2-(trifluoromethyl)phenyl)-1H - pyrazole (400 mg, 1.02 mmol), ethynyltrimethylsilane (151 mg, 1.53 mmol), copper(I) iodide (22 mg, 0.11 mmol), bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.10 mmol) were added to a reaction flask, and N,N - dimethylformamide (5 mL) and triethylamine (5 mL) were added to dissolve. After addition, the mixture was transferred to 80 °C and stirred overnight. The reaction was monitored by TLC until completion. Water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 5:1 - 3:1) to obtain 174 mg of a yellow solid with a yield of 41.7%.

[0110] LC - MS (ESI): [M + H] + = 409.1;

[0111] 1 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.61 (s, 2H), 7.48 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.20 (d, J = 5.5 Hz, 2H), 4.01 - 3.97 (m, 1H), 3.85 - 3.66 (m, 4H), 3.62 - 3.51 (m, 1H), 3.34 - 3.18 (m, 1H), 0.27 (s, 9H).

[0112] Step 2: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-ethynyl-2-(trifluoromethyl)phenyl)-1H-pyrazole

[0113] Under a nitrogen atmosphere, (S)-1-((1,4-dioxan-2-yl)methyl)-3-(2-(trifluoromethyl)-4-((trimethylsilyl)ethynyl)phenyl)-1H-pyrazole (170 mg, 0.42 mmol), dichloromethane (4 mL) were added to a reaction flask, and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.6 mL, 0.62 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 10:1 - 2:1) to obtain 98 mg of a white solid with a yield of 69.4%.

[0114] LC-MS (ESI): [M+H] + = 337.1.

[0115] Step 3: Synthesis of 1-(((S)-1,4-dioxan-2-yl)methyl)-4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole

[0116] Under a nitrogen atmosphere, (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-ethynyl-2-(trifluoromethyl)phenyl)-1H-pyrazole (90 mg, 0.27 mmol) dissolved in N,N-dimethylformamide (4 mL) and water (1 mL) was added to a reaction flask, then (S)-2-(azidomethyl)-1,4-dioxane (58 mg, 0.40 mmol), copper sulfate anhydrous (4 mg, 0.03 mmol), and sodium ascorbate (11 mg, 0.05 mmol) were added. After addition, the mixture was transferred to room temperature and stirred for 2 hours. The reaction was monitored by TLC until completion. Then water was added for dilution (20 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a white solid (30 mg) was obtained by preparative HPLC with a yield of 21.6%.

[0117] LC-MS (ESI): [M+H] + = 480.2.

[0118] Example 2 Synthesis of 1-(((R)-1,4-dioxan-2-yl)methyl)-4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)phenyl)-1H-1,2,3-triazole (Compound 2)

[0119]

[0120] Step 1: Synthesis of 1-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one

[0121] Under a nitrogen atmosphere, 1-(4-bromo-2-hydroxyphenyl)ethan-1-one (2 g, 9.30 mmol), 2,2,2-trifluoroethyl p-toluenesulfonate (3.5 mL, 13.95 mmol), cesium carbonate (6.1 g, 18.60 mmol), and N,N-dimethylformamide (6 mL) were successively added to a reaction flask and transferred to 100 °C and stirred overnight. Pure water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, and the combined organic phase was washed with water (30 mL × 2) and saturated brine (15 mL × 2) respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Separation by silica gel column chromatography (PE:EA (v / v) = 50:1) gave 2.3 g of a yellow solid with a yield of 84.3%.

[0122] 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 1H), 7.64–7.57 (m, 2H), 5.04 (q, J = 8.7 Hz, 1H), 4.91 (q, J = 8.6 Hz, 1H), 2.57 (s, 3H).

[0123] Step 2: Synthesis of 1-(2-(2,2,2-trifluoroethoxy)-4-((trimethylsilyl)ethynyl)phenyl)ethan-1-one

[0124] Under a nitrogen atmosphere, 1-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (1.2 g, 4.04 mmol), trimethylsilylacetylene (0.9 mL, 6.06 mmol), copper(I) iodide (77 mg, 0.40 mmol), bis(triphenylphosphine)palladium(II) dichloride (157.1 mg, 0.20 mmol), triethylamine (1.7 mL, 12.12 mmol), and tetrahydrofuran (20 mL) were successively added to a reaction flask and refluxed at 80 °C for 2 hours. Filtered through diatomaceous earth, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 50:1) to give 900 mg of a yellow solid with a yield of 70.9%.

[0125] 11H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 0.8 Hz, 1H), 6.96 (s, 1H), 4.45 (q, J = 7.9 Hz, 2H), 2.61 (s, 3H), 0.27 (s, 9H).

[0126] Step 3: Synthesis of 1-(4-ethynyl-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one

[0127] 1-(2-(2,2,2-Trifluoroethoxy)-4-((trimethylsilyl)ethynyl)phenyl)ethan-1-one (900 mg, 2.86 mmol), tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (4.3 mL, 4.29 mmol) were successively added to a reaction flask and stirred at room temperature for 1 hour. Concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 50:1) to obtain 300 mg of a yellow solid with a yield of 43.3%.

[0128] 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 4.45 (q, J = 7.8 Hz, 2H), 3.24 (s, 1H), 2.62 (s, 3H).

[0129] Step 4: Synthesis of (R)-1-(4-(1-((1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one

[0130] Under a nitrogen atmosphere, 1-(4-ethynyl-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (300 mg, 1.23 mmol), (R)-2-(azidomethyl)-1,4-dioxane (142 mg, 0.99 mmol), sodium ascorbate (33 mg, 0.17 mmol), anhydrous copper sulfate (15 mg, 0.08 mmol), N,N-dimethylformamide (4 mL), and water (1 mL) were successively added to a reaction flask and stirred at room temperature overnight. Diluted with pure water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, and the organic phase was washed with water (20 mL × 2) and saturated brine (20 mL × 2) respectively. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 50:1) to obtain 370 mg of a yellow oily product with a yield of 78.2%.

[0131] LC-MS (ESI): [M+H]+ = 386.1。

[0132] Step 5: Synthesis of (R)-1-((1,4-dioxan-2-yl)methyl)-4-(4-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)phenyl)-1H-1,2,3-triazole

[0133] To a 50 mL single-necked flask, (R)-1-(4-(1-((1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (370 mg, 0.96 mmol)), toluene (5 mL) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (335 mg, 1.92 mmol) were added successively, and the mixture was stirred at 110 °C for 1 h. The solvent was removed by concentration under reduced pressure. Ethanol (5 mL) and hydrazine hydrate (72 mg, 1.44 mmol) were added to the system, and the mixture was stirred at 50 °C for 1 h. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 2:1) to obtain 300 mg of a yellow solid with a yield of 76.3%.

[0134] LC-MS (ESI): [M+H] + = 410.2;

[0135] 1 H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.62 (d, J = 11.3 Hz, 3H), 6.73 (s, 1H), 4.95 (s, 3H), 4.55 (dd, J = 14.4, 3.5 Hz, 1H), 4.46 (dd, J = 14.4, 7.7 Hz, 1H), 3.96 (t, J = 8.6 Hz, 1H), 3.85 (d, J = 11.5 Hz, 1H), 3.77 (d, J = 11.5 Hz, 1H), 3.66 (d, J = 11.6 Hz, 1H), 3.58 (t, J = 11.2 Hz, 1H), 3.47 (dd, J = 15.5, 6.6 Hz, 1H).

[0136] Step 6: Synthesis of 1-(((R)-1,4-dioxan-2-yl)methyl)-4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)phenyl)-1H-1,2,3-triazole

[0137] To the reaction flask, (R)-1-((1,4-dioxan-2-yl)methyl)-4-(4-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)phenyl)-1H-1,2,3-triazole (60 mg, 0.15 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (33.4 mg, 0.25 mmol), cesium carbonate (107.6 mg, 0.33 mmol) and N,N-dimethylformamide (4 mL) were added in sequence, and then it was transferred to stir at 70 °C for 1 hour. Pure water (10 mL) was added for dilution, and it was extracted with ethyl acetate (15 mL×3). The organic phases were combined, and the organic phase was washed with water (30 mL×2) and saturated brine (15 mL×2) respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 29 mg of white solid was obtained by preparative HPLC, and the yield was 38.8%.

[0138] LC-MS(ESI): [M+H] + = 510.2;

[0139] 1 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 4.94 (q, J = 8.7 Hz, 2H), 4.55 (dd, J = 14.4, 3.6 Hz, 1H), 4.46 (dd, J = 14.4, 7.7 Hz, 1H), 4.25–4.16 (m, 2H), 4.00–3.90 (m, 2H), 3.85 (d, J = 11.5 Hz, 1H), 3.76 (t, J = 7.1 Hz, 3H), 3.68–3.62 (m, 2H), 3.62–3.53 (m, 2H), 3.46 (t, J = 10.9 Hz, 2H), 3.28 (d, J = 10.3 Hz, 2H).

[0140] Example 3 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(2,2,2-trifluoroethoxy)benzamide (Compound 3)

[0141]

[0142] Step 1: Synthesis of 3-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole

[0143] 1-(4-Bromo-2-(2,2,2-trifluoroethoxy)phenyl)ethan-1-one (2.8 g, 9.36 mmol), toluene (15 mL) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (3.9 mL, 18.72 mmol) were successively added to a reaction flask and stirred at 110 °C for 1 h. Concentrate under reduced pressure. Ethanol (15 mL) and hydrazine hydrate (0.9 mL, 18.72 mmol) were added to the system and stirred at 50 °C for 1 h. Concentrate under reduced pressure. Separate by silica gel column chromatography (PE:EA(v / v)=6:1) to obtain 1.7 g of a yellow solid with a yield of 57.6%.

[0144] LC-MS(ESI):[M+H] + = 321.0;

[0145] 1 H NMR(500 MHz, DMSO-d6)δ13.00(s, 1H), 7.93(d, J = 7.9 Hz, 1H), 7.79(s, 1H), 7.42(s, 1H), 7.29(d, J = 7.7 Hz, 1H), 6.68(s, 1H), 4.92(d, J = 8.4 Hz, 2H).

[0146] Step 2: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole

[0147] 3-(4-Bromo-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (800 mg, 2.49 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (1017.7 mg, 3.74 mmol), cesium carbonate (1623.5 mg, 4.98 mmol) and N,N-dimethylformamide (10 mL) were successively added to a reaction flask and then transferred to stir at 70 °C for 1 h. Dilute with pure water (10 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, wash the organic phases with water (50 mL×2) and saturated brine (50 mL×2) respectively, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE:EA(v / v)=6:1) to obtain 990 mg of a yellow solid with a yield of 94.3%.

