Imidazole bicyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a compound as shown in a formula (I) or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label and pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as shown in the formula (I). The compound has the effect of treating characteristic diseases caused by abnormal expression of ATX-lysophosphatidic acid (LPA). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular, to an imidazole bicyclic compound for preventing and / or treating diseases caused by abnormal expression of ATX-lysophosphatidic acid (LPA). In addition, the present invention also provides a preparation method of the imidazole bicyclic compound and its use in preparing a drug for treating and / or preventing diseases caused by abnormal expression of ATX-lysophosphatidic acid (LPA). Background Art

[0002] Autotaxin (ATX) is the only enzyme in the ectonucleotide pyrophosphatase / phosphodiesterase family with lysophospholipase D activity. It can hydrolyze lysophosphatidylcholine (LPC) into choline and lysophosphatidic acid (LPA) in vivo. The latter binds to the homologous G-protein coupled receptors LPA1-6 and activates subsequent cell cascade reactions through the receptors, thereby participating in pathological processes such as malignant cell proliferation, inflammation, pruritus, fibrosis, and sclerosis. Compared with traditional kinase inhibitors, ATX inhibitors can simultaneously act on multiple signaling pathways related to cell proliferation, growth, and apoptosis. The ATX-LPA signaling pathway is associated with many clinical diseases, such as cancer, inflammation, fibrotic diseases, autoimmune diseases, and cardiovascular diseases. At present, the ATX allosteric inhibitor (GLPG-1690) is a candidate drug for clinical trials against idiopathic pulmonary fibrosis (IPF) and can effectively reduce extracellular matrix deposition in pulmonary fibrosis models. Phase III clinical trial results showed that GLPG-1690 can significantly increase patients' vital capacity and improve lung function, and is expected to become a new therapeutic drug for IPF, but its poor metabolic stability led to the suspension of clinical trials. Therefore, there is still an urgent need for new drugs that can prevent and / or treat diseases caused by abnormal expression of ATX-lysophosphatidic acid (LPA).

[0003] ZL202011230384.8 discloses a class of ATX inhibitors, among which compound 1 closest to the present invention is shown below:

[0004]

[0005] The present invention provides a new imidazole bicyclic compound, which has extremely strong ATX inhibitory activity and excellent pharmacodynamics and pharmacokinetic properties and has good clinical application prospects. Summary of the invention

[0006] In one aspect, the present invention provides a compound having a structure shown in formula (I),

[0007]

[0008] and its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein,

[0009] R1 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by halogen, hydroxyl, amino, cyano, nitro, oxo;

[0010] Ring A is wherein B is selected from a 5-membered or 6-membered heteroaryl group, and R2 is selected from a hydrogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a halogen, an amino, a hydroxyl, a cyano, a nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R3 are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, amino, hydroxy, cyano, nitro or halogen, R4 and R4' are selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2;

[0011] X is selected from optionally substituted C4-C 14 a cycloalkyl group, a 4- to 14-membered heterocyclyl group, which is optionally substituted by a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxyalkyl group, a C1-C6 haloalkoxyalkyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkoxycarbonyl group, a carboxyl group, a hydroxyl group, an amino group, a cyano group, a nitro group, or an oxo group;

[0012] W is selected from C3-C8 cycloalkyl or 3 to 8 membered heterocycloalkyl, which is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, oxo;

[0013] Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4 to 14 membered heterocyclyl, 4 to 14 membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C14 Cycloalkyl C1-C6 alkyl, 4- to 14-membered heterocyclyl, 4- to 14-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, or oxo.

[0014] On the other hand, the present invention provides a pharmaceutical composition for preventing and / or treating ATX-mediated diseases, comprising a therapeutically effective amount of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0015] On the other hand, the present invention also provides the use of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating and / or preventing ATX-mediated diseases.

[0016] On the other hand, the present invention also provides a method for treating and / or preventing ATX-mediated diseases, comprising administering to an individual in need thereof a therapeutically effective amount of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition comprising the same.

[0017] Beneficial Effects

[0018] The present inventors surprisingly found that, compared with the currently known ATX inhibitors, the compounds of the present invention exhibit significantly better ATX inhibitory activity. DETAILED DESCRIPTION

[0019] definition

[0020] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0021] As used herein, the term "alkyl" refers to a monovalent group of a branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms, more typically 1 to 4, or 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0022] As used herein, the term "alkenyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms (more typically 2 to 5 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms) and having carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds). The term is exemplified by groups such as vinyl (i.e., -CH=CH2), propen-1-yl (i.e., -CH=CHCH3), propen-3-yl (or allyl, i.e., -CH2CH=CH2), propen-2-yl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and the like.

[0023] As used herein, the term "alkynyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms (more typically 2 to 5 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms) and having carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds). The term is exemplified by groups such as ethynyl (i.e., -C≡CH), propargyl (i.e., -CH2C≡CH), propynyl (i.e., -C≡CCH3), etc.

[0024] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0025] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0026] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein. The term is exemplified by the groups trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, etc.

[0027] As used herein, the term "cycloalkyl" refers to a saturated group of a 3- to 8-membered monocyclic or multiple condensed (fused) rings or bridged or spirocyclic rings having 3 to 14 carbon atoms as ring atoms. The cycloalkyl group may be fused to another saturated, partially unsaturated or aromatic carbocyclic ring, provided that the ring atom attached to the target molecule is a carbon atom on the cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[3,2,0]heptane, bicyclo[3,3,0]octane, bicyclo[4,2,0]octane, octahydro-1H-indenyl, decalinyl, bicyclo[2,1,1]hexane, bicyclo[2,2,1]heptane, bicyclo[2,2,2]octane, spiro[2,3]hexane, spiro[3,3]heptane, spiro[3,4]octane, spiro[4,4]nonanyl, spiro[3,5]nonanyl, spiro[4,5]decane, spiro[5,5]undecane, and the like.

[0028] As used herein, the term "heteroaryl" refers to a monocyclic aromatic ring group containing 5 to 6 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms also include at least one heteroatom selected from oxygen, nitrogen and / or sulfur. If the ring is aromatic, sulfur and nitrogen atoms can also exist in oxidized form. Exemplary heteroaryl includes, but is not limited to: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl.

[0029] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated group having a 3- to 8-membered monocyclic ring or multiple condensed (fused) rings or bridged rings or spiro rings having 3 to 14 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and / or sulfur. Examples of heterocyclyl groups include, but are not limited to, aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, azepanyl, azocanyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, oxetanyl, thiirane, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiepanyl, thiocanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, piperazinyl, morpholinyl, dioxanyl, thioxanyl, dithianyl, dihydropyridinyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridinyl, hexahydro-1H-2λ 2 -cyclopenta[c]pyrrole, tetrahydro-1H,3H-2λ 2 ,5λ 2 -pyrrolo[3,4-c]pyrrolyl, hexahydro-1λ 2 ,5λ 2 -pyrrolo[3,4-b]pyrrolyl, tetrahydro-1H,3H-2λ 2 -pyrrolo[1,2-c]imidazolyl, octahydro-2λ 2 -Isoindolyl, hexahydro-3H-2λ 2 ,5λ 2 -pyrrolo[3,4-c]pyridinyl, hexahydro-2H-1λ 2 ,6λ 2 -pyrrolo[3,4-b]pyridinyl, hexahydro-2H-1λ 2 ,4λ 2 -pyrrolo[3,2-b]pyridinyl, 2-oxa-6-azaspiro[3,3]heptyl, 7-oxa-2-azaspiro[3,5]nonanyl, 2-oxa-6-azaspiro[3,4]octanyl, 2-oxa-7-azaspiro[3,5]nonanyl, 2-azaspiro[3,3]heptyl, 2-azaspiro[4,3]octanyl, 3-azaspiro[5,3]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, etc.

[0030] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to affect treatment as defined below when administered to a mammal in need of such treatment. The therapeutically effective amount will vary with the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0031] As used herein, the term "stereoisomer" refers to a compound having the same chemical composition and connectivity, but whose atoms have different orientations in space that cannot be interchanged by single bond rotation. "Stereoisomer" includes "diastereomers" and "enantiomers". "Diastereomers" refers to stereoisomers with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics and reactivity. Diastereomeric mixtures can be separated under high-resolution analytical procedures (such as crystallization, electrophoresis and chromatography). "Enantiomers" refers to two stereoisomers that are non-overlapping mirror images of each other.

[0032] As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atoms, such as keto-enol tautomers.

[0033] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0034] As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound of the present invention.

[0035] Any formula or structure given herein, including formula (I) or any formula disclosed herein, is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically labeled" or "isotopically enriched analogs". An isotopically labeled compound has a structure as depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotope-labeled compounds of the present invention, for example, compounds into which a radioactive isotope (e.g. 3 H. 13 C and 14 C). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and characteristics of a given compound, and the salt is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be made from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, bisulfates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, etc. Salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, mesylate, ethanesulfonate, p-toluenesulfonate, salicylate, etc.

[0037] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0038] Compound

[0039] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0040] R1 is selected from hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0041] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0042] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0043] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0044] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0045] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0046] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0047] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0048] Ring A is

[0049] wherein R2, R3, and n are as defined herein.

[0050] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0051] A is selected from

[0052] wherein R2 and R3 are as defined herein.

[0053] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0054] Ring A is wherein R2 and R3 are as defined herein.

[0055] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0056] R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R4 and R4' are selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2.

[0057] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0058] R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro.

[0059] In one embodiment, R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro.

[0060] In one embodiment, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro.

[0061] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0062] R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, amino, hydroxy, cyano, nitro or halogen.

[0063] In one embodiment, R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or halogen.

[0064] In one embodiment, R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine.

[0065] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0066] X is selected from optionally substituted C4-C 10 a cycloalkyl group, a 4- to 10-membered heterocyclic group, which is optionally substituted by a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, or an oxo group.

[0067] In one embodiment, X is selected from optionally substituted cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl,

[0068]

[0069] It is optionally substituted by C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxyalkyl, C1-C3 haloalkoxyalkyl, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, carboxyl, hydroxyl, amino, cyano, nitro, or oxo.

[0070] In one embodiment, X is selected from optionally substituted

[0071] It is optionally substituted by C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxyalkyl, C1-C3 haloalkoxyalkyl, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, carboxyl, hydroxyl, amino, cyano, nitro, or oxo.

[0072] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0073] W is selected from C3-C6 cycloalkyl or 3 to 6 membered heterocycloalkyl, which is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, oxo.

[0074] In one embodiment, W is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiirane, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, oxo.

[0075] In one embodiment, W is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, hydroxy, amino, cyano, nitro.

[0076] In one embodiment, W is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane.

[0077] In one embodiment, W is selected from cyclopropane or cyclobutane.

[0078] In one embodiment, the compound of the present invention is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0079] Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 10 Cycloalkyl C1-C6 alkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C 10 Cycloalkyl C1-C6 alkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, oxo.

[0080] In one embodiment, Y is selected from C1-C6 alkyl, C1-C6 alkoxy, NR5R5', C4-C 10 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C4-C 10Cycloalkyl and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano or nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro or amino.

[0081] In one embodiment, Y is selected from C1-C6 alkoxy, NR5R5', 4 to 10 membered heterocyclyl, wherein the C1-C6 alkoxy, 4 to 10 membered heterocyclyl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino.

[0082] In one embodiment, Y is selected from CH3O-,

[0083] In one embodiment, the compound of the present invention is a compound represented by formula (II)

[0084]

[0085] or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label, or a pharmaceutically acceptable salt thereof; wherein p is selected from 0, 1, 2 or 3, and R1, A, X, and Y are as defined herein.

[0086] In one embodiment, the compound of the present invention is a compound represented by formula (III-1) or (III-2)

[0087]

[0088] or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope-labeled substance, or a pharmaceutically acceptable salt thereof; wherein R1, A, X, and Y are as defined herein.

[0089] In one embodiment, the compound of the present invention is a compound represented by formula (IV-1) or (IV-2)

[0090]

[0091] Or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label, a pharmaceutically acceptable salt thereof; wherein p is selected from 0, 1, 2, 3, r1, r2, r3, r4, r5 are selected from 0 or 1, and R1, A, and Y are as defined herein.

[0092] In one embodiment, the compound of the present invention is a compound represented by formula (V-1), (V-2), (V-3) or (V-4)

[0093]

[0094] Or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label, or a pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4, and R5 are selected from 0 or 1, and R1, A, and Y are as defined herein.

[0095] In one embodiment, the compound of the present invention is a compound represented by formula (VI-1), (VI-2), (VI-3) or (VI-4)

[0096]

[0097] Or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label, a pharmaceutically acceptable salt thereof; wherein p is selected from 0, 1, 2, 3, r1, r2, r3, r4, r5 are selected from 0 or 1, and R1, R2, R3, Y are as defined herein.

[0098] In one embodiment, the compound of the present invention is a compound represented by formula (VII-1), (VII-2), (VII-3), (VII-4), (VII-5), (VII-6), (VII-7), or (VII-8)

[0099]

[0100]

[0101] Or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope label, a pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4, R5 are selected from 0 or 1, and R1, R2, R3, Y are as defined herein.

[0102] In one embodiment, the compound of the present invention is a compound represented by formula (VIII):

[0103]

[0104] or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances, pharmaceutically acceptable salts; wherein

[0105] R1 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by halogen, hydroxyl, amino, cyano, nitro, oxo;

[0106] Ring A is wherein B is selected from a 5-membered or 6-membered heteroaryl group, and R2 is selected from a hydrogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a halogen, an amino, a hydroxyl, a cyano, a nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R3 are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, amino, hydroxy, cyano, nitro or halogen, R4 and R4' are selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2;

[0107] Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4 to 14 membered heterocyclyl, 4 to 14 membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4- to 14-membered heterocyclyl, 4- to 14-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, or oxo.

