A benzofuran derivative and its pharmaceutical applications

Abstract

A benzofuran derivative and its pharmaceutical application relate to a compound of general formula (I) or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, intermediates, and preparation methods thereof, as well as its application in the preparation of medicaments for treating diseases related to TRPM3. (I).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a compound of general formula (I) or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, intermediates, and preparation methods thereof, as well as its application in the preparation of medicaments for treating diseases related to TRPM3. Background Technology

[0002] Migraine is a type of headache that causes severe throbbing or pulsating pain, usually occurring only on one side of the head. It is often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. A migraine attack can last from hours to days, and the pain can be severe enough to interfere with daily activities. Chronic pain is defined as persistent or recurrent pain lasting longer than 3 months, or pain lasting longer than 1 month due to the absorption of acute tissue damage or a wound that fails to heal. Causes include chronic diseases (such as cancer, arthritis, and diabetes), injuries (such as herniated discs, ligament tears), and many major pain disorders (such as neuropathic pain, fibromyalgia, and chronic headaches).

[0003] TRPM3 is a calcium adenosine monophosphate (Ca) involved in pain signal transduction. 2+ Permeable, non-selective cation channels, highly expressed in pain neurons of the dorsal root ganglion (DRG) and trigeminal ganglion, play a crucial role in pain perception and may be downstream targets of endogenous pain relief pathways. Animal data indicate that TRPM3 plays a role in spontaneous pain and thermal hyperalgesia in neuropathic pain, and TRPM3 located in the spinal cord, central processes, or DRG neuron cell bodies also plays an important role in regulating thermal sensitivity. Furthermore, studies have shown that CFA-induced inflammation and inflammatory pain are eliminated in TRPM3 knockout mice. Therefore, TRPM3 antagonists could be used as analgesics to combat pain, such as inflammatory pain. Summary of the Invention

[0004] The purpose of this invention is to provide a class of compounds that have antagonistic or inhibitory activity against TRPM3, and these compounds have good pharmacokinetic properties and bioavailability, oral performance and good safety.

[0005] This invention provides a compound or stereoisomer, tautomer, racemate, or pharmaceutically acceptable salt of general formula (I), wherein,

[0006] (I);

[0007] In some embodiments, the compound represented by formula (I) is selected from compounds represented by formulas (II), (III), (IV), (V) or (VI), (VII), (VIII), (IX). (II) (III) (IV) (V) (VI) (VII) (VIII) (IX);

[0008] In some embodiments, the compound represented by formula (I) is selected from the compound represented by formula (Ia). (Ia);

[0009] In some implementations, W is selected from C. 6-10 aryl, 5-10 heteroaryl, wherein W is optionally surrounded by 1 to 4 R w replace;

[0010] In some embodiments, W is selected from phenyl, W1, and the phenyl is optionally surrounded by 1 to 4 R atoms. w replace;

[0011] In some embodiments, W is selected from W1, W1 is selected from 5-6 heteroaryl groups, and W1 is optionally surrounded by 1 to 4 R groups. w replace;

[0012] In some implementations, W1 is selected from 1 to 4 Rs. w The following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0013] In some implementations, W1 is selected from 1 to 4 Rs. w The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , ;

[0014] In some implementation schemes, Selected from , , , , Its right side is connected to X;

[0015] In some implementations, X is selected from -(C=O)-, -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0016] In some implementations, X is selected from -(C=O)- or X1;

[0017] In some implementations, X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0018] In some implementations, X1 is selected from -(C=S)-, -S(=O)2-, -NH-(C=O)-(C=O)-, its right end is connected to Q;

[0019] In some implementations, X is selected from X1;

[0020] In some implementations, Y is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-O-(CR y1 R y2 ) m -、-S-(CR y1 R y2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -O-、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NRy -;

[0021] In some implementations, Y is selected from -O-(CR) y1 R y2 ) m -、-(CR y1 R y2 ) m -O-、Y1;

[0022] In some implementations, Y is selected from -O-(CR) y1 R y2 )-、-(CR y1 R y2 )-O-、Y1;