[0148] LC-MS(ESI):[M+H] + = 421.1;

[0149] 11H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 4.19 (d, J = 5.1 Hz, 2H), 4.00–3.97 (m, J = 8.9, 4.6 Hz, 1H), 3.91 (d, J = 5.6 Hz, 1H), 3.74 (d, J = 11.4 Hz, 2H), 3.70–3.59 (m, 2H), 3.54 (dd, J = 21.7, 11.0 Hz, 2H), 3.50–3.35 (m, 1H).

[0150] Step 3: Synthesis of Methyl (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)benzoate

[0151] Add (S)-1-((1,4-Dioxan-2-yl)methyl)-3-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (200 mg, 0.47 mmol), Pd(dppp)Cl2 (20 mg, 0.47 mmol), triethylamine (96 mg, 0.95 mmol) and methanol (10 mL) into an autoclave. After protecting with nitrogen, evacuate and refill with carbon monoxide, and finally maintain 20 atmospheres of carbon monoxide. After addition, transfer it to stir at 100 °C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (PE:EA (v / v) = 8:1) to obtain 109 mg of white solid with a yield of 57.9%.

[0152] LC-MS (ESI): [M+H] + = 401.2;

[0153] 1 1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.72–7.66 (m, 2H), 6.74 (s, 1H), 4.98 (q, J = 8.6 Hz, 2H), 4.26–4.17 (m, 2H), 3.92 (s, 1H), 3.88 (s, 3H), 3.78–3.71 (m, 2H), 3.63 (d, J = 11.3 Hz, 1H), 3.55 (t, J = 12.0 Hz, 1H), 3.45 (t, J = 11.1 Hz, 1H), 3.30 - 3.26 (m, 1H).

[0154] Step 4: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)benzoic acid

[0155] Add methyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)benzoate (109 mg, 0.27 mmol), 1 M sodium hydroxide (10 mL, 10 mmol), and methanol (2 mL) to a reaction flask, and then transfer it to stir at 80 °C for 2 hours. Add 1 M dilute hydrochloric acid to adjust the pH to 2 - 4, extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 86 mg of a white solid with a yield of 81.8%.

[0156] LC-MS (ESI): [M + H] + = 387.1;

[0157] Step 5: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(2,2,2-trifluoroethoxy)benzamide

[0158] Add (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethoxy)benzoic acid (50 mg, 0.13 mmol), (S)-(tetrahydrofuran-2-yl)methylamine (64.8 μL, 0.63 mmol), HATU (73.8 mg, 0.19 mmol), and diisopropylethylamine (34 mg, 0.19 mmol) to a reaction flask in sequence, and transfer it to stir at room temperature for 2 hours under nitrogen protection. Add pure water (15 mL) for washing, extract with ethyl acetate (15 mL × 3), wash the organic phase with saturated brine (15 mL × 2), dry over anhydrous sodium sulfate, and obtain 13 mg of a colorless viscous substance by preparative HPLC with a yield of 21.4%.

[0159] LC-MS (ESI): [M + H] + = 470.2;

[0160] 11H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.65–7.56 (m, 2H), 6.71 (s, 1H), 4.25–4.17 (m, 2H), 4.02–3.95 (m, 1H), 3.93 (s, 1H), 3.82–3.72 (m, 3H), 3.64 (dd, J = 13.4, 6.2 Hz, 2H), 3.60–3.52 (m, 2H), 3.46 (d, J = 10.7 Hz, 2H), 3.26 (s, 3H), 2.06–1.75 (m, 4H).

[0161] Example 4 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 4)

[0162]

[0163] Step 1: Synthesis of 4-bromo-N-methoxy-N-methyl-2-(trifluoromethyl)benzamide

[0164] 4-Bromo-2-(trifluoromethyl)benzoic acid (50.0 g, 185 mmol) was added to dichloromethane (350 mL), stirred until completely dissolved, and then N,O-dimethylhydroxylamine hydrochloride (18 mL, 241 mmol), EDCI (39.1 g, 204 mmol), and HOBT (27.6 g, 204 mmol) were added. Diisopropylethylamine was slowly added dropwise at 10 °C. After the addition, the reaction was warmed to room temperature and stirred for 12 hours. The mixture was extracted with dichloromethane (40 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and separated by column chromatography with PE:EA = 100:0 - 93:7 to obtain 55.0 g of a pale yellow oil, with a yield of 94.8%.

[0165] 1 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (br d, J = 7.99 Hz, 1H), 7.23 (d, J = 8.11 Hz, 1H), 3.35 (m, 3H), 3.28 (s, 3H).

[0166] Step 2: Synthesis of 1-(4-bromo-2-(trifluoromethyl)phenyl)propan-1-one

[0167] 4-Bromo-N-methoxy-N-methyl-2-(trifluoromethyl)benzamide (50 g, 160 mmol) was added to tetrahydrofuran (350 mL), and stirred until completely dissolved. The temperature was cooled to 0 °C, and 3 M ethylmagnesium bromide in diethyl ether solution (53.3 g, 400 mmol) was slowly added dropwise. The temperature was controlled at 0 °C. After the addition, the mixture was stirred at 0 °C for 5 minutes, and then allowed to react naturally to warm up to 25 °C and react for 3 hours. The reaction mixture was added to ice water (100 mL), stirred to quench the reaction completely, and then extracted with ethyl acetate (40 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography separation with PE:EA = 100:0 to 90:10 gave 12.5 g of a yellow liquid with a yield of 27.8%.

[0168] 1 HNMR (400 MHz, CDCl3) δ 7.64 - 8.01 (m, 2H), 7.21 - 7.47 (m, 1H), 2.71 - 3.05 (m, 2H), 1.05 - 1.40 (m, 3H).

[0169] Step 3: Synthesis of 1-(4-bromo-2-(trifluoromethyl)phenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one

[0170] 1-(4-Bromo-2-(trifluoromethyl)phenyl)propan-1-one (12.5 g, 44.4 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (15.5 g, 174 mmol) and toluene (88 mL) were added to a reaction flask and reacted at 100 °C for 3 hours. The temperature was cooled and the solvent was concentrated to obtain a brownish oil. The crude product was directly used for the next step of the reaction.

[0171] LC-MS (ESI): [M+H] + = 336.0.

[0172] Step 4: Synthesis of 3-(4-bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole

[0173] 1-(4-Bromo-2-(trifluoromethyl)phenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one was placed in a reaction flask, ethanol (105 mL) was added and stirred until dissolved, and hydrazine hydrate (11.1 g, 222 mmol) was added dropwise. The temperature was raised to 80 °C and reacted for 3 hours. After the reaction solution was concentrated, column chromatography separation with PE:EA = 100:0 to 80:20 gave 8.00 g of a pale yellow oil with a yield of 59.0%.

[0174] 1H NMR (400MHz, CDCl3) δ7.84(d,J=1.88Hz,1H),7.65(dd,J=8.19,1.94Hz,1H),7.34(s,1H),7.13-7.23(m,1H),1.82-1.92(m,3H).

[0175] Step 5: Synthesis of (S)-1-((1,4-dioxane-2-yl)methyl)-3-(4-bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole

[0176] 3-(4-Bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole (3.0 g, 9.83 mmol) was added to DMF (21 mL) and stirred to dissolve. Potassium carbonate (4.85 g, 14.7 mmol) was added and the temperature was raised to 80°C for reaction for 12 hours. The temperature was lowered and the solid was filtered to remove the solid. The filtrate was collected and DMF was removed with an oil pump. Water (10 mL) was added to the crude product and extracted with ethyl acetate (5 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3.50 g of a brown-yellow oil with a yield of 87.8%.

[0177] 1 HNMR(400MHz, CDCl3)δ7.90-8.09(m,1H),7.82(t,J=7.46Hz,1H),7.37-7.47(m,1H),7.23-7.35(m,1H) ,4.16(dd,J=5.44,1.41Hz,2H),3.94-4.06(m,2H),3.49-3.92(m,3H),3.21-3.43(m,2H),1.93(s,3H).

[0178] Step 6: Synthesis of (S)-ethyl 4-(1-((1,4-dioxane-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0179] (S)-1-((1,4-dioxane-2-yl)methyl)-3-(4-bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole (3.00 g, 7.40 mmol) was added to ethanol (20 mL) and stirred to dissolve, and DBU (5.64 g 37.0 mmol), tri-tert-butylphosphine tetrafluoroborate (0.64 g, 2.22 mmol), hexacarbonyl molybdenum (0.98 g, 3.70 mmol), palladium acetate (0.25 g, 1.11 mmol) were added, and nitrogen was replaced three times, and the temperature was raised to 90 degrees and reacted for 12 hours. The reaction was stopped, cooled, concentrated, and purified by HPLC to obtain 2.0 g of brown oil with a yield of 67.8%.

[0180] LC-MS (ESI): [M+H] + = 399.3;

[0181] 1 H NMR (400 MHz, CDCl3) δ 8.33 - 8.42 (m, 1H), 8.13 - 8.26 (m, 1H), 7.31 - 7.43 (m, 1H), 7.21 - 7.27 (m, 1H), 4.31 - 4.43 (m, 2H), 4.03 - 4.12 (m, 2H), 3.84 - 3.96 (m, 1H), 3.35 - 3.80 (m, 5H), 3.10 - 3.27 (m, 1H), 1.84 (s, 3H), 1.32 - 1.42 (m, 3H).

[0182] Step 7: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0183] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (490 mg, 1.23 mmol) was added to tetrahydrofuran (2 mL) and water (2 mL) and stirred until dissolved. Lithium hydroxide (88.3 mg, 3.69 mmol) was added, and the reaction was carried out at room temperature for 12 hours. Concentrate under reduced pressure, extract with ethyl acetate (5 mL × 2), collect the aqueous phase, adjust the pH to about 5 - 6 with 5 mol of hydrochloric acid, add ethyl acetate (5 mL × 3) for extraction, collect the organic phase, wash with saturated brine, then dry over anhydrous sodium sulfate, filter and concentrate to obtain 0.40 g of the crude product, which was directly used for the next reaction.

[0184] LC-MS (ESI): [M+H] + = 371.1.