[0108] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0109] R1 is selected from hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0110] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0111] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0112] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0113] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo.

[0114] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0115] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0116] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0117] Ring A is

[0118] wherein R2, R3, and n are as defined herein.

[0119] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0120] A is selected from

[0121] wherein R2 and R3 are as defined herein.

[0122] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0123] Ring A is wherein R2 and R3 are as defined herein.

[0124] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0125] R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R4 and R4' are selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2.

[0126] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0127] R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro.

[0128] In one embodiment, R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro.

[0129] In one embodiment, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro.

[0130] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0131] R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, amino, hydroxy, cyano, nitro or halogen.

[0132] In one embodiment, R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or halogen.

[0133] In one embodiment, R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine.

[0134] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0135] Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 10 Cycloalkyl C1-C6 alkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C 10 Cycloalkyl C1-C6 alkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, oxo.

[0136] In one embodiment, Y is selected from C1-C6 alkyl, C1-C6 alkoxy, NR5R5', C4-C 10 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C4-C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano or nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro or amino.

[0137] In one embodiment, Y is selected from C1-C6 alkoxy, NR5R5', 4 to 10 membered heterocyclyl, wherein the C1-C6 alkoxy, 4 to 10 membered heterocyclyl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino.

[0138] In one embodiment, Y is selected from CH3O-,

[0139] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0140] R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo;

[0141] Ring A is

[0142] Wherein R2, R3, and n are as defined in claim 1;

[0143] Y is selected from C1-C6 alkyl, C1-C6 alkoxy, NR5R5', C4-C 10 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C4-C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano or nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro or amino.

[0144] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0145] A is selected from

[0146]

[0147] Wherein R2 and R3 are as defined in claim 1;

[0148] Y is selected from C1-C6 alkoxy, NR5R5', and 4- to 10-membered heterocyclyl, wherein the C1-C6 alkoxy and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano, and nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro, and amino.

[0149] In one embodiment, the compound of the present invention is a compound represented by formula (VIII) or a stereoisomer, tautomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof; wherein

[0150] R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro;

[0151] R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, amino, hydroxy, cyano, nitro or halogen.

[0152] In one embodiment, the compound of the present invention is a compound selected from any of the following:

[0153]

[0154]

[0155]

[0156]

[0157] or stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts thereof.

[0158] Pharmaceutical composition

[0159] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope label, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art, including diluents, lubricants, disintegrants, adhesives, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, colorants, flavoring agents, sweeteners, etc. Depending on the different routes of administration of the drug, such as oral administration, parenteral administration, and rectal administration, the pharmaceutical composition of the present invention can be made in solid form (including but not limited to tablets, capsules, pills, granules, powders, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants such as ascorbic acid; f) glidants, such as silicon dioxide; g) flavoring agents, such as mint, methyl salicylate; sweeteners, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0160] Indications and Administration

[0161] In one embodiment, the present invention provides a method for preventing and / or treating a disease mediated by ATX, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled, pharmaceutically acceptable salt, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. In one embodiment, the present invention provides a method for preventing and / or treating a disease characterized by abnormal expression of ATX-lysophosphatidic acid (LPA), comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled, pharmaceutically acceptable salt, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, solvate, prodrug, isotope-labeled, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. In one embodiment, the present invention provides a method for preventing and / or treating inflammation, fibrotic diseases, autoimmune diseases, cardiovascular diseases and / or cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled, pharmaceutically acceptable salts, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled, pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier. In one embodiment, the present invention provides a method for preventing and / or treating diseases such as idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, systemic sclerosis, scleroderma, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, tumors, etc., comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances, pharmaceutically acceptable salts, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances, pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

[0162] In some embodiments, the therapeutically effective amount is from about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 500 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 200 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 100 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 75 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 50 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 10 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 5 mg.

[0163] In one embodiment, the present invention provides a compound of the present invention for use in the preparation of a medicament for preventing and / or treating a disease mediated by ATX. In one embodiment, the present invention provides a compound of the present invention for use in the preparation of a medicament for preventing and / or treating a characteristic disease caused by abnormal expression of ATX-lysophosphatidic acid (LPA). In one embodiment, the present invention provides a compound of the present invention for use in the preparation of a medicament for preventing and / or treating inflammation, fibrotic diseases, autoimmune diseases, cardiovascular diseases and / or cancer. In one embodiment, the present invention provides a compound of the present invention for use in the preparation of a medicament for preventing and / or treating idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, systemic sclerosis, scleroderma, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, tumors and the like.

[0164] General synthetic method

[0165] Compounds of the present invention can be prepared using methods disclosed herein and their modified approaches and methods well known in the art. Typical embodiments of compounds according to the present invention can be synthesized using the general reaction scheme of the following arbitrary method. It is apparent from the description herein that corresponding different products can be obtained by replacing reaction raw materials with other materials having similar structures. Reaction raw materials are typically obtained from commercial sources or synthesized using disclosed methods.

[0166] Reaction process

[0167]

[0168] Step 1 Compound Ia and Compound Ib are heated to react in the presence of alkalinity and / or a metal catalyst to obtain Compound Ic, wherein R is selected from an alkyl group, and the metal catalyst is a metal catalyst conventionally used in carbon-carbon coupling reactions in the art, including but not limited to JohnPhos / Pd2(dba)3, tri(dibenzylideneacetone)dipalladium / 2-(di-tert-butylphosphine)biphenyl, tri-tert-butylphosphine / palladium acetate, 2-(di-tert-butyl)biphenyl / tridibenzylideneacetonedipalladium, etc.;

[0169] Step 2: hydrolyzing compound Ic under alkaline conditions to obtain compound Id;

[0170] Step 3: Compound Id is reacted with a YH condensing agent to obtain compound I, wherein the condensing agent is selected from conventional carboxyl groups and hydroxyl or amino groups in the art to undergo condensation reactions to generate ester bonds or amide bonds, including but not limited to 1-ethyl-3 (3-dimethylpropylamine) carbodiimide / 1-hydroxybenzotriazole, HATU, etc.

[0171] The technical solution of the present invention is further described below in conjunction with embodiments.

[0172] Example 1 Synthesis of 2-(2-ethyl-6-(4-(1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile Step 1 Synthesis of ethyl 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylate (2)

[0173]

[0174] Compound 1 (25.0 g, 93.07 mmol), diisopropylethylamine (DIPEA, 110.9 g, 850.12 mmol) and anhydrous ethanol (175 mL) were added to a 1 L single-mouth bottle in sequence, and 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride (14.1 g, 85.39 mmol) was added under stirring. After the addition was completed, the mixture was reacted at 78°C for 18 h under nitrogen protection. TLC (V 石油醚 :V 乙酸乙酯 =4:1) After the reaction was completed, H2O (50 mL) and dichloromethane (50 mL) were added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 ml × 3), the organic phases were collected and combined, dried over anhydrous sodium sulfate, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =5:1), to obtain 11.0 g of yellow oily compound 2, with a yield of 41.0%.

[0175] Step 2 Synthesis of 1-(piperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester hydrochloride (3)

[0176]

[0177] Compound 2 (11.0 g, 38.14 mmol) and dichloromethane (100 mL) were added to a 500 mL single-mouth bottle in sequence, the temperature was lowered to 0°C, and 1-chloroethyl chloroformate (7.99 g, 55.88 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 h under nitrogen protection, and the dichloromethane was removed by concentration under reduced pressure. The residue was dissolved in ethanol (100 mL) and reacted at 78°C overnight under nitrogen protection. TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​After the reaction was completed, the ethanol was removed by concentration under reduced pressure, and a mixed solution of ethanol and methyl tert-butyl ether (V 乙醇 :V 甲基叔丁基醚 =5:1, 100 mL), stirred for 30 min, solid precipitated, filtered, and the filter cake was dried to obtain 6.1 g of white solid 3, with a yield of 68.1%.

[0178] Step 3 Synthesis of 2-({6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl}(methyl)amino)-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile (6)

[0179]

[0180] Compound 4 (600 mg, 2.24 mmol) was added to a round-bottom flask and dissolved in 6 mL of anhydrous tetrahydrofuran. Sodium hydride (60%) (300 mg, 6.72 mmol) was added in an ice bath. The system was fully replaced with nitrogen. After stirring at 90°C for 50 minutes, it was cooled to 40°C. 2-Chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (5, 695 g, 2.91 mmol) was added. The nitrogen was replaced again. The reaction was stirred at 90°C for 4 hours. After TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​after the reaction was completed, the sodium hydride was quenched with a saturated ammonium chloride solution under ice bath, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =5:1) to give 640.8 mg of white solid 6, with a yield of 61.0%.

[0181] Step 4 Synthesis of methyl 1-(4-(3-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (7)

[0182]

[0183] Compound 6 (2 g, 4.25 mmol), compound 3 (1.17 g, 6.375 mmol), sodium tert-butoxide (1.23 g, 12.75 mmol), 2-(di-tert-butyl)biphenyl (508 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (584 mg, 0.638 mmol) were added to a three-necked flask, dissolved in 20 mL of toluene, the system was fully replaced with nitrogen, and the reaction was stirred at 115°C for 4 hours. After TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​after the reaction was completed, the toluene was removed by concentration under reduced pressure, and the product was purified by column chromatography (V 石油醚 :V 乙酸乙酯 =6:1) to give 1.90 g of white solid 7, with a yield of 77.9%.

[0184] Step 5 Synthesis of methyl 1-(4-(3-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid (8)

[0185]

[0186] Compound 7 (200 mg, 0.349 mmol) was added to a round-bottom flask, dissolved in 5 mL of a mixed solution of ethanol / water (1 / 1), and lithium hydroxide (200 mg, 34.9 mmol) was added. The mixture was stirred at room temperature for 5 hours. After TLC (V 二氯甲烷 :V 甲醇 =20:1) monitoring reaction completion, the pH was adjusted to 5-6 with dilute hydrochloric acid (2N) under ice bath, a large amount of solid precipitated, allowed to stand, filtered, the filter cake washed with water, column chromatography purification (V 二氯甲烷 :V 甲醇 =40:1) to give 191.2 mg of off-white solid 8, with a yield of 98.1%.

[0187] Step 6 Synthesis of 2-(2-ethyl-6-(4-(1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Example 1)

[0188]

[0189] Compound 8 (100 mg, 0.179 mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (52 mg, 0.2685 mmol), 1-hydroxybenzotriazole (36 mg, 0.2685 mmol) were added to a round-bottom flask, dissolved in 2 mL of anhydrous dichloromethane, stirred at room temperature for 30 minutes, and then 3-hydroxyazetidine hydrochloride (29 mg, 0.2685 mmol) and triethylamine (54 mg, 0.537 mmol) were added, and the mixture was reacted at room temperature for another hour. After TLC (V 二氯甲烷 :V 甲醇 =20:1) monitoring after the reaction is completed, and then washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (V 二氯甲烷 :V 甲醇 =40:1) to give 83.6 mg of off-white solid, with a yield of 76.1%. 1 H NMR(400MHz, DMSO-d6)δ:8.15-8.07(m,2H),7.42-7.40(m,2H),7.38(d,J=4.0Hz,1H),7.20(s,1H),5.59(d,J=4.0Hz,1 H),4.42-4.36(m,5H),3.57(s,3H),3.04(s,4H),2.69-2.54(m,6H),2.46(s,3H),1.43-1.19(m,3H),0.94-0.81(m,4H).

[0190] Example 2 Synthesis of methyl 1-(4-(3-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylate

[0191]

[0192] Referring to the preparation method of Example 1, methanol was used instead of 3-hydroxyazetidine hydrochloride to obtain 50.1 mg of off-white solid with a yield of 69.6%. ESI-MS: m / z 573.7 [M+H] + .

[0193] Example 3 Synthesis of (R)-1-(4-(3-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)piperazine-1-yl)-N-(2,3-dihydroxypropyl)cyclopropane-1-carboxamide

[0194]

[0195] Referring to the preparation method of Example 1, (R)-3-aminopropane-1,2-diol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride to obtain 51.2 mg of off-white solid with a yield of 64.8%. ESI-MS: m / z 633.7 [M+H] + .

[0196] Example 4 Synthesis of (S)-1-(4-(3-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)piperazine-1-yl)-N-(2,3-dihydroxypropyl)cyclopropane-1-carboxamide

[0197]

[0198] Referring to the preparation method of Example 1, (S)-3-aminopropane-1,2-diol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride to obtain 54.3 mg of off-white solid with a yield of 68.7%. 1 H NMR(400MHz,DMSO-d6)δ:8.11(dd,J=9.2,5.8Hz,3H),7.48-7.39(m,3H),7.25 (s,1H),4.84(d,J=5.0Hz,1H),4.62(t,J=5.8Hz,1H),3.58(s,3H),3.49(q,J= 5.4Hz,1H),3.32-3.02(m,12H),2.62(q,J=7.6Hz,2H),2.47(s,3H),1.28-1.1 9(m,3H),1.02(d,J=8.2Hz,2H),0.96(d,J=4.0Hz,2H).ESI-MS:m / z633.7[M+H] + ;

[0199] Example 5 Synthesis of 2-(6-(4-(1-(3,3-difluoroazetidine-1-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile.