[0185] Step 8: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0186] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (170 mg, 0.46 mmol) was placed in a 40 mL single-neck reaction flask, dissolved with dichloromethane (1 mL) under stirring, and triethylamine (92.9 mg, 0.92 mmol), (S)-(tetrahydrofuran-2-yl)methylamine (69.6 mg, 0.69 mmol), and HATU (209 mg, 0.55 mmol) were added. The reaction was carried out at room temperature for 12 hours. After purification by HPLC preparation, 80 mg of a yellow oily mixed compound was obtained, which was sent for SFC resolution. After lyophilization, 19.58 mg of a colorless oily product was obtained, with a yield of 9.4%.

[0187] LC-MS(ESI):[M+H] + = 454.2;

[0188] 1 1H NMR(400 MHz, CDCl3) δ 8.17 - 8.23 (m, 1H), 8.00 (d, J = 7.46 Hz, 1H), 7.49 (d, J = 7.95 Hz, 1H), 7.34 (s, 1H), 6.58 - 6.66 (m, 1H), 4.10 - 4.20 (m, 1H), 4.08 - 4.09 (m, 1H), 3.70 - 4.03 (m, 7H), 3.56 - 3.66 (m, 1H), 3.28 - 3.44 (m, 2H), 2.03 - 2.15 (m, 1H), 1.91 - 2.01 (m, 4H), 1.60 - 1.77 (m, 4H).

[0189] Synthesis of (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 5) in Example 5

[0190]

[0191] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (170 mg, 0.46 mmol) was added to dichloromethane (1 mL) and dissolved under stirring. Triethylamine (92.9 mg, 0.92 mmol), (5-cyclopropylpyrazin-2-yl)methylamine (69.6 mg, 0.69 mmol), and HATU (209 mg, 0.55 mmol) were added. The reaction was carried out at room temperature for 12 hours, and then the reaction was stopped. The reaction solution was concentrated and sent for purification by HPLC preparation. After lyophilization, 34.3 mg of a colorless oily product was obtained, with a yield of 14.9%.

[0192] LC-MS (ESI): [M+H] + = 502.2;

[0193] 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.48 (d, J = 1.34 Hz, 1H), 8.26 (d, J = 1.34 Hz, 1H), 8.06 (dd, J = 7.89, 1.53 Hz, 1H), 7.51 (d, J = 7.82 Hz, 1H), 7.32 - 7.40 (m, 2H), 4.80 (d, J = 5.01 Hz, 2H), 4.13 - 4.21 (m, 2H), 3.94 - 4.03 (m, 1H), 3.70 - 3.90 (m, 4H), 3.55 - 3.67 (m, 1H), 3.33 (dd, J = 11.55, 10.09 Hz, 1H), 2.07 - 2.18 (m, 1H), 1.89 - 1.99 (m, 3H), 1.11 (d, J = 6.36 Hz, 4H).

[0194] Example 6 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 6)

[0195]

[0196] Step 1: Synthesis of 4-bromo-N-methoxy-N-methyl-2-(trifluoromethyl)benzamide

[0197] Add 4-bromo-2-(trifluoromethyl)benzoic acid (50.0 g, 185 mmol) and dichloromethane (350 mL) to a reaction flask and dissolve thoroughly. Then add N,O-dimethylhydroxylamine hydrochloride (18 mL, 241 mmol), EDCI (39.1 g, 204 mmol), HOBT (27.6 g, 204 mmol). After controlling the temperature to 10 °C, slowly add diisopropylethylamine dropwise. After the addition, react at room temperature for 12 hours. Extract with dichloromethane (40 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and separate by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain 40.0 g of pale yellow oil, with a yield of 69.0%.

[0198] 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.75 (br d, J = 8.07 Hz, 1H), 7.33 (d, J = 8.19 Hz, 1H), 3.45 (s, 3H), 3.38 (s, 3H).

[0199] Step 2: Synthesis of 1-[4-bromo-2-(trifluoromethyl)phenyl]ethan-1-one

[0200] Add 4-bromo-N-methoxy-N-methyl-2-(trifluoromethyl)benzamide (10.0 g, 32.0 mmol) to a reaction flask containing tetrahydrofuran (100 mL), start stirring to dissolve it completely, then control the temperature to 0 - 5 °C, and slowly add 3 M ethylmagnesium bromide ether solution (19.1 g, 119 mmol). While maintaining the temperature at 0 °C, after the addition, allow the reaction mixture to react and warm up to 25 °C for 3 hours. Add ice water (100 ml), stir well to quench the reaction, then extract with ethyl acetate (20 mL × 3). Combine the organic phases and dry over anhydrous sodium sulfate. After silica gel column chromatography separation (PE:EA(v / v) = 5:1), 8.50 g of a yellow liquid is obtained, with a yield of 99.3%.

[0201] 1 H NMR(400MHz,CDCl3)δ7.78(d,J=1.25Hz,1H),7.68(dd,J=8.19,1.44Hz,1H),7.28(d,J=8.25Hz,1H),2.50(s,3H).

[0202] Step 3: Synthesis of 1-(4-bromo-2-(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one

[0203] Add 1-[4-bromo-2-(trifluoromethyl)phenyl]ethan-1-one (3.5 g, 267 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (4.6 g, 174 mmol), and toluene (28 mL) to the reaction flask in sequence, and react at 100 °C for 3 hours. Concentrate to obtain a brownish oil, and use the crude product directly for the next step.

[0204] Step 4: Synthesis of 3-(4-bromo-2-(trifluoromethyl)phenyl)-1H-pyrazole

[0205] Add 1-(4-bromo-2-(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one (4.2 g, 13.1 mmol) to ethanol (35.0 mL) and stir to dissolve. Dropwise add hydrazine hydrate (3.2 g, 65.5 mmol), heat the reaction to 20 °C, and stir for 3 hours. Concentrate under reduced pressure. After silica gel column chromatography separation (PE:EA(v / v) = 1:1), 3.50 g of a pale yellow oil is obtained, with a yield of 91.8%.

[0206] Step 5: Synthesis of (S)-1-((1,4-dioxane-2-yl)methyl)-3-(4-bromo-2-(trifluoromethyl)phenyl)-1H-pyrazole

[0207] 3-[4-bromo-2-(trifluoromethyl)phenyl]-1H-pyrazole (1.0 g, 3.28 mmol) and DMF (10 mL), cesium carbonate (1.6 g, 5.15 mmol), (R)-(1,4-dioxane-2-yl)methyl p-toluenesulfonate (1.1 g, 4.12 mmol) were added to the reaction bottle, and the temperature was raised to 80°C for 12 hours. The solid was removed by filtration through diatomaceous earth, the filtrate was collected, and DMF was removed by an oil pump. Water (10 mL) was added to the crude product, and it was extracted with ethyl acetate (15 mL×2). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.30 g of brown oil with a yield of 97.0%.

[0208] LC-MS(ESI):[M+1] + =391.0.

[0209] Step 6: Synthesis of ethyl (S)-4-(1-((1,4-dioxane-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0210] (S)-1-((1,4-dioxane-2-yl)methyl)-3-(4-bromo-2-(trifluoromethyl)phenyl)-1H-pyrazole (1.3 g, 3.32 mmol) was placed in a reaction bottle, ethanol (20 mL) and DBU (2.5 g, 16.6 mmol), tri-tert-butylphosphine tetrafluoroborate (0.20 g, 1.00 mmol), hexacarbonyl molybdenum (0.4 g, 1.66 mmol), palladium acetate (0.1 g, 0.50 mmol) were added, nitrogen was replaced three times, the temperature was raised to 90°C and the reaction was carried out for 12 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 1.20 g of a brown-yellow oil with a yield of 93.9%.

[0211] LC-MS(ESI):[M+H] + =385.1;

[0212] 11H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.22 (d, J = 8.13 Hz, 1H), 7.78 (d, J = 8.00 Hz, 1H), 7.52 (d, J = 2.25 Hz, 1H), 6.53 (s, 1H), 4.39 - 4.52 (m, 2H), 4.18 - 4.29 (m, 2H), 3.96 - 4.07 (m, 1H), 3.78 - 3.85 (m, 2H), 3.69 - 3.77 (m, 2H), 3.55 - 3.68 (m, 2H), 1.44 (t, J = 7.07 Hz, 3H).

[0213] Step 7: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0214] (S)-Ethyl 4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (0.5 g, 1.30 mmol) was placed in a reaction flask, dissolved by stirring with tetrahydrofuran (2.0 mL) and water (2.0 mL), lithium hydroxide (1.4 g, 3.90 mmol) was added, and the reaction was carried out at room temperature for 12 hours. The organic solvent was removed at low temperature, and then extracted with ethyl acetate (5 mL × 2). The aqueous phase was collected, adjusted to pH = 5 - 6 with 5 M hydrochloric acid, extracted with ethyl acetate (5.0 mL × 3), the organic phase was collected, washed with saturated brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.50 g of crude product, which was directly used for the next reaction.

[0215] LC-MS (ESI): [M + H] + = 357.1.

[0216] Step 8: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0217] (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (0.40 g, 1.12 mmol), dichloromethane (5.00 mL), triethylamine (0.70 g, 2.25 mmol), (S)-(tetrahydrofuran-2-yl)methylamine (0.10 g, 1.68 mmol), and HATU (0.5 g, 1.35 mmol) were added to a reaction flask, and stirred at room temperature for 12 hours. After concentration under reduced pressure, the product was purified by HPLC preparative method to obtain 33 mg of a colorless oily product, with a yield of 6.7%.

[0218] LC-MS (ESI): [M+H] + = 440.2;

[0219] 1 H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.96 (d, J = 7.82 Hz, 1H), 7.76 (d, J = 8.07 Hz, 1H), 7.51 (d, J = 2.20 Hz, 1H), 6.63 (br s, 1H), 6.51 (s, 1H), 4.22 (d, J = 5.38 Hz, 2H), 4.10 (qd, J = 7.23, 3.12 Hz, 1H), 3.97 - 4.05 (m, 1H), 3.88 - 3.94 (m, 1H), 3.82 - 3.88 (m, 2H), 3.79 - 3.82 (m, 2H), 3.69 - 3.78 (m, 2H), 3.54 - 3.63 (m, 1H), 3.35 - 3.40 (m, 1H), 3.28 - 3.34 (m, 1H), 2.01 - 2.12 (m, 1H), 1.95 (quin, J = 7.03 Hz, 2H), 1.58 - 1.66 (m, 1H).