[0200]

[0201] Referring to the preparation method of Example 1, 3,3-difluoroazetidine hydrochloride was used instead of 3-hydroxyazetidine hydrochloride to obtain 24.5 mg of off-white solid with a yield of 68.0%. 1H NMR(400MHz, DMSO-d6)δ:8.10(dd,J=8.6,5.4Hz,2H),7.51-7.35(m,3H),7.21(s,1H),4.52(s,4H),3.57(s,3H),3.07(s,5H) ,2.61(q,J=7.6Hz,2H),2.53(s,3H),2.46(s,3H),1.23(t,J=7.2Hz,3H),1.06-1.01(m,2H),1.01-0.93(m,2H).ESI-HRMS:m / z C 34 H 37 F3N8OS[M+H] + Theoretical value 635.2528; measured value 635.2483

[0202] Example 6 Synthesis of 2-(6-(4-(1-(3-(dimethylamino)azetidine-1-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0203]

[0204] Referring to the preparation method of Example 1, 3-hydroxyazetidine hydrochloride was replaced with N,N-dimethylazetidine-3-amine hydrochloride to obtain 25.0 mg of off-white solid with a yield of 74.8%. 1 H NMR(600MHz, DMSO-d6)δ:8.15-8.05(m,2H),7.41(t,J=8.8Hz,2H),7.34(s,1H),7.18(s,1H),4.46-3.72(m,5H),3.57(s,3H ),3.04(s,4H),2.69-2.54(m,6H),2.47(s,3H),2.11(s,6H),1.23(t,J=4.9Hz,3H),0.90(s,1H),0.86(s,4H).ESI-HRMS:m / z C 34 H 40 FN9OS[M+H] + Theoretical value 642.3139; measured value 642.3101

[0205] Example 7 Synthesis of 2-(2-ethyl-8-methyl-6-(4-(1-(1-(pyrrolidine-1-carbonyl)cyclopropyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0206]

[0207] Referring to the preparation method of Example 1, pyrrolidine was used instead of 3-hydroxyazetidine hydrochloride to obtain 25.8 mg of off-white solid with a yield of 59.9%. 1 H NMR(400MHz, DMSO-d6)δ:8.14-8.06(m,2H),7.48-7.39(m,2H),7.36(s,1H),7.21-7.17(m,1H),3.59-3.54(m,5H),3.32-3.24(m, 2H),3.01(t,J=5.0Hz,4H),2.79-2.54(m,6H),2.46(s,3H),1.77(s,4H),1.27-1.14(m,3H),0.97-0.85(m,2H),0.82-0.72(m,2H).

[0208] Example 8 Synthesis of (S)-2-(2-ethyl-6-(4-(1-(3-hydroxypyrrolidine-1-carbonyl)cyclopropyl)piperazine-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0209]

[0210] Referring to the preparation method of Example 1, (S)-3-hydroxypyrrolidine was used instead of 3-hydroxyazetidine hydrochloride to obtain 18.5 mg of off-white solid, 51.2%. 1 H NMR (600MHz, DMSO-d6) δ8.10 (dd, J=9, 5.4Hz, 2H), 7.41 (t, J=8.8Hz, 2H), 7.34 (d, J= 2.2Hz,1H),7.18(s,1H),4.80(d,J=3.8Hz,1H),4.29-4.20(m,1H),3.83-3.61(m,2H ),3.57(s,3H),3.38-3.28(m,2H),3.01(t,J=5.4Hz,4H),2.65-2.55(m,6H),2.47(s ,3H),1.84(s,1H),1.73(s,1H),1.30-1.14(m,3H),0.91-0.81(m,4H).ESI-HRMS:m / z C 33 H 37 FN8O2S[M+H] + Theoretical value 629.2822; measured value 629.2781

[0211] Example 9 Synthesis of (R)-2-(2-ethyl-6-(4-(1-(3-hydroxypyrrolidine-1-carbonyl)cyclopropyl)piperazine-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0212]

[0213] Referring to the preparation method of Example 1, (R)-3-hydroxypyrrolidine was used instead of 3-hydroxyazetidine hydrochloride to obtain 21.2 mg of off-white solid with a yield of 37.5%. 1 H NMR (400MHz, DMSO-d6) δ: 8.10 (dd, J=8.6, 5.4Hz, 2H), 7.42 (t, J=9.0Hz, 2H), 7.38 (s,1H),7.20(s,1H),4.89(s,1H),4.23(s,1H),3.92-3.61(m,2H),3.56(s,3H),3. 26-3.13(m,2H),3.00(t,J=5.2Hz,4H),2.67-2.55(m,6H),2.46(s,3H),1.89-1.6 5(m,2H),1.23(t,J=7.6,3H),0.97-0.91(m,1H),0.87-0.81(m,3H).ESI-HRMS:m / z C 34 H 37 F3N8OS[M+H] + Theoretical value 629.2822; measured value 629.2794

[0214] Example 10 Synthesis of 2-(2-ethyl-8-methyl-6-(4-(1-(1-(morpholine-4-carbonyl)cyclopropyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0215]

[0216] Referring to the preparation method of Example 1, morpholine was used instead of 3-hydroxyazetidine hydrochloride to obtain 24.5 mg of off-white solid with a yield of 45.5%. 1H NMR(400MHz, DMSO-d6)δ:8.10(dd,J=8.6,5.6Hz,2H),7.42(t,J=8.8Hz,2H),7.36(s,1H),7.20(s,1H),3.56(d,J=6.0Hz ,11H),3.04-2.99(m,4H),2.60(q,J=6.4Hz,6H),2.46(s,3H),1.32-1.19(m,3H),0.94-0.89(m,2H),0.78-0.74(m,2H).

[0217] Example 11 Synthesis of 2-(2-ethyl-6-(4-(1-(4-hydroxypiperidine-1-carbonyl)cyclopropyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0218]

[0219] Referring to the preparation method of Example 1, 4-hydroxypiperidine was used instead of 3-hydroxyazetidine hydrochloride to obtain 19.2 mg of off-white solid with a yield of 33.1%. 1 H NMR(600MHz, DMSO-d6)δ:8.13-8.07(m,2H),7.41(t,J=8.8Hz,2H),7.38(s,1H),7.27-7. 18(m,1H),4.62(s,1H),3.97-3.87(m,2H),3.73-3.64(m,1H),3.57(s,3H),3.23(s,6H),3 .17-3.08(m,2H),2.62-2.59(m,4H),2.48(s,3H),2.04-1.95(m,1H),1.75-1.70(m,2H),1 .53-1.44(m,1H),1.26-1.22(m,3H),0.93-0.89(m,2H),0.75-0.72(m,2H).ESI-HRMS:m / z C 34 H 39 FN8O2S[M+H] + Calculated value: 643.2979; Measured value: 643.2942

[0220] Example 12 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0221]

[0222] Referring to the preparation method of Example 1, 2-oxa-6-aza-spiro[3,3]heptane was used instead of 3-hydroxyazetidine hydrochloride to obtain 27.5 mg of off-white solid with a yield of 47.4%. ESI-MS: m / z 641.7 [M+H] +

[0223] Example 13 Synthesis of 2-(6-(4-(1-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0224]

[0225] Referring to the preparation method of Example 1, 7-oxa-2-aza-spiro[3,5]nonane was used instead of 3-hydroxyazetidine hydrochloride to obtain 24.2 mg of off-white solid with a yield of 40.3%. 1 H NMR(600MHz,DMSO-d6)δ:8.13-8.07(m,2H),7.46-7.38(m,2H),7.36(s,1H),7.19(s,1H),4.30(s,4H),3.56(s,3H),3.52-3.38(m,4H),3.00 (s,4H),2.64-2.56(m,6H),2.45(s,3H),1.99(s,1H),1.74(s,3H),1.27-1.20(m,3H),0.93-0.88(m,2H),0.73-0.68(m,2H).ESI-HRMS:m / zC 35 H 42 FN8O2S[M+H] + Theoretical value 669.3135; measured value 669.3095

[0226] Example 14 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.4]octane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0227]

[0228] Referring to the preparation method of Example 1, 2-oxa-6-azaspiro[3.4]octane was used instead of 3-hydroxyazetidine hydrochloride to obtain 23.5 mg of off-white solid with a yield of 39.2%. 1H NMR(600MHz,DMSO-d6)δ:8.12-8.07(m,2H),7.45-7.38(m,2H),7.36(s,1H),7.20 (s,1H),4.49(s,2H),4.46-4.42(m,2H),3.92-3.78(m,1H),3.56(s,3H),3.54-3. 46(m,1H),3.32-3.24(m,1H),3.01(s,4H),2.65-2.54(m,6H),2.46(s,3H),2.16- 1.99(m,3H),1.22(t,J=7.6Hz,3H),0.91(s,2H),0.79-0.76(m,2H).ESI-HRMS:m / z C 35 H 39 F1N8O2S[M+H] + Theoretical value 655.2979; measured value 655.2938

[0229] Example 15 Synthesis of 2-(6-(4-(1-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0230]

[0231] Referring to the preparation method of Example 1, 2-oxa-7-azaspiro[3.5]nonane was used instead of 3-hydroxyazetidine hydrochloride to obtain 24.2 mg of off-white solid with a yield of 40.3%. 1 H NMR(600MHz, DMSO-d6)δ:8.13-8.07(m,2H),7.45-7.39(m,2H),7.36(s,1H),7.21(s,1H),4.11-3.98(m,2H),3.57(s,4H),3.47(s, 5H),3.03(s,4H),2.64-2.55(m,6H),2.46(s,3H),1.63(t,J=5.4Hz,4H),1.22(t,J=7.6Hz,3H),0.88-0.81(m,4H).ESI-HRMS:m / zC 36 H 41 FN8O2S[M+H] + Theoretical value 669.3135; measured value 669.3095

[0232] Example 16 Synthesis of 2-(2-ethyl-6-(4-(1-(3-hydroxyazetidine-1-carbonyl)cyclobutyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0233]

[0234] Referring to the preparation method of Example 1, 1-aminocyclobutane-1-carboxylic acid methyl ester was used instead of 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride to obtain 23.4 mg of off-white solid with a yield of 42.5%. 1 H NMR(400MHz,DMSO-d6)δ:8.15-8.07(m,2H),7.47-7.36(m,3H),7.23(s,1H),5 .58(dd,J=6.2,2.4Hz,1H),4.41-4.29(m,2H),4.04(t,J=8.2Hz,1H),3.93(d,J =9.2Hz,1H),3.58(s,4H),3.08(d,J=6.8Hz,4H),2.70-2.52(m,6H),2.47(s,3 H),2.28-2.14(m,4H),1.68-1.52(m,2H),1.23(t,J=7.6Hz,3H).ESI-HRMS:m / z C 33 H 37 FN8O2S[M+H] + Theoretical value 629.2822; measured value 629.2789

[0235] Example 17 Synthesis of (R)-2-(2-ethyl-6-(4-(1-(3-hydroxypyrrolidine-1-carbonyl)cyclobutyl)piperazine-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0236]

[0237] Referring to the preparation method of Example 1, 1-aminocyclobutane-1-carboxylic acid methyl ester was used instead of 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride in step 1, and (R)-3-hydroxypyrrolidine was used instead of 3-hydroxyazetidine hydrochloride in step 6 to obtain 21.8 mg of an off-white solid with a yield of 38.9%. 1H NMR (600MHz, DMSO-d6) δ8.10 (dd, J=9.0, 5.4Hz, 2H), 7.41 (t, J=10.0Hz, 2H), 7.3 6(s,1H),7.22(s,1H),4.75(s,1H),4.20(s,1H),3.83(s,2H),3.58(s,3H),3.44- 3.34(m,2H),3.06(d,J=5.4Hz,4H),2.67-2.53(m,6H),2.48(s,3H),2.39-2.25(m ,4H),1.69-1.61(m,2H),1.60-1.50(m,2H),1.24(t,J=7.6Hz,3H).ESI-HRMS:m / z C 34 H 39 FN8O2S[M+H] + Theoretical value 643.2979; measured value 643.2937

[0238] Example 18 Synthesis of 2-(2-ethyl-6-(4-(1-(4-hydroxypiperidine-1-carbonyl)cyclobutyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0239]

[0240] Referring to the preparation method of Example 1, 1-aminocyclobutane-1-carboxylic acid methyl ester was used instead of 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride in step 1, and 4-hydroxypiperidine was used instead of 3-hydroxyazetidine hydrochloride in step 6 to obtain 22.9 mg of an off-white solid with a yield of 40.0%. 1 H NMR (400MHz, DMSO-d6) δ: 8.10 (t, J = 6.8 Hz, 2H), 7.47-7.38 (m, 3H), 7.23 (s, 1H), 4.68 (s, 1H), 4.08-3.77 (m, 3H), 3.63 (s, 1H), 3.57 (s, 3H), 3. 19-2.88(m,7H),2.60(q,J=7.4Hz,4H),2.47(s,3H),2.39-2.16(m,5H),1.90(s,1H),1.76-1.48(m,4H),1.22(t,J=7.6Hz,3H).ESI-HRMS:m / z C 35 H 41 FN8O2S[M+H] + Theoretical value 657.3135; measured value 657.3094

[0241] Example 19 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclobutyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0242]

[0243] Referring to the preparation method of Example 1, 1-aminocyclobutane-1-carboxylic acid methyl ester was used instead of 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride in step 1, and 2-oxa-6-aza-spiro[3,3]heptane was used instead of 3-hydroxyazetidine hydrochloride in step 6 to obtain 25.2 mg of off-white solid with a yield of 44.2%. 1 H NMR(600MHz,DMSO-d6)δ:8.11(t,J=7.0Hz,2H),7.43(t,J=8.8Hz,2H),7.38(s, 1H),7.23(s,1H),4.69-4.57(m,4H),4.34(s,2H),4.06-4.01(m,2H),3.58(s,3H ),3.08(s,4H),2.62(q,J=7.8Hz,2H),2.53(s,4H),2.47(s,3H),2.28-2.18(m, 2H),2.17-2.11(m,2H),1.65-1.53(m,2H),1.24(t,J=8.2Hz,3H).ESI-HRMS:m / z C 35 H 39 FN8O2S[M+H] + Theoretical value 655.2979; measured value 655.2938

[0244] Example 20 Synthesis of 2-(2-ethyl-6-(2-(1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl)-2,7-diazaspiro[3.5]non-7-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0245] Step 1 Synthesis of 1-(tert-butyl)4-methyl4-(chloromethyl)piperidine-1,4-dicarboxylate (2)

[0246]

[0247] Compound 1 (10.0 g, 41.10 mmol) and anhydrous tetrahydrofuran (200 mL) were added to a 500 mL three-necked flask in sequence. After the addition was completed, lithium diisopropylamide (2M THF solution, 41.1 mL, 82.20 mmol) was added dropwise at -78°C under nitrogen protection. After the addition was completed, the mixture was kept warm for 2 h. Chloroiodomethane (21.75 mmol, 123.30 mmol) was added dropwise. After the addition was completed, the mixture was slowly heated to room temperature and the reaction was continued for 36 h. TLC (V 石油醚 :V 乙酸乙酯 =10:1) to monitor the complete reaction of the raw materials. Water (500 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (120 g, V 石油醚 :V 乙酸乙酯 =10:1) to give 5.02 g of yellow oil 2, with a yield of 41.9%. 1 HNMR (400MHz, CDCl3) δ (ppm): 3.87-3.74 (m, 2H, NCH2), 3.69 (s, 3H, OCH3), 3.52 (s, 2H, CH2Cl), 3.02-2.81(m,2H,NCH2),2.15-2.04(m,2H,CH2),1.44-1.40(m,2H,CH2),1.38(s,9H,C(CH3)3).

[0248] Step 2 Synthesis of tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (3)

[0249]

[0250] Compound 2 (4.76 g, 16.31 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL single-necked bottle in sequence. After the addition was completed, lithium aluminum hydride (1 M THF solution, 19.58 mL, 19.58 mmol) was added dropwise under nitrogen protection in an ice bath. After the addition was completed, the reaction was kept warm for 1 h. TLC (V 石油醚 :V 乙酸乙酯 =4:1) to monitor the complete reaction of the raw materials. Water (20 mL) and 1M sodium hydroxide aqueous solution (20 mL) were added to the reaction solution. After the addition was completed, it was stirred for 5 min and filtered through diatomaceous earth. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4.4 g of yellow oil 3, which was used directly in the next step without purification.

[0251] Step 3 Synthesis of tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (4)

[0252]

[0253] Oxalyl chloride (3.19 g, 19.57 mmol) and anhydrous dichloromethane (100 mL) were added to a 250 mL three-necked flask in sequence. Dimethyl sulfoxide (2.93 g, 37.51 mmol) was added dropwise under nitrogen protection at -78°C. After the reaction was kept warm for 10 min, a solution of compound 3 (4.40 g, 16.31 mmol) in anhydrous dichloromethane (10 mL) was added dropwise. After the addition was completed, the reaction was kept warm for 1 h. Triethylamine (8.25 g, 81.55 mmol) was added dropwise, and the mixture was moved to room temperature and stirred for 30 min. TLC (V 石油醚 :V 乙酸乙酯 =4:1) to monitor the complete reaction of the raw materials. Water (200 mL) was added to the reaction solution to quench, and the liquid was separated. The aqueous phase was extracted with dichloromethane (200 mL×3), and the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid preparative chromatography (80 g, V 石油醚 :V 乙酸乙酯 =4:1) to give 3.70 g of yellow oil 4 with a yield of 86.7%. 1 H NMR (400MHz, CDCl3) δ (ppm): 9.51 (s, 1H, CHO), 3.77-3.62 (m, 2H, NCH2), 3.53 (s, 2H, CH2Cl), 3.0 2(t,J=12.4Hz,2H,NCH2),2.03-1.96(m,2H,CH2),1.51-1.43(m,2H,CH2),1.39(s,9H,C(CH3)3).

[0254] Step 4 Synthesis of tert-butyl 4-(chloromethyl)-4-(((1-(ethoxycarbonyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (5)

[0255]

[0256] Compound 4 (2.90 g, 11.08 mmol), 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride (1.84 g, 11.08 mmol), methanol (40 mL) and acetic acid (665 mg, 11.08 mmol) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the reaction was carried out at 60° C. under nitrogen protection overnight. TLC (V 石油醚 :V 乙酸乙酯=2:1) ​​to monitor the complete reaction of the raw materials. Water (50 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (40 g, V 石油醚 :V 乙酸乙酯 =2:1) ​​to give 1.44 g of colorless oil 5, with a yield of 34.7%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.06 (q, J = 7.1 Hz, 2H, OCH2), 3.43 (s, 2H, ClCH2), 3.36-3.25 (m, 4H, N(CH2)2), 2.72 (s, 2H, NHCH2), 1.38 (s, 13H, piperidine-C(CH2)2, C(CH3)3), 1.20-1.16 (m, 5H, CH2CH3, CH2), 0.92-0.85 (m, 2H, CH2). Step 5 Synthesis of tert-butyl 2-(1-(ethoxycarbonyl)cyclopropyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6)

[0257]

[0258] Compound 5 (1.44 g, 3.85 mmol), potassium carbonate (1.60 g, 11.55 mmol), potassium iodide (128 mg, 0.77 mmol) and acetonitrile (30 mL) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the reaction was carried out at 80° C. under nitrogen protection overnight. TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​to monitor the complete reaction of the raw material. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by rapid preparative chromatography (40 g, V 石油醚 :V 乙酸乙酯 =2:1) ​​to give 770 mg of colorless oil 6, with a yield of 51.9%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.08 (q, J = 7.1 Hz, 2H, OCH2), 3.28-3.20 (m, 8H, CH2NCH2 and CH2NCH2), 1.68-1.60 (m, 4H, piperidine-C(CH2)2), 1.38 (s, 9H, C(CH3)3), 1.21-1.18 (m, 3H, CH2CH3), 1.10 (q, J = 4.0 Hz, 2H, CH2), 0.81 (q, J = 4.0 Hz, 2H, CH2).

[0259] Step 6 Synthesis of ethyl 1-(2,7-diazaspiro[3.5]nonan-2-yl)cyclopropane-1-carboxylate (7)

[0260]

[0261] Compound 6 (540 mg, 1.60 mmol), methanol (5 mL) and ethyl acetate solution of hydrogen chloride (4 M, 5 mL) were added to a 50 mL single-necked bottle in sequence. After the addition was complete, the mixture was reacted at room temperature for 30 min. TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​monitor the complete reaction of the raw materials. The reaction solution was concentrated. Dichloromethane (20 mL) was added to the residue, and sodium bicarbonate was added thereto under stirring until no more bubbles were released. Filter, concentrate the filtrate, add ethyl acetate (2 mL) and petroleum ether (10 mL) to the residue and slurry for 1 h. Filter, and dry the filter cake in vacuum to obtain 330 mg of white solid 7, with a yield of 86.8%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.06 (q, J = 7.1 Hz, 2H, OCH2), 3.32 (s, 4H, azetidine-N(CH2)2), 3.03 (t, J = 5.7 Hz, 4H, piperidine-N(CH2)2), 2.10-1.99 (m, 4H, piperidine-C(CH2)2), 1.18 (t, J = 7.1 Hz, 3H, CH2CH3), 1.11 (q, J = 4.0 Hz, 2H, CH2), 0.79 (q, J = 4.0 Hz, 2H, CH2).

[0262] Step 7 Synthesis of ethyl 1-(7-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)cyclopropane-1-carboxylate (8)

[0263]

[0264] Into a 100 mL Schlenk reaction tube, intermediate 6 of Example 1 (200 mg, 0.43 mmol), compound 7 (153 mg, 0.64 mmol), tri-tert-butylphosphine (9 mg, 0.043 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), anhydrous toluene (5 mL) and palladium acetate (10 mg, 0.043 mmol) were added in sequence. After the addition was completed, the reaction was carried out at 110° C. under nitrogen protection overnight. TLC (V 石油醚 :V 乙酸乙酯 =0:1) to monitor the reaction of the raw materials. Ethyl acetate (20 mL) was added to the reaction solution for dilution and then filtered through celite. The filtrate was concentrated and purified by flash preparative chromatography (12 g, V 石油醚 :V 乙酸乙酯 =2:1~0:1) to obtain 115 mg of yellow solid 8 with a yield of 42.6%.1 HNMR (400MHz,CDCl3)δ(ppm):8.13-8.06(m,2H,ArH),7.11(t,J=8.7Hz,2H,ArH),6.95-6.87(m,2H,ArH),4.07(q,J=7.1Hz,2H,OCH2CH3),3.54(s,3H,NCH3),3.26(s,4H,piperidine-N(CH2)2),2.91-2.82(m,4H,nitrogen heterocyclic Butane-N(CH2)2), 2.72-2.63(m, 2H, CH2CH3), 2.52(s, 3H, ArCH3), 1.90-1.82(m, 4H, piperidine-C(CH2)2), 1.26(t, J=7.6Hz, 3H, OCH2CH3), 1.21-1.18(m, 3H, CH2CH3), 1.10(q, J=4.0Hz, 2H, CH2), 0.85-0.80(m, 2H, CH2)

[0265] Step 8 Synthesis of 1-(7-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2-a]pyridin-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)cyclopropane-1-carboxylic acid (9)

[0266]

[0267] Compound 8 (165 mg, 0.26 mmol), lithium hydroxide monohydrate (109 mg, 2.60 mmol), methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) were added to a 25 mL single-necked bottle in sequence. After the addition was complete, the reaction was allowed to proceed at room temperature overnight. TLC (V 石油醚 :V 乙酸乙酯 =0:1) to monitor the complete reaction of the raw materials. The reaction solution was concentrated, and water (10 mL) was added to the residue. After stirring until the solid was completely dissolved, 1N hydrochloric acid aqueous solution was added dropwise to adjust the pH to 6. The mixture was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 130 mg of yellow solid 9, which was used directly in the next step without purification.

[0268] Step 9 Synthesis of 2-(2-ethyl-6-(2-(1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl)-2,7-diazaspiro[3.5]non-7-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0269]

[0270] Compound 9 (125 mg, 0.26 mmol), 3-hydroxyazetidine hydrochloride (43 mg, 0.39 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 148 mg, 0.39 mmol), N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (101 mg, 0.78 mmol) were added to a 25 mL single-mouth bottle in sequence. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. TLC (V 二氯甲烷 :V 甲醇 =10:1) to monitor the reaction of the raw materials. Water (20 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (12 g, V 二氯甲烷 :V 甲醇 =20:1), to give 85 mg of a white solid with a yield of 49.9%. 1 HNMR(400MHz,CD3OD)δ(ppm):8.19-8.09(m,2H,ArH),7.29-7.19(m,4H,ArH),4.78-4.65(m,1H,H of CH(CH2)2),4.56-4.47(m,1H,H of CH(CH2)2),4.37-4.08(m,2H,H of CH(CH2)2),3.78-3.66(m,1H,H of CH(CH -2 )2),3.64(s,3H,NCH3),3.01(t,J=5.7Hz,4H,N(CH2)2),2.92(s,4H,N(CH2)2),2.77-2.69(m,2H,CH2CH3),2.55(s,3H, ArCH3),1.85(t,J=5.6Hz,4H,C(CH2)2),1.32(t,J=7.6Hz,3H,CH2CH3),1.04-0.97(m,2H,CH2),0.96-0.90(m,2H,CH2). 13 CNMR (100MHz, CDCl3) δ (ppm): 173.48, 172.49, 163.73 (d, J = 250.0Hz), 160.55, 143.54, 141.24, 140.51, 130.05 (d, J C-F =8.5Hz),128.91(d,J C-F =3.2Hz),127.53,122.22,122.05,115.55(d,J C-F=26.0Hz),114.56,105.13,88.63,62.09,59.75,48.23,45.17,39.12,35.31,33.31,29.69,26.91,20.89,16.85,13.62.HRMS(ESI):m / z[M+H] + C 35 H 39 FN8O2S: Theoretical value 655.2979; Measured value 655.2960.

[0271] Example 21 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile Step 1 Synthesis of 6-bromo-2-ethyl-8-fluoro-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (2)

[0272]

[0273] Compound 1 (5.0 g, 26.2 mmol), 1,1,3,3-tetramethylbutyl isocyanide (4.4 g, 31.4 mmol), magnesium chloride (120 mg, 1.30 mmol), propionaldehyde (3.8 g, 65.5 mmol) and n-butanol (100 mL) were added to a 250 mL three-necked flask in sequence and heated under reflux for 3 h. TLC (V 石油醚 :V 乙酸乙酯 =10:1) to monitor the completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by rapid preparative chromatography (V 石油醚 :V 乙酸乙酯 =20:1), to obtain 8.8 g of white solid 2, with a yield of 90.7%. 1 H NMR (400MHz, CDCl3) δ (ppm): 8.09 (d, J=1.6Hz, 1H, ArH), 6.90 (dd, J1=9.6Hz, J2=1.6Hz, 1H, ArH), 2.81 (s, 1H, NH), 2.75 (q, J=7.5Hz ,2H,CH2CH3),1.66(s,2H,CH2),1.35(t,J=7.5Hz,3H,CH2CH3),1.15(s,6H,CH3CCH3),1.09(s,9H,C(CH3)3).HRMS(ESI):m / z[M+H] + C 17 H 25 BrFN3: theoretical value 372.1274; measured value 372.1256.