[0220] Example 7 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 7)

[0221]

[0222] Step 1: Synthesis of Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0223] Place ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (1.00 g, 2.16 mmol) in a reaction flask, add cyclopropylboronic acid (0.37 g, 4.32 mmol), potassium phosphate (1.37 g, 6.48 mmol), tricyclohexylphosphine (0.12 g, 0.43 mmol) and toluene (10.0 mL) respectively. After purging with nitrogen, add palladium acetate (0.05 g, 0.22 mmol) to the reaction solution. After raising the external temperature of the reaction to 100 °C, stir for 12 hours. Dilute the reaction solution with water, filter, extract with ethyl acetate (30 mL × 4), combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate to dryness to obtain 900 mg of a yellow oil, with a yield of 98.2%.

[0224] LC-MS(ESI): [M+H] + = 425.1;

[0225] 1 H NMR(400 MHz, CDCl3) δ ppm 8.45(s, 1H), 8.24(d, J = 8.03 Hz, 1H), 7.59(d, J = 8.03 Hz, 1H), 7.14(s, 1H), 4.44(q, J = 7.11 Hz, 2H), 4.15 - 4.18(m, 2H), 3.91 - 4.00(m, 1H), 3.68 - 3.85(m, 4H), 3.53 - 3.62(m, 1H), 3.29(dd, J = 11.42, 10.16 Hz, 1H), 1.74(br s, 1H), 1.44(t, J = 7.09 Hz, 3H), 0.68 - 0.77(m, 2H), 0.38 - 0.45(m, 2H).

[0226] Step 2: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0227] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (900 mg, 2.12 mmol) was placed in a reaction flask, and lithium hydroxide monohydrate (267 mg, 6.36 mmol), tetrahydrofuran (10.0 mL), and water (10.0 mL) were added respectively. The reaction was stirred at room temperature for 4 hours. Dichloromethane (20 mL x 3) was added for extraction and liquid separation. The aqueous phase was adjusted to pH = 3 with 1 M dilute hydrochloric acid, and ethyl acetate (10 mL x 3) was added for extraction and liquid separation. The organic phases were combined and dried over anhydrous sodium sulfate to obtain 830 mg of a yellow oil, with a yield of 89.9%.

[0228] LC-MS(ESI): [M+H] + = 397.1;

[0229] 11H NMR (400 MHz, DMSO-d6) δ ppm 13.41 (br s, 1H), 8.29 (s, 1H), 8.24 (d, J = 7.95 Hz, 1H), 7.70 (d, J = 8.07 Hz, 1H), 7.48 (s, 1H), 4.04 - 4.19 (m, 2H), 3.80 - 3.90 (m, 1H), 3.75 (brd, J = 10.76 Hz, 1H), 3.63 (dt, J = 11.55, 2.96 Hz, 2H), 3.55 (td, J = 11.13, 2.45 Hz, 1H), 3.37 - 3.46 (m, 1H), 3.22 (dd, J = 11.43, 9.84 Hz, 1H), 1.34 - 1.45 (m, 1H), 0.62 - 0.76 (m, 2H), 0.36 - 0.44 (m, 2H).

[0230] Step 3: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0231] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (100 mg, 0.25 mmol) was placed in a reaction flask, and (S)-(tetrahydrofuran-2-yl)methylamine (32.3 mg, 0.38 mmol), HATU (115 mg, 0.30 mmol), N,N-diisopropylethylamine (0.1 mL, 0.50 mmol) and N,N-dimethylformamide (2.00 mL) were added respectively. The reaction was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, it was purified by HPLC preparation and then freeze-dried to obtain 31.2 mg of a yellow oil, with a yield of 25.8%.

[0232] LC-MS (ESI): [M + H] + = 480.2;

[0233] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (t, J = 5.69 Hz, 1H), 8.29 (d, J = 1.00 Hz, 1H), 8.17 (d, J = 8.00 Hz, 1H), 7.64 (d, J = 8.00 Hz, 1H), 7.47 (s, 1H), 4.03 - 4.15 (m, 2H), 3.96 - 4.03 (m, 1H), 3.81 - 3.89 (m, 1H), 3.72 - 3.80 (m, 2H), 3.60 - 3.68 (m, 3H), 3.51 - 3.59 (m, 1H), 3.42 (td, J = 11.04, 2.56 Hz, 1H), 3.34 - 3.38 (m, 2H), 3.22 (dd, J = 11.51, 9.88 Hz, 1H), 1.88 - 1.98 (m, 1H), 1.75 - 1.87 (m, 2H), 1.52 - 1.66 (m, 1H), 1.30 - 1.44 (m, 1H), 0.62 - 0.73 (m, 2H), 0.32 - 0.48 (m, 2H).

[0234] Synthesis of Example 8 (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-((5-cyanopyridin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 8)

[0235]

[0236] To a reaction flask were successively added (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (100 mg, 0.25 mmol), 6-(aminomethyl)pyridine-3-carbonitrile (50.4 mg, 0.38 mmol), HATU (115 mg, 0.30 mmol), diisopropylethylamine (0.1 mL, 0.50 mmol), and N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature overnight. Concentrated under reduced pressure, purified by preparative liquid chromatography, and lyophilized to obtain 31.4 mg of a yellow solid with a yield of 24.3%.

[0237] LC-MS (ESI): [M + H] + = 512.2;

[0238] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (t, J = 5.8 Hz, 1H), 8.98 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 1.1 Hz, 1H), 8.27 (dd, J = 8.1, 2.1 Hz, 1H), 8.21 - 8.25 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 4.69 (d, J = 5.8 Hz, 2H), 4.09 (t, J = 5.5 Hz, 2H), 3.80 - 3.88 (m, 1H), 3.72 - 3.78 (m, 1H), 3.63 (dt, J = 11.7, 3.1 Hz, 2H), 3.52 - 3.59 (m, 1H), 3.37 - 3.46 (m, 1H), 3.22 (dd, J = 11.4, 9.8 Hz, 1H), 1.30 - 1.47 (m, 1H), 0.61 - 0.73 (m, 2H), 0.31 - 0.47 (m, 2H).

[0239] Example 9 Synthesis of 4-(1-(((S)-1,4-Dioxan-2-yl)methyl)-4-isopropyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 9)

[0240]

[0241] Step 1: Synthesis of Ethyl (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0242] Place ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (900 mg, 1.94 mmol) in a reaction flask, and add prop-2-en-1-ylboronic acid (334 mg, 3.89 mmol), potassium phosphate (1.24 g, 5.83 mmol), n-butyl-di(1-adamantyl)phosphine (69.7 mg, 0.19 mmol), water (1.00 mL), and 1,4-dioxane (10.0 mL). After purging with nitrogen, add cataCXium A Pd G3 (142 mg, 0.19 mmol) to the reaction solution. After raising the external temperature of the reaction to 100 °C, stir overnight. Add water to the reaction solution and filter. Extract the filtrate with ethyl acetate (20.0 mL × 4). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 800 mg of a yellow oil, with a yield of 97.0%.

[0243] LC-MS(ESI): [M+H] + = 425.3

[0244] Step 2: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0245] Place ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (800 mg, 2.12 mmol) in a reaction flask, and add lithium hydroxide monohydrate (267 mg, 6.36 mmol), tetrahydrofuran (8.00 mL), and water (8.00 mL) respectively. The reaction is stirred at room temperature for 4 hours. Extract and separate with dichloromethane (10.0 mL x 3). Add 1M dilute hydrochloric acid to the aqueous phase until pH = 3, extract with ethyl acetate (10.0 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and obtain 770 mg of a white solid with a yield of 91.6%.

[0246] LC-MS(ESI): [M+H] + = 397.1

[0247] Step 3: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0248] Place (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (200 mg, 0.50 mmol) in a reaction flask, and add (S)-(tetrahydrofuran-2-yl)methylamine (0.10 mL, 0.76 mmol), HATU (230 mg, 0.61 mmol), N,N-diisopropylethylamine (0.2 mL, 1.01 mmol), and dichloromethane (2.0 mL) respectively. The reaction is stirred at room temperature overnight. After concentrating the reaction solution to dryness, 240 mg of a crude product is obtained and directly used for the next step.

[0249] LC-MS(ESI): [M+H] + = 480.2

[0250] Step 4: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-isopropyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0251] 4-(1-(((S)-1,4-Dioxan-2-yl)methyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (240 mg, 0.50 mmol), wet palladium on carbon (26.7 mg, 0.25 mmol) were placed in a reaction flask, methanol (3.00 mL) was added, hydrogen (1.01 mg, 0.50 mmol, 15 psi), the hydrogen was displaced 3 times and the hydrogen atmosphere was maintained, and the reaction was carried out at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth to remove palladium on carbon, and the filter cake was washed with methanol (20.0 mL). The organic phases were combined, methanol was removed by distillation under reduced pressure, and after purification by HPLC preparation and freeze-drying, 33.1 mg of a yellow solid was obtained, with a yield of 13.7%.

[0252] LC-MS (ESI): [M+H] + = 482.2;

[0253] 1 HNMR (400 MHz, DMSO-d6) δ ppm 8.90 (t, J = 5.75 Hz, 1H), 8.28 (d, J = 1.00 Hz, 1H), 8.16 (d, J = 8.00 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 8.00 Hz, 1H), 4.06 - 4.20 (m, 2H), 4.01 (q, J = 6.32 Hz, 1H), 3.82 - 3.92 (m, 1H), 3.73 - 3.82 (m, 2H), 3.61 - 3.68 (m, 3H), 3.53 - 3.60 (m, 1H), 3.43 (td, J = 11.01, 2.63 Hz, 1H), 3.35 - 3.38 (m, 2H), 3.23 (dd, J = 11.44, 9.94 Hz, 1H), 2.55 - 2.65 (m, 1H), 1.88 - 2.00 (m, 1H), 1.76 - 1.87 (m, 2H), 1.51 - 1.67 (m, 1H), 1.02 (dd, J = 6.88, 1.63 Hz, 6H).

[0254] Example 10 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 10)

[0255]

[0256] Step 1: Synthesis of Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate Add ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (30 mg, 0.08 mmol), acetonitrile (1 mL) to the reaction flask in sequence, and slowly add NCS (10 mg, 0.08 mmol). React at room temperature for 16 hours. Extract with dichloromethane (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 30 mg of pale yellow oil, with a yield of 89.6%.

[0257] Step 2: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0258] Add ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (30 mg, 0.07 mmol), tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide (5.1 mg, 0.21 mmol) to the reaction flask in sequence. React at room temperature for 3 hours. Add water (1 mL) to the system, extract with ethyl acetate (5 mL × 3), collect the aqueous phase, adjust the pH to about 5 - 6 with 5N hydrochloric acid, extract with ethyl acetate (5 mL × 3), collect the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain 0.03 g of crude product, which is directly used for the next step of the reaction.