[0274] Step 2 Synthesis of N-(6-bromo-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-3-yl)formamide (3)

[0275]

[0276] Compound 2 (4 g, 10.8 mmol) and formic acid (40 mL) were added to a 250 mL single-necked bottle in sequence, and the mixture was refluxed for 3 h under nitrogen protection. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the reaction completion, concentrate under reduced pressure and purify by flash preparative chromatography (80 g, V 石油醚 :V 乙酸乙酯 =1:2), to obtain 2.51 g of white solid 3, with a yield of 81.5%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.08 (s, 1H, NH), 8.37 (s, 0.85H, ArH), 8.32 (s, 0.15H, ArH), 8.20 (s, 0. 85H,CHO),8.12(s,0.15H,CHO),7.52-7.45(m,1H,ArH),2.67-2.58(m,2H,CH2),1.24-1.19(m,3H,CH3).

[0277] Step 3 6-Bromo-2-ethyl-8-fluoro-N-methylimidazo[1,2-a]pyridin-3-amine (4)

[0278]

[0279] Compound 3 (2.03 g, 7.00 mmol) and anhydrous THF (36 mL) were added to a 250 mL single-necked bottle in sequence. BH3·THF (10.5 mL, 10.50 mmol) was slowly added dropwise at 0°C under nitrogen protection. After the addition was completed, the reaction was allowed to proceed at 50°C overnight. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the reaction completion, the reaction solution was cooled to room temperature, methanol (20 mL) was added to quench the reaction, concentrated under reduced pressure and purified by flash preparative chromatography (40 g, V 石油醚 :V 乙酸乙酯 =1:1), to give 1.70 g of yellow solid 4, with a yield of 89.5%. 1H NMR (600MHz, CDCl3) δ (ppm): 7.96 (d, J=1.6Hz, 1H, ArH), 6.90 (dd, J1=9.7Hz, J2=1.6Hz ,1H,ArH),2.80(s,4H,NHCH3),2.77(q,J=7.6Hz,2H,CH2),1.33(t,J=7.6Hz,3H,CH3).

[0280] Step 4 Synthesis of 2-((6-bromo-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (5)

[0281]

[0282] Compound 4 (1.00 g, 3.67 mmol), 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (1.32 g, 5.51 mmol), potassium carbonate (1.52 g, 11.01 mmol) and acetonitrile (20 mL) were added to a 250 mL single-necked bottle in sequence, and the mixture was reacted at 85°C for 24 h under nitrogen protection. TLC (V 石油醚 :V 乙酸乙酯 =1:1) monitor the reaction raw material remaining about 10%, the reaction solution was cooled to room temperature, water (20mL) was added to quench the reaction, ethyl acetate (30ml×3) was extracted, the organic phase was collected, washed with saturated brine (30ml×3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (40g, V 石油醚 :V 乙酸乙酯 =10:1), to obtain 0.46 g of white solid 5, with a yield of 24.0%. 1 H NMR (400MHz, CDCl3) δ (ppm): 8.15-8.10 (m, 2H, ArH), 7.76 (dd, J1=1.5Hz, J2=0.7Hz, 1H, ArH), 7.20-7.13(m,3H,ArH),3.62(s,3H,NCH3),2.79-2.72(m,2H,CH2),1.36(t,J=7.6Hz,3H,CH3).

[0283] Step 5 Synthesis of ethyl 1-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylate (6)

[0284]

[0285] Compound 5 (0.36 g, 0.76 mmol), intermediate 3 of Example 1 (0.27 g, 1.14 mmol), sodium tert-butoxide (0.31 g, 2.28 mmol), 2-(di-tert-butylphosphino)biphenyl (John Phos, 92 mg, 0.31 mmol), Pd2(dba)3 (105 mg, 0.114 mmol) and anhydrous toluene (3 mL) were added to a 100 mL Schlenk reaction tube in sequence for dissolution. The system was fully replaced with N2 and stirred at 115°C for overnight reaction. TLC (V 石油醚 :V 乙酸乙酯 =2:1) ​​to monitor the completion of the reaction, add water (10 mL) to quench the reaction, extract with ethyl acetate (30 ml × 3), collect the organic phase, wash with saturated brine (30 ml × 3), dry over anhydrous sodium sulfate, filter, concentrate and purify by flash preparative chromatography (12 g, V 石油醚 :V 乙酸乙酯 =2:1), to give 151 mg of brown solid 6, with a yield of 34.2%. 1 HNMR (400MHz, CDCl3) δ (ppm): 8.12-8.06 (m, 2H, ArH), 7.14-7.08 (m, 2H, ArH), 6.8 9-6.81(m,2H,ArH),4.07(q,J=7.1Hz,2H,OCH2),3.54(s,3H,NCH3),3.10-2.83(m, 8H,piperazine-H),2.71-2.63(m,2H,CH2CH3),1.40-1.34(m,2H,CH2),1.28(t,J=7.6Hz,3 H,OCH2CH3),1.20-1.18(m,3H,CH3),0.88-0.84(m,2H,CH2).HRMS(ESI):m / z[M+H] + C 30 H 31 F2N7O2S: theoretical value 592.2306; measured value 592.2293.

[0286] Step 6 Synthesis of 1-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid (7)

[0287]

[0288] Compound 6 (137 mg, 0.23 mmol), methanol (1 ml), tetrahydrofuran (3 ml), water (1 ml) and lithium hydroxide monohydrate (97 mg, 2.30 mmol) were added to a 25 mL round-bottom flask in sequence and reacted at room temperature overnight. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the reaction completion, cool to 0°C, adjust pH to 6 with 1N hydrochloric acid, concentrate, extract with dichloromethane (30ml×3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate and purify on a preparative plate (V 二氯甲烷 :V 甲醇 =10:1), to obtain 75 mg of brown solid 7, yield 57.8%. HRMS (ESI): m / z [M+H] + C 28 H 27 F2N7O2S: theoretical value 564.1993; measured value 564.1969.

[0289] Step 7 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0290]

[0291] Compound 7 (75 mg, 0.133 mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI, 38 mg, 0.20 mmol), 1-hydroxybenzotriazole (HOBt, 27 mg, 0.20 mmol) and dichloromethane (3 mL) were added to a 25 mL round-bottom flask in sequence. After stirring at room temperature for 30 min, 2-oxa-6-aza-spiro [3,3] heptane (20 mg, 0.20 mmol) and triethylamine (40 mg, 0.40 mmol) were added and reacted at room temperature overnight. TLC (V 乙酸乙酯 :V 甲醇 =1:1) monitoring reaction completion, water (10 mL) was added to quench the reaction, and dichloromethane (30 ml × 3) was used for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (4 g, V 乙酸乙酯 :V 甲醇 =20:1), to give 64 mg of a white solid with a yield of 74.1%. 1H NMR (400MHz, CDCl3) δ (ppm): 8.13-8.07 (m, 2H, ArH), 7.15-7.08 (m, 2H, ArH), 6.87 (d, J = 1. 9Hz,1H,ArH),6.85-6.80(m,1H,ArH),4.70(s,4H,CH2OCH2),4.53-4.07(m,4H,CH2NCH2),3 .56(s,3H,NCH3),3.04-2.95(m,4H,Piperazine-H),2.73-2.63(m,2H,CH2CH3),2.62-2.5 6(m,4H,piperazine-H),1.29(t,J=7.6Hz,3H,CH3),1.04-0.98(m,2H,CH2),0.95-0.89(m,2H,CH2). 13 C NMR (101MHz, CDCl3) δ (ppm): 171.65, 170.97, 162.78 (d, J C-F =253.0Hz),159.50,150.22(d,J C-F =254.6Hz),143.82,139.35(d,J C-F =8.4Hz),131.80(d,J C-F =29.4Hz),129.03(d,J C-F =8.5Hz),127.74(d,J C-F =3.0Hz),122.28,114.97(d,J C-F =21.9Hz),113.31,104.22(d,J C-F =17.9Hz),102.10(d,J C-F =4.3Hz),87.91,79.90,49.40,48.28,46.25,38.13,37.40,19.81,12.15,10.07,9.84.HRMS(ESI):m / z[M+H] + C 33 H 34 F2N8O2S: Theoretical value 645.2572; Measured value 645.2565.

[0292] Example 22 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0293] Step 1 Synthesis of 6-bromo-2-ethyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine (2)

[0294]

[0295] 1 (5.00 g, 28.70 mmol), magnesium chloride (110 mg, 1.15 mmol), n-butanol (30 mL), 1,1,3,3-tetramethylbutyl isocyanide (4.60 g, 33.00 mmol) and n-propanal (4.17 g, 71.80 mmol) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the mixture was reacted at 130 °C under nitrogen protection overnight. TLC (V 石油醚 :V 乙酸乙酯 =3:1) to monitor the reaction until it is complete, and about 10% of the raw material remains. The reaction solution is concentrated and purified by rapid preparative chromatography (80 g, V 石油醚 :V 乙酸乙酯 =3:1) to give 9.10 g of yellow oil 2, with a yield of 89.7%. 1 HNMR (400MHz, CDCl3) δ (ppm): 8.67 (d, J = 1.3Hz, 1H, ArH), 8.20 (d, J = 1.3Hz, 1H, ArH), 2.85 (s, 1H, NH), 2.83-2.7 7(m,2H,CH2CH3),1.68(s,2H,CH2),1.37(t,J=7.5Hz,3H,CH2CH3),1.18(s,6H,C(CH3)2),1.10(s,9H,C(CH3)3)

[0296] Step 2 Synthesis of N-(6-bromo-2-ethylimidazo[1,2-a]pyrazin-3-yl)formamide (3)

[0297]

[0298] 2 (6.70 g, 18.97 mmol) and formic acid (54 mL) were added to a 100 mL single-necked bottle in sequence. After the addition was complete, the reaction system was placed in an 80°C oil bath for 4 h. TLC (V 石油醚 :V 乙酸乙酯 =1:2) to monitor the complete reaction of the raw materials. The reaction solution was concentrated and purified by rapid preparative chromatography (40 g, V 石油醚 :V 乙酸乙酯 =1:2) to give 4.80 g of white solid 3 with a yield of 94.0%. 1H NMR (600MHz, CDCl3) δ (ppm): 10.32 (s, 1H, NH), 8.85 (d, J = 1.3Hz, 0.12H, ArH), 8.83 ( d,J=1.3Hz,0.88H,ArH),8.58(d,J=1.4Hz,0.12H,ArH),8.40(d,J=1.3Hz,0.88H,Ar H),8.38(s,0.88H,CHO),8.18(s,0.12H,CHO),2.73(q,J=7.6Hz,0.25H,CH2),2.68( q,J=7.6Hz,1.75H,CH2),1.26(t,J=7.4Hz,0.4H,CH3),1.23(t,J=7.6Hz,2.6H,CH3).

[0299] Step 3 Synthesis of N-(6-bromo-2-ethylimidazo[1,2-a]pyrazin-3-yl)-N-methylformamide (4)

[0300]

[0301] Compound 3 (3.90 g, 14.49 mmol), potassium carbonate (6.00 g, 43.47 mmol), acetone (40 mL) and iodomethane (3.09 g, 21.74 mmol) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the reaction system was placed in an oil bath at 56°C for 3 h. TLC (V 石油醚 :V 乙酸乙酯 =1:2) to monitor the complete reaction of the raw materials. The reaction solution was filtered, the residue was washed with acetone (40 mL), the filtrate was concentrated, and purified by rapid preparative chromatography (40 g, V 石油醚 :V 乙酸乙酯 =1:2), to obtain 3.15 g of white solid 4, with a yield of 76.8%. 1 H NMR (400MHz, CDCl3) δ (ppm): 8.84 (d, J=1.4Hz, 0.87H, ArH), 8.81 (d, J=1.4Hz, 0.13H, ArH), 8.47 (s, 0.13H, ArH), 8.19 (s, 0.87H, ArH), 7.95 (d, J= 1.4Hz,0.87H,CHO),7.78(d,J=1.4Hz,0.13H,CHO),3.40(s,0.41H,NCH3),3.26(s,2.59H,NCH3),2.81-2.73(m,2H,CH2),1.38-1.33(m,3H,CH3).

[0302] Step 4 Synthesis of 6-bromo-2-ethyl-N-methylimidazo[1,2-a]pyrazin-3-amine (5)

[0303]

[0304] Compound 4 (2.55 g, 9.00 mmol), methanol (15 mL) and potassium hydroxide aqueous solution (10 M, 13.5 mL) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the reaction system was placed at room temperature for 1 h. TLC (V 石油醚 :V 乙酸乙酯 =1:2) monitor the reaction of the raw materials to complete. Filter the reaction solution, wash the filter cake with water (50 mL), and dry the filter cake to obtain 1.93 g of yellow solid 5, with a yield of 84.0%. 1 H NMR (400MHz, CDCl3) δ (ppm): 8.69 (d, J = 1.3Hz, 1H, ArH), 8.08 (d, J = 1.3Hz, 1H, ArH), 2.98-2.80 (m, 6H, NHCH3 and CH2CH3), 1.37 (t, J = 7.6Hz, 3H, CH2CH3).