[0259] Step 3: Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0260] Add (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-chloro-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (30 mg, 0.08 mmol), dichloromethane (1 mL), HATU (36.5 mg, 0.096 mmol), diisopropylethylamine (20.7 mg, 0.16 mmol) and (S)-(tetrahydrofuran-2-yl)methylamine (12 mg, 0.12 mmol) to the reaction flask in sequence. React at 25 °C for 12 hours, and subject it to preparative HPLC purification to obtain 33 mg of colorless oil, with a yield of 90.7%.

[0261] LC-MS(ESI): [M+1] + = 474.1;

[0262] 1 H NMR(400 MHz, CDCl3) δ 8.14 (d, J = 1.13 Hz, 1H), 7.93 (dd, J = 7.94, 1.44 Hz, 1H), 7.45 - 7.52 (m, 2H), 6.54 (br t, J = 5.07 Hz, 1H), 3.99 - 4.13 (m, 3H), 3.60 - 3.93 (m, 8H), 3.43 - 3.55 (m, 1H), 3.17 - 3.34 (m, 2H), 1.93 - 2.06 (m, 1H), 1.87 (quin, J = 7.07 Hz, 1H), 1.48 - 1.63 (m, 2H).

[0263] Synthesis of Example 11 (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 11)

[0264]

[0265] Step 1: Synthesis of Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0266] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (2.00 g, 5.20 mmol) was placed in a reaction flask, and N-bromosuccinimide (0.93 g, 5.20 mmol) and acetonitrile (20.0 mL) were added respectively. The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness and purified by column chromatography to obtain 2.10 g of a yellow oil, with a yield of 87.1%.

[0267] LC-MS(ESI): [M+H] + = 463.1.

[0268] Step 2: Synthesis of Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0269] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (300 mg, 0.65 mmol) was placed in a reaction flask, and zinc cyanide (152 mg, 1.30 mmol), tetrakis(triphenylphosphine)palladium (74.8 mg, 0.06 mmol), and N,N-dimethylacetamide (3.00 mL) were added respectively. The external temperature of the reaction was raised to 120 °C and stirred for 3 hours. After the reaction solution was concentrated, dichloromethane (10.0 mL) was added, and the mixture was filtered and concentrated to obtain 260 mg of the crude product, which was directly used for the next step.

[0270] LC-MS(ESI):[M+H] + = 410.1.

[0271] Step 3: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0272] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (260 mg, 0.64 mmol) was placed in a reaction flask, and lithium hydroxide monohydrate (29.3 mg, 0.70 mmol), tetrahydrofuran (5.00 mL), and water (5.00 mL) were added respectively. The reaction was stirred at room temperature for 2 hours. The mixture was extracted and separated with dichloromethane (10.0 mL × 3). The aqueous phase was adjusted to pH = 3 with 1 M dilute hydrochloric acid, and then extracted and separated with ethyl acetate (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and 200 mg of a transparent oily substance was obtained with a yield of 82.6%.

[0273] LC-MS(ESI):[M+H] + = 382.2.

[0274] Step 4: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0275] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-cyano-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (200 mg, 0.52 mmol) was placed in a reaction flask, and (5-cyclopropylpyrazin-2-yl)methanamine (313 mg, 2.10 mmol), HATU (239 mg, 0.63 mmol), N,N-diisopropylethylamine (0.2 mL, 1.05 mmol), and dichloromethane (2.00 mL) were added respectively. The reaction was stirred overnight at room temperature. The mixture was extracted with dichloromethane (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and purified by HPLC preparative method to obtain 32.1 mg of a yellow solid with a yield of 12.0%.

[0276] LC-MS (ESI): [M+H] + = 513.2;

[0277] 1 1H NMR (400 MHz, DMSO-d6) δ 9.50 (br t, J = 5.57 Hz, 1H), 8.68 (s, 1H), 8.56 (d, J = 1.13 Hz, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 8.29 (br d, J = 8.00 Hz, 1H), 7.76 (d, J = 8.00 Hz, 1H), 4.60 (d, J = 5.63 Hz, 2H), 4.28 - 4.36 (m, 2H), 3.86 - 3.97 (m, 1H), 3.76 (br d, J = 11.51 Hz, 2H), 3.64 (br d, J = 11.26 Hz, 1H), 3.51 - 3.61 (m, 1H), 3.39 - 3.49 (m, 1H), 3.23 - 3.29 (m, 1H), 2.13 - 2.25 (m, 1H), 1.00 - 1.05 (m, 2H), 0.90 - 0.96 (m, 2H).

[0278] Synthesis of Example 12 (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 12)

[0279]

[0280] Step 1: Synthesis of ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0281] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (500 mg, 1.08 mmol) was placed in a reaction flask. Cesium fluoride (0.10 mL, 3.24 mmol) and dioxane (10.0 mL) were added respectively. After purging with nitrogen, 1,1-bis(diphenylphosphino)ferrocene palladium chloride (78.9 mg, 0.11 mmol) was added. The external temperature of the reaction was raised to 90 °C and stirred overnight. Ethyl acetate (20.0 mL x 3) was added for extraction and liquid separation. The organic phases were combined, dried over anhydrous sodium sulfate, and 490 mg of a black oil was obtained with a yield of 98.6%.

[0282] LC-MS(ESI):[M+H] + = 461.3。

[0283] Step 2: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0284] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (490 mg, 1.06 mmol) was placed in a reaction flask. Lithium hydroxide monohydrate (134 mg, 3.19 mmol), tetrahydrofuran (10.0 mL) and water (10.0 mL) were added respectively. The reaction was stirred at room temperature for 3 hours. Dichloromethane (20 mL x 3) was added for extraction and liquid separation. The aqueous phase was adjusted to pH = 3 with 1 M dilute hydrochloric acid, and ethyl acetate (20.0 mL x 3) was added for extraction and liquid separation. The organic phases were combined, dried over anhydrous sodium sulfate, and 450 mg of a crude brown solid was obtained with a yield of 97.8%

[0285] LC-MS(ESI):[M+H] + = 433.1。

[0286] Step 3: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0287] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (200 mg, 0.52 mmol) was placed in a reaction flask, and (5-cyclopropylpyrazin-2-yl)methanamine (138 mg, 0.93 mmol), HATU (296 mg, 0.78 mmol), N,N-diisopropylethylamine (134 mg, 1.04 mmol) and dichloromethane (2.00 mL) were added respectively. The reaction was stirred overnight at room temperature. Purification by HPLC preparation and lyophilization gave 25.8 mg of a white solid with a yield of 19.8%.

[0288] LC-MS (ESI): [M+H] + = 564.2;

[0289] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.45 (t, J = 5.50 Hz, 1H), 8.56 (d, J = 1.00 Hz, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 8.10 - 8.18 (m, 2H), 7.47 (d, J = 8.00 Hz, 1H), 7.18 - 7.26 (m, 2H), 7.10 - 7.16 (m, 1H), 7.05 (d, J = 7.25 Hz, 2H), 4.59 (d, J = 5.75 Hz, 2H), 4.21 - 4.26 (m, 2H), 3.88 - 3.99 (m, 1H), 3.78 (br d, J = 10.51 Hz, 1H), 3.70 - 3.75 (m, 1H), 3.65 (br d, J = 12.01 Hz, 1H), 3.55 - 3.62 (m, 1H), 3.40 - 3.49 (m, 1H), 3.27 (br s, 1H) 2.15 - 2.24 (m, 1H), 1.00 - 1.06 (m, 2H), 0.89 - 0.96 (m, 2H).

[0290] Example 13 Synthesis of 4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 13)

[0291]

[0292] (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-phenyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (100 mg, 0.35 mmol) was placed in a reaction flask, and (S)-(tetrahydrofuran-2-yl)methanamine (34.9 mg, 1.01 mmol), HATU (200 mg, 0.53 mmol), N,N-diisopropylethylamine (0.1 mL, 0.46 mmol) and dichloromethane (2.00 mL) were added respectively. The reaction was stirred overnight at room temperature. After purification by HPLC preparation and freeze-drying, 31.9 mg of white solid was obtained, with a yield of 52.2%.

[0293] LC-MS (ESI): [M+H] + = 516.2;

[0294] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (t, J = 5.69 Hz, 1H), 8.31 (d, J = 1.00 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 7.88 Hz, 1H), 7.44 (d, J = 8.00 Hz, 1H), 7.18 - 7.25 (m, 2H), 7.08 - 7.15 (m, 1H), 7.02 - 7.07 (m, 2H), 4.23 (dd, J = 5.75, 2.13 Hz, 2H), 3.98 - 4.06 (m, 1H), 3.87 - 3.97 (m, 1H), 3.77 - 3.82 (m, 1H), 3.69 - 3.77 (m, 2H), 3.62 - 3.68 (m, 2H), 3.59 (td, J = 11.04, 2.56 Hz, 1H), 3.40 - 3.49 (m, 1H), 3.35 (t, J = 5.94 Hz, 2H), 3.26 - 3.29 (m, 1H), 1.88 - 1.99 (m, 1H), 1.75 - 1.87 (m, 2H), 1.51 - 1.65 (m, 1H).

[0295] Synthesis of Example 14 (S)-4-(1-((1,4-Dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 14)

[0296]

[0297] Step 1: Synthesis of ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate

[0298] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-bromo-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (200 mg, 0.43 mmol), ethynylcyclopropane (0.2 mL, 2.16 mmol), cesium carbonate (422 mg, 1.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (33.6 mg, 0.04 mmol) and N,N-dimethylformamide (4.00 mL) were successively added to a reaction flask, and the mixture was stirred at 100 °C overnight. Water (5.00 mL) was added, and the aqueous phase was extracted and separated with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC preparative to obtain 50.0 mg of a brown oil.

[0299] LC-MS (ESI): [M+H] + = 449.1.

[0300] Step 2: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid

[0301] Ethyl (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoate (50.0 mg, 0.11 mmol), lithium hydroxide monohydrate (14.1 mg, 0.33 mmol), tetrahydrofuran (5.00 mL) and water (5.00 mL) were successively added to a reaction flask, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated to dryness, dichloromethane (10 mL) was added for extraction and separation. The aqueous phase was neutralized to pH = 3 with 1 M HCl, ethyl acetate (10 mL) was added, and the mixture was extracted and separated. The organic phases were combined, dried over anhydrous sodium sulfate, and 45.0 mg of a crude product was obtained and directly used for the next step.

[0302] LC-MS (ESI): [M+H] + = 421.1.