[0305] Step 5 Synthesis of 2-((6-bromo-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (6)

[0306]

[0307] Compound 5 (3.36 g, 13.17 mmol), 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (3.77 g, 15.81 mmol), potassium carbonate (5.46 g, 39.51 mmol) and acetonitrile (35 mL) were added to a 250 mL three-necked flask in sequence. The reaction system was placed in an oil bath at 80°C for 36 h under nitrogen protection. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor that the raw material is about 10% remaining. The reaction solution was filtered, the residue was washed with acetonitrile (30 mL), the filtrate was concentrated, and purified by flash preparative chromatography (80 g, V 石油醚 :V 乙酸乙酯 =1:2) to obtain 4.50 g of off-white solid 6 with a yield of 74.7%. 1H NMR (400MHz, CDCl3) δ (ppm): 8.90 (d, J = 1.4Hz, 1H, ArH), 8.16-8.07 (m, 2H, ArH), 7.95 (d, J = 1.4Hz, 1H, ArH), 7.2 1-7.13(m,2H,ArH),3.64(s,3H,NCH3),2.87-2.77(m,2H,CH2),1.38(t,J=7.6Hz,3H,CH3).HRMS(ESI):m / z[M+H] + C 19 H 14 BrFN6S: theoretical value 457.0696 / 459.0226; found value 459.0215. Step 6 Synthesis of ethyl 1-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylate (7)

[0308]

[0309] 6 (810 mg, 1.77 mmol), intermediate 3 of Example 1 (831 mg, 3.54 mmol), sodium tert-butoxide (340 mg, 3.54 mmol), tris(dibenzylideneacetone)dipalladium (162 mg, 0.177 mmol), 2-(di-tert-butylphosphine)biphenyl (69 mg, 0.23 mmol) and toluene (16 mL) were added to a 50 mL single-mouth bottle in sequence. Under nitrogen protection, the reaction system was placed in an oil bath at 115° C. and reacted overnight. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the complete reaction of the raw materials. The reaction system was quenched with water (15 mL), extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (20 g, V 石油醚 :V 乙酸乙酯 =1:1), to give 279 mg of light green oil 7, with a yield of 27.4%. 1H NMR (400MHz, CDCl3) δ (ppm): 8.82 (d, J = 1.4Hz, 1H, ArH), 8.18-8.12 (m, 2H, ArH), 7.20-7.1 4(m,2H,ArH),6.87(d,J=1.4Hz,1H,ArH),4.12(q,J=7.1Hz,2H,OCH2),3.61(s,3H,NCH3),3 .43-2.95(m,8H,piperazine-H),2.80-2.71(m,2H,CH2CH3),1.36(t,J=7.6Hz,3H,OCH2CH3),1.32- 1.29(m,2H,CH2),1.25-1.23(m,3H,CH2CH3),0.99-0.93(m,2H,CH2).HRMS(ESI):m / z[M+H] + C 29 H 31 FN8O2S: Theoretical value 575.2353; Measured value 575.2318.

[0310] Step 7 Synthesis of 1-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid (8)

[0311]

[0312] Compound 7 (240 mg, 0.42 mmol), methanol (1 mL), tetrahydrofuran (3 mL), water (1 mL) and lithium hydroxide monohydrate (177 mg, 4.20 mmol) were added to a 50 mL single-necked bottle in sequence. After the addition was complete, the reaction was carried out at room temperature for 48 h. TLC (V 二氯甲烷 :V 甲醇 =20:1) monitoring raw material remaining about 50%. After the methanol and tetrahydrofuran in the system were concentrated under reduced pressure, the pH was adjusted to 6 with 1N hydrochloric acid, the mixture was extracted with ethyl acetate (10mL×3), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a preparative plate (SiO2, V 二氯甲烷 :V 甲醇 =15:1), to give 130 mg of white solid 8, with a yield of 31.7%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.29 (s, 1H, COOH), 8.82 (d, J = 1.4Hz, 1H, ArH), 8.11- 8.05(m,2H,ArH),7.62(d,J=1.5Hz,1H,ArH),7.45-7.39(m,2H,ArH),3.58(s,3H,NCH 3),3.19(s,4H,piperazine-H),3.02(s,4H,piperazine-H),2.66(q,J=7.5Hz,2H,CH2CH3),1.27-1.23( m,3H,CH2CH3),1.18-1.15(m,2H,CH2),0.91-0.86(m,2H,CH2).HRMS(ESI):m / z[M+H] + C 27 H 27 FN8O2S: Theoretical value 547.2040; Measured value 547.2033.

[0313] Step 8 Synthesis of 2-(6-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0314]

[0315] Compound 8 (130 mg, 0.238 mmol), EDCI (69 mg, 0.357 mmol), HOBT (49 mg, 0.357 mmol) and dichloromethane (2 mL) were added to the thumb flask in sequence, and stirred at room temperature for 30 min before adding 2-oxa-6-azaspiro[3.3]heptane (36 mg, 0.357 mmol) and triethylamine (73 mg, 0.714 mmol). After the addition was completed, the reaction was allowed to react at room temperature overnight under nitrogen protection. TLC (V 二氯甲烷 :V 甲醇 =20:1) to monitor the complete reaction of the raw materials. The reaction solution was diluted with dichloromethane (10 mL) and then washed with saturated sodium bicarbonate solution (10 mL), water (10 mL), and saturated brine (10 mL). The mixture was extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thick preparative plate (V 二氯甲烷 :V 甲醇 =20:1), to give 110 mg of a white solid with a yield of 73.6%. 1H NMR (400MHz, CDCl3) δ (ppm): 8.83 (d, J = 1.4Hz, 1H, ArH), 8.19-8.11 (m, 2H, ArH), 7.21-7.1 3(m,2H,ArH),6.91(d,J=1.5Hz,1H,ArH),4.77(s,4H,O(CH2)2),4.33(s,4H,CON(CH2)2), 3.62 (s, 3H, NCH3), 3.41-3.29 (m, 4H, piperazine-H), 2.82-2.71 (m, 2H, CH2CH3), 2.64 (t, J = 5.0 Hz, 4H, piperazine-H), 1.36 (t, J = 7.6 Hz, 3H, CH2CH3), 1.11-1.03 (m, 2H, CH2), 1.02-0.97 (m, 2H, CH2). 13 C NMR (101MHz, CDCl3) δ (ppm): 172.80, 171.28, 163.75 (d, J C-F =251.8Hz),160.48,149.01,146.88,141.07,135.64,129.99(d,J C-F =8.5Hz),128.60(d,J C-F =3.3Hz),122.63,115.93(d,J C-F =21.8Hz),114.14,95.96,88.93,80.88,49.16,47.43,46.93,38.88,38.36,20.78,12.78,10.95,10.74.HRMS(ESI):m / z[M+H] + C 32 H 34 FN9O2S: Theoretical value 628.2618; Measured value 628.2605.

[0316] Example 23 Synthesis of 2-(2-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile Step 1 Synthesis of 2-bromo-6-ethyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-amine (2)

[0317]

[0318] Compound 1 (5.00 g, 1.56 mmol), 40 mL of n-butanol, magnesium chloride (1.33 g, 13.98 mmol), 1,1,3,3-tetramethylbutyl isocyanide (5.2 mL, 29.34 mmol) and n-propionaldehyde (4.06 g, 69.88 mmol) were added to a round-bottom flask in sequence. After nitrogen was replaced, the mixture was stirred at 120°C for 4 hours. After TLC (V 石油醚 :V 乙酸乙酯 =10:1) monitoring reaction completion, the reaction solution was cooled to room temperature, concentrated under reduced pressure at 60°C to evaporate most of the n-butanol, diluted with dichloromethane, mixed, concentrated and purified by rapid preparative chromatography (80 g, V 石油醚 :V 乙酸乙酯 =10:1), to obtain 7.50 g of yellow solid 2, with a yield of 68.8%. 1 HNMR (400MHz,CDCl3)δ(ppm):2.60(q,J=7.6Hz,2H,CH2CH3),1.60(s,2H,CH2),1.26(t,J=7.6Hz,3H,CH2CH3),1.17(s,6H,CH3CCH3),1.07(s,9H,C(CH3)3).Step 2 Synthesis of N-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)formamide (3)

[0319]

[0320] Compound 2 (1.00 mg, 2.81 mmol) and 8 mL of formic acid were added to a round-bottom flask in sequence, and after replacing the nitrogen atmosphere, the mixture was stirred at 80°C for 3 hours. 石油醚 :V 乙酸乙酯 =3:1) After the reaction was completed, the reaction solution was directly concentrated and evaporated to dryness, petroleum ether was added and stirred at room temperature for 2 hours, filtered, and the filter cake was dried to obtain 660 mg of off-white solid 3, with a yield of 78.4%.

[0321] Step 3 Synthesis of 2-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (4)

[0322]

[0323] Compound 3 (660 mg, 2.36 mmol) was added to a three-necked flask and dissolved in 10 mL of tetrahydrofuran. Under nitrogen protection, sodium hydride (60%) (285 mg, 7.08 mmol) was added in batches under ice bath. After the addition was completed, a tetrahydrofuran solution of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (563 mg, 2.36 mmol) was added dropwise and reacted at room temperature for 4 hours. TLC (V 乙酸乙酯 :V 石油醚 =1:1) After the reaction of the raw materials was completed, water was added to quench, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain 500 mg of a white solid with a yield of 55.1%.

[0324] Step 4 Synthesis of 2-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (5)

[0325]

[0326] Compound 4 (500 mg, 1.12 mmol) was added to a single-mouth bottle and dissolved in 7 mL of tetrahydrofuran. Under nitrogen protection, sodium hydride (60%) (285 mg, 7.08 mmol) was added in batches under ice bath. After reacting for 30 minutes, iodomethane (0.14 mL, 2.23 mmol) was added dropwise and reacted at room temperature for 2 hours. TLC (V 乙酸乙酯 :V 石油醚 =3:1) after the reaction of the raw material was completed, water was added to quench, ethyl acetate was extracted, the mixture was washed with saturated brine, dried, filtered, concentrated and purified by flash chromatography (20 g, V 乙酸乙酯 :V 石油醚 =5:1), to give 350 mg of white solid 5, with a yield of 57.1%. 1 H NMR (400MHz, CDCl3) δ (ppm): 8.15-8.09 (m, 2H, ArH), 7.19-7.12 (m, 2H ArH), 3.62 (s, 3H, NCH3), 2.64 (q, J = 7.6Hz, 2H, CH2), 1.31 (t, J = 7.6Hz, 3H, CH3).

[0327] Step 5 Synthesis of ethyl 1-(4-(5-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)cyclopropane-1-carboxylate (6)

[0328]

[0329] Compound 5 (200 mg, 0.433 mmol), 6 mL of N,N-dimethylformamide, potassium carbonate (240 mg, 1.733 mmol) and intermediate 3 of Example 1 (122 mg, 0.518 mmol) were added to a single-mouth bottle in sequence, and the mixture was reacted at 70° C. for 3 hours under a nitrogen atmosphere. TLC (V 乙酸乙酯 :V 石油醚 =1:1) monitoring the raw material reaction after completion, cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried, filtered, concentrated and purified by flash preparative chromatography (12 g, V 乙酸乙酯 :V 石油醚 =3:1), to give 210 mg of white solid 6, with a yield of 83.7%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.09-8.05 (m, 2H, ArH), 7.41 (t, J = 8.7Hz, 2H, ArH), 4.04 (q, J = 7.2Hz, 2H, OCH2), 3.5 3(s,3H,NCH3),3.32(s,4H,N(CH2)2),3.00(br,4H,N(CH2)2),2.53-2.49(m,2H,CH2CH3),1.20-1.13(m,8H,CH3,CH3 and CH2),0.99-0.96(m,2H,CH2).HRMS(ESI):m / z[M+H] + C 27 H 29 FN8O2S2: Theoretical value 581.1922; Measured value 581.1917.

[0330] Step 6 Synthesis of 1-(4-(5-(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)cyclopropane-1-carboxylic acid (7)

[0331]

[0332] Compound 6 (200 mg, 0.353 mmol), 1 mL of methanol, 3 mL of tetrahydrofuran, 1 mL of water and lithium hydroxide monohydrate (149 mg, 3.53 mmol) were added to a single-necked bottle in sequence and stirred at room temperature for 16 hours. TLC (V 二氯甲烷 :V 甲醇 =15:1) After the reaction of the raw material was completed, water was added to quench, and the methanol was removed by concentration under reduced pressure. The pH was adjusted to 6 with dilute hydrochloric acid (1N) under ice bath, and a large amount of solid precipitated. The solid was filtered and the filter cake was dried to obtain 180 mg of white solid 7, with a yield of 94.7%.

[0333] Step 7 Synthesis of 2-(2-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0334] Compound 7 (175 mg, 0.33 mmol), 10 mL of dichloromethane, 0.5 mL of N,N-dimethylformamide, triethylamine (0.15 mL, 1.00 mmol), 1-hydroxybenzotriazole (HOBT, 68 mg, 0.50 mmol), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI, 96 mg, 0.50 mmol) and 2-oxa-6-aza-spiro [3,3] heptane (50 mg, 0.50 mmol) were added to a single-mouth bottle in sequence, and the reaction was carried out at room temperature overnight under a nitrogen atmosphere. TLC (V 二氯甲烷 :V 甲醇 =20:1) to monitor the reaction of the raw material, add water to quench, evaporate the dichloromethane under reduced pressure, add ethyl acetate to extract, wash with saturated brine, dry, filter, concentrate and purify by flash preparative chromatography (12 g, V 二氯甲烷 :V 甲醇 =50:1), to give 150 mg of a white solid with a yield of 71.4%. 1 H NMR(600MHz,CDCl3)δ(ppm):8.17-8.11(m,2H,ArH),7.18-7.13(m,2H,ArH),4 .77(s,4H,spiro-CH2OCH2),4.33(s,4H,spiro-CH2NCH2),3.57(s,3H,NCH3),3.45-3.42 (m,4H,N(CH2)2),2.67(t,J=5.1Hz,4H,N(CH2)2),2.59(q,J=7.5Hz,2H,CH2CH 3),1.29(t,J=7.6Hz,3H,CH3),1.09-1.06(m,2H,CH2),0.97-0.94(m,2H,CH2). 13 C NMR (101MHz, CDCl3) δ (ppm): 171.51, 171.17, 163.88, 162.71 (d, J C-F =266.8Hz),159.38,139.87,138.32,129.01(d,J C-F =8.4Hz),128.04(d,J C-F =3.5Hz),122.47,114.80(d,JC-F =21.8Hz),113.74,87.35,79.82,47.80,47.52,46.35,38.52,37.32,28.67,20.02,12.16,10.51.HRMS(ESI):m / z[M+H] + C 30 H 32 FN9O2S2: Theoretical value 634.2187; Measured value 634.2166.

[0335] Example 24 Synthesis of 2-(2-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)piperazin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl-d3)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0336]

[0337] Referring to the preparation method of Example 23, deuterated iodomethane was used instead of iodomethane to obtain 820 mg of an off-white solid with a yield of 58.6%. 1 H NMR (600 MHz, CDCl3) δ (ppm): 8.07 (dd, J1 = 8.8 Hz, J2 = 5.6 Hz, 2H, ArH), 7.09 (t, J = 8.8 Hz, 2H, ArH), 4.71 (s, 4H, spiro-CH2OCH2), 4.23 (s, 4H, spiro-CH2NCH2), 3.37 (d, J = 4.4 Hz, 4H, piperazine-H), 2.60 (t, J = 4.8 Hz, 4H, piperazine-H), 2.52 (q, J = 7.6 Hz, 2H, CH2CH3), 1.21 (t, J = 7.6 Hz, 3H, CH3), 1.02-0.99 (m, J = 3.2 Hz, 2H, cyclopropyl-CH2), 0.91-0.87 (m, 2H, cyclopropyl-CH2). 13 C NMR (101MHz, CDCl3) δ (ppm): 171.52, 171.13, 162.65 (d, J C-F =252.0Hz),159.36,139.86,138.30,129.00(d,J C-F =8.7Hz),128.03(d,J C-F =3.2Hz),122.43,114.80(d,J C-F=21.9Hz),113.74,79.81,47.79,47.52,46.34,37.32,20.02,12.15,10.52.HRMS(ESI):m / z[M+H] + C 30 H 30 D3FN9O2S2: Theoretical value 637.2371; Measured value 637.2364.

[0338] Example 25 Synthesis of 2-(6-ethyl-2-(4-(1-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)cyclopropyl)piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl-d3)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0339]

[0340] Referring to the preparation method of Example 23, deuterated iodomethane was used instead of iodomethane, and 2-azaspiro[3.3]heptan-6-ol was used instead of 2-oxa-6-aza-spiro[3,3]heptane to obtain 180 mg of an off-white solid with a yield of 79.3%. 1 H NMR (400 MHz, methanol-d4) δ (ppm): 8.14-8.11 (m, 2H, ArH), 7.24 (t, J = 8.4 Hz, 2H, ArH), 4.40 (s, 2H, spiro-N(CH2)2), 4.13-4.07 (m, 1H, CH), 3.93 (s, 2H, spiro-N(CH2)2), 3.47 (s, 4H, piperazine-H), 2.70 (t, J = 5 .2 Hz, 4H, piperazine-H), 2.59 (q, J = 7.6 Hz, 2H, CH2CH3), 2.53-2.47 (m, 2H, H of CHCH2 and H of CHCH2), 2.09-2.03 (m, 2H, H of CHCH2 and H of CHCH2), 1.26 (t, J = 7.6 Hz, 3H, CH2CH3), 0.98-0.95 (m, 4H, cyclopropyl-CH2). 13 CNMR(101MHz,CDCl3)δ(ppm):171.54,170.21,162.65(d,J C-F =256.5Hz),161.38,159.43,139.79,138.29,129.00(d,J C-F =8.4Hz),128.01(d,J C-F =3.2Hz),122.41,114.44(d,J C-F=21.9Hz),113.77,60.38,47.86,47.63,46.03,42.26,29.17,19.99,12.18,10.68.HRMS(ESI):m / z[M+H] + C 31 H 32 D3FN9O2S2: Theoretical value 651.2527; Measured value 651.2514.

[0341] Example 26 Synthesis of methyl 1-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carboxyl)cyclopropyl)-4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-2-carboxylate

[0342] Step 1 Synthesis of ethyl 2-bromo-2-cyanoacetate (2)

[0343]

[0344] Compound 1 (5.00 g, 50.5 mmol) and carbon tetrachloride (100 mL) were added to a 250 mL single-necked bottle in sequence. Under nitrogen protection, NBS (2.87 g, 50.5 mmol) was added in batches at room temperature. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. TLC (V 石油醚 :V 乙酸乙酯 =5:1) to monitor the complete reaction of the raw material, filter through diatomaceous earth, concentrate, and purify by column chromatography (V 石油醚 :V 乙酸乙酯 =15:1), to obtain 6.00 g of yellow oily compound 2, with a yield of 66.9%.

[0345] Step 2 Synthesis of tert-butyl 1-((1-cyano-2-methoxy-2-oxoethyl)amino)cyclopropane-1-carboxylate (3)

[0346]

[0347] Compound 2 (2.50 g, 14.1 mmol), DMF (50 mL), cesium carbonate (9.15 g, 28.1 mmol), potassium iodide (2.33 g, 14.1 mmol) and tert-butyl 1-aminocyclopropane-1-carboxylate (2.65 g, 16.9 mmol) were added to a 100 mL single-mouth bottle in sequence. After the addition was completed, nitrogen was protected and the reaction was allowed to proceed at room temperature overnight. TLC (V 石油醚 :V 乙酸乙酯=5:1) to monitor the reaction completion of the raw material, add water (140 mL) to quench the reaction, extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated sodium chloride solution (100 mL×3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (V 石油醚 :V 乙酸乙酯 =4:1), to obtain 1.85 g of yellow oily compound 3 with a yield of 51.8%.

[0348] Step 3 Synthesis of tert-butyl 1-((3-amino-1-methoxy-1-oxopropan-2-yl)amino)cyclopropane-1-carboxylate (4)

[0349]

[0350] Compound 3 (1.50 g, 5.9 mmol), ethanol (40 mL) and Raney nickel (150 mg) were added to a 100 mL single-necked bottle in sequence. After the addition was completed, the mixture was reacted at room temperature under a hydrogen pressure of 80 psi for 5 h. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the complete reaction of the raw material, filter through diatomaceous earth, concentrate, and purify by column chromatography (V 石油醚 :V 乙酸乙酯 =1:1), to obtain 1.00 g of yellow oily compound 4 with a yield of 65.6%.

[0351] Step 4 Synthesis of 1-(1-(tert-butyloxycarbonyl)cyclopropyl)-5-oxopiperazine-2-carboxylic acid methyl ester (5)

[0352]

[0353] Compound 4 (2.00 g, 7.74 mmol), 1,2-dichloroethane (40 mL) and sodium bicarbonate (1.30 g, 15.5 mmol) were added to a 100 mL single-necked bottle in sequence. Under nitrogen protection, bromoacetyl chloride (1.22 g, 7.74 mmol) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature overnight. TLC (V 石油醚 :V 乙酸乙酯 =1:1) to monitor the complete reaction of the raw material, filter through diatomaceous earth, concentrate, and purify by column chromatography (V 石油醚 :V 乙酸乙酯 =1:1), to obtain 1.30 g of yellow solid compound 5, with a yield of 56.3%.

[0354] Step 5 Synthesis of methyl 1-(1-(tert-butyloxycarbonyl)cyclopropyl)piperazine-2-carboxylate (6)

[0355]

[0356] Compound 5 (1.00 g, 3.35 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL single-necked bottle in sequence. Borane dimethyl sulfide complex (33.5 mL, 1 mol / L) was added dropwise under nitrogen protection in an ice-water bath. After the addition was complete, the mixture was kept warm for 5 h. TLC (V 石油醚 :V 乙酸乙酯 =1:1) monitor the reaction of the raw material to complete, add methanol (5 mL) dropwise at low temperature to quench the reaction, add water (40 mL) to dilute, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (V 石油醚 :V 乙酸乙酯 =1:1), to obtain 410 mg of yellow solid compound 6, with a yield of 43.0%.

[0357] Step 6 Synthesis of methyl 1-(1-(tert-butyloxycarbonyl)cyclopropyl)-4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-2-carboxylate (7)

[0358]

[0359] Compound 6 (300 mg, 1.06 mmol), DMF (6 mL), potassium carbonate (291 mg, 2.11 mmol), potassium iodide (175 mg, 1.06 mmol) and intermediate 4 of Example 22 (488 mg, 1.06 mmol) were added to a 25 mL single-mouth bottle in sequence. After the addition was completed, nitrogen was protected and the reaction was carried out at 60° C. overnight. TLC (V 石油醚 :V 乙酸乙酯 =5:1) monitor the reaction of the raw material to be complete, cool, add water (15 mL) to quench the reaction, extract with ethyl acetate (15 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×3), dry with anhydrous sodium sulfate, filter, concentrate, and purify with column chromatography (V 石油醚 :V 乙酸乙酯 =1:1), to give 450 mg of yellow solid 7, with a yield of 64.0%.

[0360] Step 7 Synthesis of 1-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-(methoxycarbonyl)piperazin-1-yl)cyclopropane-1-carboxylic acid (8)

[0361]

[0362] Compound 7 (250 mg, 0.37 mmol) and HCl / ethyl acetate (4 mL, 4 mol / L ethyl acetate solution) were added to a 25 mL single-necked bottle in sequence. After the addition was complete, nitrogen was protected and the reaction was carried out at room temperature for 2 h. TLC (V 二氯甲烷 :V 甲醇 =10:1) monitor the reaction of the raw material, concentrate, add water (15 mL) to dissolve, add saturated sodium bicarbonate solution to adjust the pH to 5, extract with dichloromethane (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (V 二氯甲烷 :V 甲醇 =10:1), to obtain 245 mg of yellow solid compound 8, with a yield of 65.5%.

[0363] Step 8 Synthesis of methyl 1-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carboxyl)cyclopropyl)-4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-2-carboxylate (Example 26)

[0364]

[0365] Compound 8 (100 mg, 0.16 mmol), dichloromethane (5 mL), EDCI (61 mg, 0.32 mmol), HOBT (143 mg, 0.32 mmol), triethylamine (49 mg, 0.48 mmol) and 2-oxa-6-azaspiro[3,3]heptane (20 mg, 0.19 mmol) were added to a 25 mL single-mouth bottle in sequence. After the addition was completed, nitrogen was protected and the reaction was carried out at room temperature overnight. TLC (V 二氯甲烷 :V 甲醇 =10:1) to monitor the reaction of the raw material, add dichloromethane (40 mL) to dilute, wash with saturated sodium chloride solution (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (V 二氯甲烷 :V 甲醇 =10:1), to obtain 80 mg of yellow solid, yield 70.6%. HRMS (ESI): m / z [M+H] + C 32 H 34 FN9O4S2: Theoretical value 691.2159; Measured value 691.2163.

[0366] Example 27 Synthesis of 1-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)-4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-2-carboxylic acid

[0367]

[0368] The compound of Example 26 (100 mg, 0.14 mmol), tetrahydrofuran (2 mL), water (2 mL) and lithium hydroxide monohydrate (12 mg, 0.28 mmol) were added to a 25 mL single-necked bottle in sequence. After the addition was completed, nitrogen was protected and the reaction was carried out at room temperature overnight. TLC (V 二氯甲烷 :V 甲醇 =10:1) monitor the reaction of the raw material, add water (10 mL) to dilute, wash with ethyl acetate (5 mL×3), add 1 mol / L dilute hydrochloric acid to adjust the pH to 5, a white solid precipitates, filter and dry to obtain 70 mg of white solid Example 27, yield 71.5%. HRMS (ESI): m / z[M+H] + C 31 H 33 FN9O4S2: Theoretical value 678.7824; Measured value 678.7836.

[0369] Example 28 Synthesis of 2-((2-(4-(1-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)cyclopropyl)-3-(hydroxymethyl)piperazin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0370]

[0371] The compound of Example 26 (645 mg, 0.93 mmol), THF (6 mL), ethanol (18 mL), lithium bromide (283 mg, 3.26 mmol) and sodium borohydride (123 mg, 3.26 mmol) were added to a 100 mL single-necked bottle in sequence, and the reaction was carried out at room temperature overnight under N2 protection. TLC (V 二氯甲烷 :V 甲醇 =20:1) monitoring reaction after completion, water (10 mL) quenched the reaction system, ethyl acetate (10 mL × 3) extracted, collected the organic phase. Saturated brine (10 mL × 3) washed, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (V 二氯甲烷 :V 甲醇=50:1), to obtain 68 mg of white solid, yield 11.0%. HRMS (ESI): m / z [M+H] + C 31 H 34 FN9O3S2: Theoretical value 663.2210; Measured value 663.2234

[0372] Example 29 Synthesis of 2-((2-(3-((difluoromethoxy)methyl)-4-(1-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)cyclopropyl)piperazin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0373]

[0374] The compound of Example 28 (100 mg, 0.15 mmol), dichloromethane (2 mL) and an aqueous solution (0.5 mL) of potassium bifluoride (70 mg, 0.90 mmol) were added to a 50 mL single-necked bottle in sequence. Under N2 protection, difluorobromomethyltrimethylsilane (91 mg, 0.45 mmol) was added and the reaction was allowed to proceed at room temperature overnight. TLC (V 二氯甲烷 :V 甲醇 =50:1) After the reaction was completed, water (5 mL) was added to quench the reaction system, extracted with ethyl acetate (5 mL×3), and the organic phase was collected. Washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative plate (V 二氯甲烷 :V 甲醇 =40:1), to obtain 27 mg of white solid, yield 25.0%. HRMS (ESI): m / z [M+H] + C 32 H 34 F3N9O3S2: Theoretical value 713.2178; Measured value 713.2209

[0375] Example 30 Synthesis of 2-((6-ethyl-2-(5-(1-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)cyclopropyl)-2-oxa-5,8-diazaspiro[3.5]nonane-8-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl-d3)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0376]

[0377] Referring to the preparation method of Example 23, methyl iodide was replaced with deuterated methyl iodide, intermediate 3 of Example 1 was replaced with tert-butyl 1-(2-oxa-5,8-diazaspiro[3.5]nonane-8-yl)cyclopropane-1-carboxylate, and 2-oxa-6-aza-spiro[3,3]heptane was replaced with 2-azaspiro[3.3]hept-6-ol, and then 16.8 mg of compound of Example 30 was prepared by a similar method as an off-white solid with a yield of 19.2%. HRMS (ESI): m / z[M+H] + C 33 H 34 D3FN9O3S2: Theoretical value 693.8557; Measured value 693.8569.