[0303] Step 3: Synthesis of (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide

[0304] To the reaction flask were successively added (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-(cyclopropylethynyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (45.0 mg, 0.11 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (63.9 mg, 0.43 mmol), HATU (48.8 mg, 0.13 mmol), DIEA (27.7 mg, 0.21 mmol) and dichloromethane (2.00 mL), and the reaction mixture was stirred at room temperature overnight. The reaction solution was added with water (5.00 mL), and extracted with dichloromethane (5.00 mL × 3). The organic phases were combined, purified by HPLC preparation, and freeze-dried to obtain 22.3 mg of a yellow solid with a yield of 39.5%.

[0305] LC-MS(ESI):[M+H] + = 552.2;

[0306] 1 H NMR(400 MHz, CDCl3) δ 8.52(s, 1H), 8.46(s, 1H), 8.24(s, 1H), 8.06(d, J = 8.00 Hz, 1H), 7.70(d, J = 8.13 Hz, 1H), 7.60(s, 1H), 7.35(br s, 1H), 4.79(d, J = 5.00 Hz, 2H), 4.15(d, J = 5.25 Hz, 2H), 3.91 - 3.99(m, 1H), 3.77 - 3.84(m, 2H), 3.69 - 3.77(m, 2H), 3.53 - 3.63(m, 1H), 3.26 - 3.34(m, 1H), 2.10(quin, J = 6.44 Hz, 1H), 1.25 - 1.34(m, 1H), 1.11(s, 2H), 1.09(s, 2H), 0.73 - 0.80(m, 2H), 0.59 - 0.66(m, 2H).

[0307] Synthesis of Example 15 (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 15)

[0308]

[0309] To the reaction flask, (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (150 mg, 0.38 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (225.8 mg, 1.51 mmol), HATU (172.7 mg, 0.45 mmol), diisopropylethylamine (0.1 mL, 0.76 mmol) and dichloromethane (2 mL) were added successively, and the reaction was stirred at room temperature for 12 hours. The reaction solution was directly concentrated and purified by HPLC to obtain 36.5 mg of a white solid with a yield of 18.3%.

[0310] LC-MS(ESI):[M+H] + = 528.2;

[0311] 1 H NMR(400MHz,CDCl3)δ8.51(s,1H),8.46(d,J = 1.25Hz,1H),8.24(s,1H),8.04(dd,J = 7.94,1.31Hz,1H),7.60(d,J = 8.00Hz,1H),7.34(br s,1H),7.13(s,1H),4.78(d,J = 5.13Hz,2H),4.08 - 4.15(m,2H),3.95(dtt,J = 7.50,5.22,5.22,2.72,2.72Hz,1H),3.77(br d,J = 2.88Hz,2H),3.68 - 3.76(m,2H),3.54 - 3.61(m,1H),3.29(dd,J = 11.57,10.07Hz,1H),2.09(quin,J = 6.47Hz,1H),1.36 - 1.49(m,1H),1.03 - 1.14(m,4H),0.64 - 0.77(m,2H),0.40 - 0.45(m,2H).

[0312] Synthesis of Example 16 (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-((5-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 16)

[0313]

[0314] To the reaction flask, (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (150 mg, 0.38 mmol), dichloromethane (5 mL), HATU (172.7 mg, 0.45 mmol), diisopropylethylamine (0.1 mL, 0.76 mmol) and (5-chloropyrazin-2-yl)methanamine (81.5 mg, 0.57 mmol) were added successively, and the reaction was carried out at room temperature for 3 hours. The reaction solution was directly concentrated, purified by HPLC and freeze-dried to obtain 70.0 mg of a white solid, with a yield of 35.4%.

[0315] LC-MS(ESI):[M+H] + = 522.2;

[0316] 1 H NMR(400 MHz, CDCl3) δ 8.59 (d, J = 1.13 Hz, 1H), 8.51 (s, 1H), 8.23 (d, J = 1.25 Hz, 1H), 8.03 (dd, J = 7.94, 1.44 Hz, 1H), 7.61 (d, J = 8.00 Hz, 1H), 7.20 (br t, J = 5.07 Hz, 1H), 7.14 (s, 1H), 4.84 (d, J = 5.38 Hz, 2H), 4.11 - 4.15 (m, 2H), 3.91 - 4.01 (m, 1H), 3.80 - 3.85 (m, 1H), 3.76 - 3.79 (m, 1H), 3.67 - 3.76 (m, 2H), 3.53 - 3.62 (m, 1H), 3.29 (dd, J = 11.51, 10.13 Hz, 1H), 1.36 - 1.46 (m, 1H), 0.69 - 0.75 (m, 2H), 0.40 - 0.46 (m, 2H).

[0317] Synthesis of Example 17 (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-N-(pyrimidin-2-ylmethyl)-3-(trifluoromethyl)benzamide (Compound 17)

[0318]

[0319] To the reaction flask, (S)-4-(1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzoic acid (70 mg, 0.18 mmol), 2-(methylamino)pyrimidine (28.9 mg, 0.26 mmol), HATU (80.6 mg, 0.21 mmol), diisopropylethylamine (45.7 mg, 0.35 mmol) and dichloromethane (2.00 mL) were added successively. The reaction was stirred overnight at room temperature, purified by HPLC preparation, and freeze-dried to obtain 35.7 mg of a white solid with a yield of 41.8%.

[0320] LC-MS(ESI): [M+H] + = 488.2;

[0321] 1 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.88 Hz, 2H), 8.31 (d, J = 1.50 Hz, 1H), 8.11 (dd, J = 7.88, 1.50 Hz, 1H), 7.64 (br s, 1H), 7.62 (d, J = 8.00 Hz, 1H), 7.27 - 7.30 (m, 1H), 7.14 (s, 1H), 4.96 (d, J = 4.50 Hz, 2H), 4.13 (dd, J = 5.44, 1.81 Hz, 2H), 3.96 (dtt, J = 7.62, 5.24, 5.24, 2.64, 2.64 Hz, 1H), 3.80 - 3.85 (m, 1H), 3.74 - 3.80 (m, 2H), 3.71 (br d, J = 9.51 Hz, 1H), 3.54 - 3.63 (m, 1H), 3.30 (dd, J = 11.57, 10.07 Hz, 1H), 1.39 - 1.49 (m, 1H), 0.69 - 0.78 (m, 2H), 0.41 - 0.48 (m, 2H).

[0322] Example 18 Synthesis of 4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-1H-pyrazol-3-yl)-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (Compound 18)

[0323]

[0324] Under a nitrogen atmosphere, (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-ethynyl-3-methylphenyl)-1H-pyrazole (98 mg, 0.35 mmol) dissolved in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added to a reaction flask. Then, 2-(azidomethyl)tetrahydro-2H-pyran (74 mg, 0.52 mmol), anhydrous copper sulfate (6 mg, 0.03 mmol), and sodium ascorbate (14 mg, 0.07 mmol) were added. After addition, the mixture was transferred to room temperature and stirred for 2 hours. The reaction was monitored by TLC and was found to be complete. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A white solid (134 mg) was obtained by preparative HPLC with a yield of 89.1%.

[0325] LC-MS(ESI):[M+H] + = 424.4;

[0326] 1 H NMR(500MHz,DMSO-d6)δ8.31(s,1H),7.79(d,J = 8.0Hz,1H),7.76 - 7.71(m,2H),7.71 - 7.66(m,1H),6.72(d,J = 2.3Hz,1H),4.51 - 4.38(m,2H),4.25 - 4.14(m,2H),3.96 - 3.84(m,2H),3.78 - 3.72(m,3H),3.67 - 3.53(m,2H),3.50 - 3.42(m,1H),3.38 - 3.29(m,1H),3.28(d,J = 9.8Hz,1H),2.49(s,3H),1.83 - 1.78(m,1H),1.68 - 1.61(m,1H),1.55 - 1.40(m,3H),1.28 - 1.16(m,1H).

[0327] Example 19 Synthesis of 4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)phenyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazole (Compound 19)

[0328]

[0329] Step 1: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole

[0330] Add (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-bromo-2-(trifluoromethyl)phenyl)-1H-pyrazole (2.20 g, 5.62 mmol), ethynyl[tris(propan-2-yl)]silane (1.50 mL, 6.75 mmol), triethylamine (3.90 mL, 28.12 mmol), copper(I) iodide (0.54 g, 2.81 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.44 g, 0.56 mmol) and tetrahydrofuran (20 mL) into a reaction flask. Heat to 80 °C and stir overnight. After filtration and concentration, purify by column chromatography (PE:EA(v / v) = 5:1) to obtain 2.40 g of a brown oil, with a yield of 86.6%.

[0331] LC-MS(ESI): [M+H] + = 493.3;

[0332] 1 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.63 (s, 2H), 7.50 (s, 1H), 6.48 (s, 1H), 4.22 (d, J = 5.38 Hz, 2H), 3.95 - 4.07 (m, 1H), 3.77 - 3.85 (m, 2H), 3.68 - 3.76 (m, 2H), 3.54 - 3.63 (m, 1H), 3.28 - 3.35 (m, 1H), 1.13 - 1.18 (m, 21H).

[0333] Step 2: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-bromo-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole

[0334] Add (S)-1-((1,4-dioxan-2-yl)methyl)-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole (1.00 g, 2.03 mmol), N-bromosuccinimide (0.36 g, 2.03 mmol) and acetonitrile (10.0 mL) into a reaction flask. React at room temperature and stir overnight. After concentration, purify by column chromatography to obtain 700 mg of a transparent oil, with a yield of 60.3%.

[0335] LC-MS(ESI): [M+H] + = 573.1;

[0336] 11H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.68 (dd, J = 7.94, 0.94 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J = 7.88 Hz, 1H), 4.18 (dd, J = 5.19, 2.44 Hz, 2H), 4.10 - 4.16 (m, 1H), 3.96 (dtd, J = 10.05, 5.14, 5.14, 2.69 Hz, 1H), 3.81 - 3.86 (m, 1H), 3.74 - 3.79 (m, 1H), 3.69 - 3.74 (m, 1H), 3.53 - 3.62 (m, 1H), 3.29 (dd, J = 11.51, 10.13 Hz, 1H), 1.09 - 1.22 (m, 21H).

[0337] Step 3: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole

[0338] Add (S)-1-((1,4-dioxan-2-yl)methyl)-4-bromo-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole (700 mg, 1.22 mmol), cyclopropylboronic acid (158 mg, 1.84 mmol), potassium phosphate (564 mg, 2.45 mmol), tricyclohexylphosphine (68.7 mg, 0.24 mmol) and toluene (7.0 mL) into a reaction flask. After purging with nitrogen, add palladium(II) acetate (27.5 mg, 0.12 mmol), and heat the mixture to 100 °C and stir for 2 h. After the reaction mixture is cooled to room temperature, filter it, extract with ethyl acetate (20.0 mL × 3), separate the layers, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate to obtain 400 mg of a brown oil, with a yield of 61.3%.

[0339] LC-MS (ESI): [M + H] + = 533.3

[0340] Step 4: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(4-ethynyl-2-(trifluoromethyl)phenyl)-1H-pyrazole

[0341] Add (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(2-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole (350 mg, 0.66 mmol) and tetrahydrofuran (10 mL) to a reaction flask. After cooling in an ice bath, add tetrabutylammonium fluoride (0.7 mL, 0.66 mmol) dropwise. The reaction is stirred at room temperature for 1 hour. After concentration, it is purified by column chromatography to obtain 200 mg of a yellow oil with a yield of 76.8%.

[0342] LC-MS(ESI): [M+H] + = 377.0.

[0343] Step 5: Synthesis of 4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)phenyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazole

[0344] Add (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(4-ethynyl-2-(trifluoromethyl)phenyl)-1H-pyrazole (170 mg, 0.45 mmol), anhydrous copper sulfate (97.7 mg, 0.68 mmol), sodium L-ascorbate (107.4 mg, 0.54 mmol) and (2S)-2-(azidomethyl)tetrahydrofuran (86.14 mg, 0.68 mmol) in DMF (5.0 mL) to a reaction flask. The reaction is stirred at room temperature overnight. The reaction solution is slowly added to ice water and the pH is adjusted to >9. Extract with ethyl acetate (30 mL x 3) and separate the layers. Combine the organic phases, wash with brine, and dry over anhydrous sodium sulfate. Dilute the aqueous phase with 50-fold water. While stirring continuously, slowly add an aqueous sodium hypochlorite solution to quench. Let stand overnight. Purify by HPLC preparation and separate impurities by SFC to obtain 33.4 mg of a white solid with a yield of 14.7%.

[0345] LC-MS(ESI): [M+H] + = 504.2;

[0346] 11H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 1.38 Hz, 1H), 8.09 (dd, J = 8.00, 1.38 Hz, 1H), 8.07 (s, 1H), 7.55 (d, J = 8.00 Hz, 1H), 7.13 (s, 1H), 4.65 (dd, J = 14.13, 3.25 Hz, 1H), 4.38 - 4.51 (m, 1H), 4.30 (qd, J = 6.86, 3.19 Hz, 1H), 4.14 (d, J = 2.13 Hz, 1H), 4.13 (d, J = 1.00 Hz, 1H), 3.93 - 4.01 (m, 1H), 3.87 - 3.93 (m, 1H), 3.83 - 3.87 (m, 1H), 3.80 - 3.83 (m, 1H), 3.79 (brdd, J = 4.63, 2.63 Hz, 1H), 3.74 - 3.77 (m, 1H), 3.69 - 3.74 (m, 1H), 3.54 - 3.63 (m, 1H), 3.30 (dd, J = 11.63, 10.01 Hz, 1H), 2.12 (dtd, J = 12.51, 7.38, 7.38, 5.13 Hz, 1H), 1.87 - 2.00 (m, 1H), 1.76 - 1.87 (m, 1H), 1.66 - 1.73 (m, 1H), 1.42 - 1.51 (m, 1H), 0.68 - 0.77 (m, 2H), 0.39 - 0.48 (m, 2H).

[0347] Example 20 Synthesis of 4-(4-(1-(((S)-1,4-Dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)phenyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazole (Compound 20)

[0348]

[0349] Step 1: Synthesis of 4-Bromo-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide

[0350] 4-Bromo-3-(trifluoromethyl)benzoic acid (30 g, 186 mmol) was placed in a reaction flask, DCM (240 mL) was added, and stirring was started to dissolve it completely. Methoxy(methyl)amine hydrochloride (11.1 mL, 145 mmol), EDCI (23.5 g, 123 mmol) and HATU (16.6 g, 123 mmol) were added. After controlling the temperature at 10 °C, diisopropylethylamine (61.4 mL, 371 mmol) was slowly added dropwise. The reaction was carried out at 20 °C for 12 hours. TLC detected that the raw materials had completely reacted. Water (100 mL) was added to quench the reaction, and it was extracted with dichloromethane (100 mL x 3). The organic phase was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography separation (PE:EA (v / v) = 10:1) for purification to obtain 30 g of a light yellow oil, with a yield of 86.2%.

[0351] LC-MS (ESI): [M+H] + = 312.0;

[0352] 1 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.78 - 7.72 (m, 2H), 3.55 (s, 3H), 3.38 (s, 3H).

[0353] Step 2: Synthesis of 1-[4-bromo-3-(trifluoromethyl)phenyl]ethan-1-one

[0354] 4-Bromo-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (25.0 g, 80.1 mmol) was placed in a reaction flask, dissolved in tetrahydrofuran (250 mL), cooled to 0 °C, and methylmagnesium bromide (160 mL, 401 mmol) was slowly added dropwise under a nitrogen atmosphere. The reaction was carried out at room temperature. After the reaction was completed, the reaction solution was poured into an ice-cold aqueous ammonium chloride solution, stirred for 10 minutes, extracted with ethyl acetate (150 mL x 2), the combined organic phases were dried over sodium sulfate, filtered, and concentrated to obtain 18 g of a yellow oil, with a yield of 84.1%.

[0355] Step 3: Synthesis of 1-[4-bromo-3-(trifluoromethyl)phenyl]-3-(dimethylamino)prop-2-en-1-one

[0356] 1-[4-Bromo-3-(trifluoromethyl)phenyl]ethan-1-one (15.0 g, 56.2 mmol) was placed in a reaction flask, dissolved in toluene (150 mL), and [(tert-butoxy)(dimethylamino)methyl]dimethylamine (23.2 mL, 112 mmol) was added. The reaction was carried out at 100 °C overnight. After the reaction was completed, it was concentrated to obtain 13.5 g of a yellow solid, with a yield of 74.6%.

[0357] 11H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 1.6 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 5.65 (d, J = 12.3 Hz, 1H), 3.20 (br s, 3H), 2.96 (br d, J = 2.6 Hz, 3H).

[0358] Step 4: Synthesis of 3-[4-Bromo-3-(trifluoromethyl)phenyl]-1H-pyrazole

[0359] Place 1-[4-Bromo-3-(trifluoromethyl)phenyl]-3-(dimethylamino)prop-2-en-1-one (13 g, 40.4 mmol) in a reaction flask, dissolve it in ethanol (100 mL), then add hydrazine hydrate (4.5 g), and react at 80 °C for 12 hours. After detecting the completion of the reaction, directly concentrate the reaction solution to obtain 8.90 g of a yellow solid with a yield of 75.8%.

[0360] LC-MS (ESI): [M + H] + = 290.8.

[0361] Step 5: Synthesis of (S)-1-((1,4-Dioxan-2-yl)methyl)-3-(4-bromo-3-(trifluoromethyl)phenyl)-1H-pyrazole

[0362] Place 3-[4-Bromo-3-(trifluoromethyl)phenyl]-1H-pyrazole (2.0 g, 6.87 mmol) in a reaction flask, dissolve it in DMF (20.0 mL), add (R)-(1,4-Dioxan-2-yl)methyl p-toluenesulfonate (2.24 g, 8.24 mmol) and cesium carbonate (3.36 g, 10.3 mmol), and stir at 80 °C overnight. After detecting the completion of the reaction, filter the reaction solution and concentrate it, and purify it by column chromatography (PE:EA (v / v) = 5:1) to obtain 1.8 g of a yellow oil with a yield of 67.0%.

[0363] LC-MS (ESI): [M + H] + = 390.9;

[0364] 11H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 1.8 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.76 - 7.68 (m, 1H), 7.51 (d, J = 2.3 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.19 (dd, J = 1.6, 5.5 Hz, 2H), 4.09 - 3.97 (m, 1H), 3.83 (dt, J = 2.4, 10.8 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.63 - 3.54 (m, 1H), 3.34 (dd, J = 10.1, 11.6 Hz, 1H).

[0365] Step 6: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-3-(3-(trifluoromethyl)-4-((triisopropylsilylethynyl)phenyl)-1H-pyrazole

[0366] Place (S)-1-((1,4-dioxan-2-yl)methyl)-3-(4-bromo-3-(trifluoromethyl)phenyl)-1H-pyrazole (1.2 g, 3.07 mmol) in a reaction flask, dissolve it in DMF (10 mL), add ethynyl[tris(propan-2-yl)]silane (2.1 mL, 9.20 mmol), potassium carbonate (1.27 g, 9.20 mmol), copper(I) iodide (0.03 g, 0.15 mmol), and finally add Pd(dppf)Cl2 (0.11 g, 0.15 mmol). Heat the reaction to 140 °C and react. After detecting the completion of the reaction, cool the reaction solution to room temperature and filter. Concentrate the filtrate and perform column chromatography separation (PE:EA (v / v) = 10:1) to obtain 1.30 g of a brown oil, with a yield of 86.0%.

[0367] LC-MS (ESI): [M+H] + = 493.3.

[0368] Step 7: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-bromo-3-(3-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole

[0369] Place (S)-1-((1,4-dioxan-2-yl)methyl)-3-(3-(trifluoromethyl)-4-((triisopropylsilylethynyl)phenyl)-1H-pyrazole (1.30 g, 2.64 mmol) in a reaction flask, add acetonitrile (13 mL), and then add NBS (0.47 g, 2.64 mmol). After detecting the end of the reaction, purify it by column chromatography separation (PE:EA (v / v) = 20:1) to obtain 890 mg of a brown oil, with a yield of 59.0%.

[0370] LC-MS(ESI): [M+H] + = 571.2。

[0371] Step 8: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(3-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole

[0372] Place (S)-1-((1,4-dioxan-2-yl)methyl)-4-bromo-3-(3-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole (650 mg, 1.14 mmol) in a reaction flask, dissolve it in toluene (5 mL), add potassium phosphate (724 mg, 3.41 mmol), tricyclohexylphosphine (20.0 mg, 0.11 mmol), palladium(II) acetate (25.5 mg, 0.11 mmol), and displace the air with nitrogen three times. Heat the mixture to 100 °C overnight. After detecting the completion of the reaction, filter the reaction solution directly and concentrate the filtrate to obtain 180 mg of a brown oil, with a yield of 29.7%.