[0378] Embodiment 31

[0379] Step 1 Synthesis of tert-butyl 5-(2-methoxy-2-oxoethyl)-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (2)

[0380]

[0381] To a 100 mL reaction bottle, tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonene-8-carboxylate (1, 1.00 g, 4.39 mmol) and tetrahydrofuran (10 mL) were added in sequence. Under nitrogen protection, 60% NaH (264 mg, 6.58 mmol) was added in batches under ice bath. After reacting at room temperature for 0.5 h, a solution of methyl bromoacetate (1.00 g, 6.58 mmol) in tetrahydrofuran (3 mL) was added dropwise. After addition, the reaction was continued at room temperature for 16 h. TLC (V 乙酸乙酯 :V 石油醚 =1:2) monitor the reaction of the raw materials to complete, add water (20 mL) to quench the reaction solution in an ice bath, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by flash preparative chromatography (40 g, V 乙酸乙酯 :V 石油醚 =1:4), to obtain 1.05 g of light yellow solid 2, with a yield of 80.2%.

[0382] Step 2 Synthesis of methyl 2-(2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)acetate (3)

[0383]

[0384] 2 (1.20 g, 4.00 mmol) and HCl / dioxane (15 mL, 4 mol / L) solution were added to a 50 mL reaction bottle in sequence, and the reaction was carried out at room temperature for 2 h under nitrogen protection. TLC (V 二氯甲烷 :V甲醇 =15:1) Monitor the reaction of the starting material to complete. The reaction solution was directly concentrated, evaporated with ethyl acetate (20 mL×3), and then vacuum dried for 3 h to obtain 830 mg of crude white solid 3, which was used directly in the next step without purification.

[0385] Step 3 Synthesis of 2-((6-ethyl-2-(5-(2-oxo-2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethyl)-2-oxa-5,8-diazaspiro[3.5]nonane-8-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Example 31)

[0386]

[0387] Refer to the subsequent synthesis steps of Example 23 to obtain 180 mg of white solid Example 31 with a yield of 63.0%. HRMS (ESI): m / z [M+H] + C 30 H 32 FN9O3S2: Theoretical value 509.1834; Measured value 509.1822. Biological activity test

[0388] (1) ATX inhibitory activity of the compounds of the present invention

[0389] In this example, the IV type ATX inhibitor GLPG-1690 was used as a positive control, and the ATX inhibitory activity of the compounds of the present invention and GLPG-1690 was evaluated by using the Fluorescent-based ATXActivity Assay: 1) the compounds were serially diluted using an Echo instrument, with final concentrations ranging from 10 μM, 1.7 μM, 0.17 μM, 0.017 μM, 0.0017 μM, and 0.00017 μM; 2) 5 μL / well of a mixture of ATX and buffer (2 U / mL horseradish peroxidase and 2 U / mL choline oxidase) was added to the assay plate (containing the compounds), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes; 3) 5 μL of substrate (lysophosphatidylcholine LPC) and AmplexRed were added to each well. Reagent mixture to start the reaction; 4) Centrifuge the test plate at 1000 rpm for about 1 minute and seal the test plate with a film; Incubate at 25°C for 150 minutes; Read the fluorescence signal of 530nM excitation light and 590nM emission light on Envision, calculate the enzyme inhibition rate based on the fluorescence ratio, and calculate the compound IC by software analysis 50 .

[0390] Other compounds of the present invention have similar beneficial effects as the compounds listed below as shown in Table 1, but this should not be understood as the compounds of the present invention only having the following beneficial effects.

[0391] Table 1: Inhibitory activity of the compounds of the present invention on ATX

[0392]

[0393]

[0394] In Table 1: "++++" represents 0.01-20 nM, "+++" represents 20-100 nM, and "++" represents 100-1000 nM.

[0395] It can be seen from the data in Table 1 that the listed compounds exhibit significant ATX inhibitory activity, and the ATX inhibitory activity of some compounds is significantly better than that of GLPG-1690 and comparative compound 1.

[0396] (2) Carrageenan-induced air sac inflammation experiment

[0397] 1. Experimental Materials

[0398] 40 male SD rats (200-220 g) aged 6-8 weeks; 20 ml syringe, hair shaver, 5 ml syringe, 2 ml syringe, Pasteur pipette; chloral hydrate, 1% carrageenan, compound of Example 24, GLPG-1690.

[0399] 2. Reagent Preparation

[0400] 1% carrageenan solution: Take 1g of carrageenan powder, add 100ml of normal saline and mix well to obtain 1% carrageenan solution.

[0401] Compound: the compound of Example 24, dissolved in 0.5% CMC-Na to prepare a suspension solution of corresponding concentration; the positive control GLPG-1690, dissolved in 0.5% CMC-Na to prepare a suspension solution of corresponding concentration.

[0402] 3. Experimental Methods

[0403] All rats were randomly divided into 4 groups (model group, blank control group, GLP1690 (30 mg BID) administration group, Example 24 (30 mg BID) administration group, 10 rats in each group), and the rats were anesthetized with chloral hydrate and the backs were shaved; on the first day, 20 mL of sterile air was injected subcutaneously in the dorsal shoulder to form a dorsal air bag; on the third day, 10 ml of sterile air was used to inflate the air bag again to maintain it, and sterile air was injected twice in total; on the 4th to 6th days, the blank control group and the model group rats were gavaged with 10 ml / kg of normal saline, and the other groups were gavaged with the treatment compound (administration volume 10 mL / kg). One hour after the last treatment on the 6th day, 2 ml of sterile saline was injected into the air bag of the blank control group, and 2 ml of 1% carrageenan was injected into the air bag of all other rats. 3 hours after the injection of carrageenan, the rats were anesthetized with chloral hydrate, and the air bag of each rat was flushed with 2 mL of sterile saline, and the exudate was recovered with a Pasteur pipette (this step was placed on ice).

[0404] 4. Index determination

[0405] Lysophosphatidic acid (LPA) analysis: The exudate was centrifuged at 800 g for 10 min at 4 °C, and the supernatant was collected and LPA was determined by ELISA.

[0406] 5. Experimental Results

[0407] Table 1. Effects of compounds on LPA release in carrageenan-induced rat air pouch inflammation model

[0408]

[0409] ## P<0.01vs blank group; * P<0.05, ** P<0.01vs model group;

[0410] △ P<0.05, △△ P<0.01 vs GLPG-1690

[0411] According to the above results, compared with the blank group, the LPA content in the dorsal air sac exudate of rats in the model group was significantly increased (P<0.01), indicating that the model was successful; compared with the model group, the positive control GLPG1690 and the Example 24 dosage group were able to significantly reduce the LPA content in the dorsal air sac exudate of rats (P<0.01); compared with the positive control GLPG1690 dosage group, the Example 24 dosage group was able to significantly reduce the LPA content in the dorsal air sac exudate of rats (P<0.01).

[0412] In conclusion, the compounds of the present invention have good inhibitory activity against ATX, excellent in vitro and in vivo efficacy and pharmacokinetic properties, and have good prospects for clinical application.

[0413] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0414] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound represented by formula (I), or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein R1 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by halogen, hydroxyl, amino, cyano, nitro, oxo; Ring A is wherein B is selected from a 5-membered or 6-membered heteroaryl group, and R2 is selected from a hydrogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a halogen, an amino, a hydroxyl, a cyano, a nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R3 are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, amino, hydroxy, cyano, nitro or halogen, R4 and R4' are selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2; X is selected from optionally substituted C4-C 14 a cycloalkyl group, a 4- to 14-membered heterocyclyl group, which is optionally substituted by a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 alkoxyalkyl group, a C1-C6 haloalkoxyalkyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 haloalkoxycarbonyl group, a carboxyl group, a hydroxyl group, an amino group, a cyano group, a nitro group, or an oxo group; W is selected from C3-C8 cycloalkyl or 3 to 8 membered heterocycloalkyl, which is optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, oxo; Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4 to 14 membered heterocyclyl, 4 to 14 membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4- to 14-membered heterocyclyl, 4- to 14-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, or oxo.

2. The compound of formula (I) according to claim 1 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein: R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo; Ring A is Wherein R2, R3, and n are as defined in claim 1; X is selected from the group consisting of optionally substituted cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, It is optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxyalkyl, C1-C3 haloalkoxyalkyl, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, carboxyl, hydroxyl, amino, cyano, nitro, oxo; W is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiirane, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, halogen, hydroxy, amino, cyano, nitro, oxo; Y is selected from C1-C6 alkyl, C1-C6 alkoxy, NR5R5', C4-C 10 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C4-C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano or nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro or amino.

3. The compound of formula (I) according to claim 2 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein, A is selected from Wherein R2 and R3 are as defined in claim 1; X is selected from optionally substituted It is optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxyalkyl, C1-C3 haloalkoxyalkyl, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, carboxyl, hydroxyl, amino, cyano, nitro, oxo; W is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, which is optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, hydroxy, amino, cyano, nitro; Y is selected from C1-C6 alkoxy, NR5R5', and 4- to 10-membered heterocyclyl, wherein the C1-C6 alkoxy and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano, and nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro, and amino.

4. The compound of formula (I) according to claim 2 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein, R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro; R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, amino, hydroxy, cyano, nitro or halogen.

5. The compound of formula (I) according to claim 2 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein, Y is selected from CH3O-, 6. The compound according to any one of claims 1 to 5, which is a compound represented by formula (II) Or its stereoisomers, tautomers, solvates, prodrugs, isotope labels and pharmaceutically acceptable salts, wherein p is selected from 0, 1, 2 or 3, and R1, A, X, Y are as defined in any one of claims 1-5.

7. The compound according to any one of claims 1 to 5, which is a compound represented by formula (III-1) or (III-2) or a stereoisomer, a tautomer, a solvate, a prodrug, an isotope-labeled substance or a pharmaceutically acceptable salt thereof, wherein R1, A, X and Y are as defined in any one of claims 1 to 5.

8. A compound represented by formula (VIII), or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein R1 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by halogen, hydroxyl, amino, cyano, nitro, oxo; Ring A is wherein B is selected from a 5-membered or 6-membered heteroaryl group, and R2 is selected from a hydrogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a halogen, an amino, a hydroxyl, a cyano, a nitro, -C(O)OR4, -C(O)R4, -S(O) m OR4, S(O)R4, -C(O)NR4R4', -S(O)NR4R4', -OC(O)R4, -OS(O) m R4, R3 are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, amino, hydroxy, cyano, nitro or halogen, R4 and R4' are selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, m is selected from 1 or 2, and n is selected from 0, 1 or 2; Y is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NR5R5', C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4 to 14 membered heterocyclyl, 4 to 14 membered heterocyclyl C1-C6 alkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C4-C 14 Cycloalkyl, C4-C 14 Cycloalkyl C1-C6 alkyl, 4- to 14-membered heterocyclyl, 4- to 14-membered heterocyclyl C1-C6 alkyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, cyano, nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxyl, halogen, cyano, nitro, amino, or oxo.

9. The compound represented by formula (VIII) according to claim 8 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein: R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen, hydroxy, amino, cyano, nitro, oxo; Ring A is Wherein R2, R3, and n are as defined in claim 1; Y is selected from C1-C6 alkyl, C1-C6 alkoxy, NR5R5', C4-C 10 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C4-C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano or nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro or amino.

10. The compound represented by formula (VIII) according to claim 9 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein: A is selected from Wherein R2 and R3 are as defined in claim 1; Y is selected from C1-C6 alkoxy, NR5R5', and 4- to 10-membered heterocyclyl, wherein the C1-C6 alkoxy and 4- to 10-membered heterocyclyl are optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, cyano, and nitro, and R5 and R5' are selected from H or C1-C6 alkyl optionally substituted by hydroxy, halogen, cyano, nitro, and amino.

11. The compound represented by formula (VIII) according to claim 9 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein: R2 is selected from hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, amino, hydroxy, cyano, nitro; R3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, amino, hydroxy, cyano, nitro or halogen.

12. The compound represented by formula (VIII) according to claim 9 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts; wherein: Y is selected from CH3O-, 13. A compound selected from: or stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or its stereoisomer, tautomer, solvate, prodrug, isotope label, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 13 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating ATX-mediated diseases.

16. Use of the compound according to any one of claims 1 to 13 or its stereoisomers, tautomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating characteristic diseases caused by abnormal expression of ATX-lysophosphatidic acid (LPA).

17. The use according to claim 15 or 16, wherein the disease is selected from inflammation, fibrotic disease, autoimmune disease, cardiovascular disease, and / or cancer.

18. The use according to claim 17, wherein the disease is selected from idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, systemic sclerosis, scleroderma, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, and / or tumors.

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