[0373] LC-MS(ESI): [M+H] + = 533.4。

[0374] Step 9: Synthesis of (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(4-ethynyl-3-(trifluoromethyl)phenyl)-1H-pyrazole

[0375] Place (S)-1-((1,4-dioxan-2-yl)methyl)-4-cyclopropyl-3-(3-(trifluoromethyl)-4-((triisopropylsilyl)ethynyl)phenyl)-1H-pyrazole (180 mg, 0.34 mmol) in a reaction flask, add DCM (5 mL), and then add TBAF (123 mg). Stir the mixture at room temperature. After detecting the completion of the reaction, concentrate the reaction solution to remove DCM and purify it by preparative TLC to obtain 50.0 mg of a colorless oil, with a yield of 28.3%.

[0376] LC-MS(ESI): [M+H] + = 377.2。

[0377] Step 10: Synthesis of 4-(4-(1-(((S)-1,4-dioxan-2-yl)methyl)-4-cyclopropyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)phenyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazole

[0378] (S)-1-((1,4-Dioxan-2-yl)methyl)-4-cyclopropyl-3-(4-ethynyl-3-(trifluoromethyl)phenyl)-1H-pyrazole (50 mg, 0.16 mmol) was added to a solution of (S)-2-(azidomethyl)tetrahydrofuran (21.0 mg, 0.16 mmol) in DMF (5 mL). Copper(II) sulfate pentahydrate (29.3 mg, 0.16 mmol) and L-ascorbic acid (52.1 mg, 0.16 mmol) were then added, and the mixture was stirred at room temperature overnight. After completion of the reaction was detected, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give 44.7 mg of a white solid with a yield of 53.9%.

[0379] LC-MS (ESI): [M+H] + = 504.2;

[0380] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.27 (s, 1H), 8.24 (dd, J = 1.1, 8.3 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 4.61 - 4.45 (m, 2H), 4.26 (br dd, J = 4.4, 6.6 Hz, 1H), 4.16 - 4.09 (m, 2H), 3.95 - 3.88 (m, 1H), 3.75 (br d, J = 9.4 Hz, 3H), 3.70 - 3.63 (m, 2H), 3.60 - 3.51 (m, 1H), 3.47 (dd, J = 2.4, 11.0 Hz, 1H), 3.30 - 3.20 (m, 1H), 2.06 - 1.95 (m, 1H), 1.87 - 1.78 (m, 2H), 1.73 - 1.67 (m, 1H), 1.63 - 1.56 (m, 1H), 0.96 - 0.87 (m, 2H), 0.56 (br d, J = 3.8 Hz, 2H).

[0381] Experimental Example 1 Determination of GPR84 Antagonist Activity

[0382] 1. Experimental Principle

[0383] The GPR84 receptor protein is a GPCR coupled to G αi protein. After activation of such receptors, the adenylate cyclase activity of the downstream signaling pathway is inhibited through G αi protein, and the cAMP level is downregulated. Therefore, the use of a cAMP quantification kit (LANCE UltracAMP Detection Kit) to detect the cAMP level can reflect the activity of GPR84 antagonists.

[0384] 2. Experimental Procedure

[0385] (1) The HEK293-GPR84 stable cell line was cultured in complete medium at 37 °C and 5% CO2 until the confluence reached 70% - 90%.

[0386] (2) After trypsin digestion, the cells were seeded into a 384-well cell culture plate, with 2000 cells seeded in each well.

[0387] (3) Working solutions of a series of concentrations of positive compounds and test compounds were prepared respectively.

[0388] (4) A working solution of forskolin plus embelin at a certain concentration was prepared.

[0389] (5) 2.5 μL of the antagonist in step (3) was added to the corresponding test wells of the cell plate and cultured at 37 °C for 10 minutes.

[0390] (6) 2.5 μL of the forskolin plus embelin working solution in step (4) was added to the corresponding test wells of the cell plate and cultured at 37 °C for 30 minutes.

[0391] (7) The europium-labeled cAMP tracer and the Uliaght-labeled cAMP antibody were freeze-thawed. The labeled cAMP tracer was diluted 50-fold with buffer, and the Uliaght-labeled cAMP antibody was diluted 150-fold.

[0392] (8) 10 μL of the europium-labeled cAMP tracer was added to all the experimental wells of the cell plate.

[0393] (9) 10 μL of the Uliaght-labeled cAMP antibody was added to all the experimental wells of the cell plate.

[0394] (10) The cell plate was centrifuged at 200 g for 30 seconds at room temperature and then allowed to stand for 1 hour. Then, data was collected using a multimode microplate reader (Envision 2105), and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated using GraphPad PRISM software.

[0395] The results are shown in Table 1.

[0396] Table 1 Experimental results of the antagonistic effects of the compounds provided in some embodiments of the present invention

[0397]

[0398]

[0399] Results and Discussion: The compounds of the present invention exhibited strong GPR84 antagonistic effects.

[0400] Experimental Example 2 Determination of human neutrophil migration

[0401] Experimental procedures

[0402] (1) Sort neutrophils from fresh whole blood and allow them to recover in the culture medium for half an hour;

[0403] (2) Resuspend neutrophils in chemotaxis buffer (complete culture medium without fetal bovine serum);

[0404] (3) Seed 800,000 cells per well in a 96-well V-bottom plate and pre-incubate with the compound for 0.5 hour;

[0405] (4) Transfer the cells to a chamber of a 96-well multi-well cell culture plate with the lower layer filled with chemotaxis buffer containing different concentrations of chemokines, and then place it in a cell culture incubator for 1 hour;

[0406] (5) Remove the chamber of the transwell plate, add the Luminescent Cell Viability Assay solution to the cells in the lower layer, and incubate in the dark at room temperature for 30 min;

[0407] (6) Read the fluorescence signal value with a microplate reader, and then calculate the half-maximal inhibitory concentration (IC 50 ) of the compound using GraphPad PRISM software.

[0408] Results and discussion: The experimental results show that the compounds of the present invention exhibit strong inhibitory ability against human neutrophil migration.

[0409] Experimental example 3: Pharmacokinetic study of the compounds of the present invention in mice

[0410] 1. Experimental materials

[0411] C57BL / 6 mice: male, 6 - 8 weeks old, weighing 20 - 30 g, purchased from Vital River (Beijing) Laboratory Animal Technology Co., Ltd.

[0412] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, the experimental water was ultrapure water, and the remaining reagents were all commercially available analytical grade.

[0413] Instruments: AB LCMS-5500 tandem mass spectrometer

[0414] 2. Experimental methods

[0415] Weigh the compound and dissolve it in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate systems. The preparations are all clear solutions. Administer the drug to mice via intravenous injection or gavage. Collect blood samples at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Transfer 30 μL of whole blood from each PK sampling point to an EDTA-K2 anticoagulant blood collection tube and centrifuge at 4°C within 30 min to obtain plasma. Place the whole blood samples on wet ice before centrifugation. Store all the collected plasma samples on dry ice or in frozen storage until analysis and detection.

[0416] Weigh approximately 1 mg of the compound and dissolve it in DMSO. Vortex and sonicate to obtain a 1 mg / mL standard stock solution. Dilute the standard stock solution with 50% aqueous acetonitrile to obtain standard working solutions with concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10000 ng / mL. Prepare quality control working solutions with concentrations of 10, 20, 500, and 8000 ng / mL using the same dilution method. Add 3 μL of the standard working solutions with concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000, and 10000 ng / mL) to 30 μL of blank C57BL / 6 mouse plasma to obtain standard curve samples with a total volume of 33 μL and concentrations of 0.5 - 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL). Prepare quality control samples with concentrations of (1 ng / ml (low-1) and 2 ng / ml (low-2), 50 ng / ml (medium), 800 ng / ml (high)) separately.

[0417] Add 33 μL of standard samples, 33 μL of quality control samples, or 33 μL of unknown samples (30 μL plasma and 3 μL blank solution) to 200 μL of acetonitrile containing an internal standard (dexamethasone) to precipitate proteins. Then vortex the samples for 30 seconds, centrifuge at 4000 g at 4°C for 15 minutes, take the supernatant, dilute it 3-fold with water, and inject 10 μL of the diluted supernatant into the LC-MS / MS system for quantitative analysis. The detection conditions are as follows:

[0418] Chromatographic column: Raptor Biphenyl 2.7 μm 2.1×50 mm

[0419] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water). Perform gradient elution according to the following table.

[0420]

[0421]

[0422] 3. Data processing

[0423] Use Phoenix TM Perform pharmacokinetic data analysis using the non-compartmental model of 8.3 software.

[0424] Results and Discussion: The experimental results show that the compound of the present invention has good oral absorption in mice and has a high exposure.

[0425] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

Claims

1. A compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound as represented by formula (I), in: L1 is -O-, -S-, -CR 9 R 10 -, -O-CR 11 R 12 - or -S-CR 13 R 14 -; L2 is -C(=O)NR 15 -or L3 is a key or -CR 17 R 18 -; R 3 and R 4 Each independently is C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-10 membered heteroaryl, the C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently and optionally substituted by 1, 2 or 3 R a Substitution, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 16 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 Substituted by a cycloalkyl substituent; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted independently with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; R 15 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

2. The compound according to claim 1, wherein R 3 and R 4 Each independently is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently and optionally substituted by 1, 2 or 3 R a Substitution, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group.

3. The compound according to claim 1, wherein R 3 and R 4 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, can be independently optionally replaced by 1, 2 or 3 R a Substitution, the R a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

4. The compound according to claim 1, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 16 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, phenyl, C 2-3 Alkynyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-3 Alkynyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 Alkoxy, C 1-3 Alkylamino and C 3-6 Substituted by a cycloalkyl substituent; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted independently with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; R 15 H, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

5. The compound according to claim 1, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 16 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, phenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the phenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. , -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 17 and R 18 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; R 15 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

6. The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing, treating or alleviating a GPR84 antagonist-mediated disease in a patient.

9. The use according to claim 8, wherein The diseases mediated by the GPR84 antagonist are inflammatory diseases, autoimmune diseases, lung diseases, metabolic disorders and metabolic endocrine disorders.

10. The use according to claim 9, wherein The inflammatory diseases are endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver diseases; Autoimmune diseases were inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, or primary and secondary autoimmune uveitis; Lung disease is asthma, idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease; Metabolic disorders and metabolic-endocrine disorders are metabolic syndrome, insulin resistance, type I and type II diabetes, diabetic neuropathy, obesity or polycystic ovary syndrome.

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