[0023] In some implementations, V is selected from -O-, -S-, -NR. y -;

[0024] In some embodiments, Y is selected from -O-CH2-, -CH2-O-, Y1, and the CH2 is optionally substituted with one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, or CH2F;

[0025] In some implementations, Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-S-(CR y1 R y2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -;

[0026] In some implementation schemes, Y is selected from Y1;

[0027] In some implementations, Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y-(C=O)-、-S-(CR y1 R y2 )-、-NR y -(CR y1 R y2 )-、-(CR y1 R y2 )2-、 , , 、-(CR y1 R y2 )-S-、-(CR y1 R y2 )-NR y -;

[0028] In some implementations, Y1 is selected from -CH=CH-, -(C=O)-NH, -NH-(C=O)-, -S-CH2-, -NR y -CH2-, -CH2CH2-, , , -CH2-S-, -CH2NR y - The =CH- and CH2 groups are optionally substituted with one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, or CH2F;

[0029] In some implementation schemes, R 6c R 4 The linked skeleton forms a 6- to 20-membered heterocycle, which is optionally divided by 1 to 6 R... k replace;

[0030] In some implementation schemes, R 6c R 4 The linked skeleton forms a ring B, which is selected from 6 to 20-membered heterocycles, wherein the heterocycle is optionally divided by 1 to 6 R... k replace

[0031] In some embodiments, ring B is selected from 6- to 18-membered heterocycles, which are optionally bounded by 1 to 6 R groups. k replace;

[0032] In some implementations, Z is selected from -C 1-12 Alkylene, wherein the alkylene group is optionally replaced by 1 to 6 groups of the following: -(C=O)-, -O-, -S-, -NR- y - The Z is arbitrarily selected by 1 to 5 R k replace;

[0033] In some embodiments, Z is selected from -(CH2CH2)2-, -(CH2CH2)3-, -(CH2CH2)4-, -(CH2CH2)5-, -(CH2CH2)6-, -(CH2CH2CH2)3-, -(CH2CH2CH2)-, -(CH2)5-, -(CH2)7-, wherein CH2 is optionally replaced by 1 to 4 of the following groups: -(C=O)-, -O-, -S-, -NR. y - The Z is arbitrarily selected by 1 to 5 R k replace;

[0034] In some implementations, Z is selected from -CH2OCH2CH2NR y CH2CH2NR y CH2-、-CH2OCH2CH2OCH2CH2NR y CH2-、-CH2OCH2CH2SCH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2CH2NR y CH2-,-CH2OCH2CH2CH2CH2CH2CH2NR y CH2-, -CH2OCH2CH2CH2CH2(C=O)-NR y CH2-, CH2OCH2CH2CH2CH2CH2(C=O)-NR y CH2-, wherein Z is optionally divided by 1 to 5 R k replace;

[0035] In some implementations, Z is selected from -CH2OCH2CH2NR y CH2CH2NR y CH2-、-CH2OCH2CH2OCH2CH2NR y CH2-、-CH2OCH2CH2SCH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2CH2NR y CH2-,-CH2OCH2CH2CH2CH2CH2CH2NR y CH2-, -CH2OCH2CH2CH2CH2(C=O)-NR y CH2-, CH2OCH2CH2CH2CH2CH2(C=O)-NR yCH2-, wherein Z is optionally substituted with 1 to 4 substituents of deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3, cyclopropyl, =O, =S;

[0036] In some implementations, ring A is selected from C. 3-8 Carbon rings, 4- to 8-membered heterocycles, wherein ring A is optionally divided by 1 to 4 R... k replace;

[0037] In some implementations, ring A is selected from C. 3-6 Monocycloalkyl, C 4-8 cycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Spirocycloalkyl, 4- to 7-membered monoheterocyclic, 4- to 8-membered fused heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered spiroheterocyclic, wherein ring A is optionally surrounded by 1 to 4 R k replace;

[0038] In some implementation schemes, Selected from 1 to 4 Rs k The following groups are substituted: , , ;

[0039] In some implementation schemes, R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace;

[0040] In some implementation schemes, R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace;

[0041] In some implementation schemes, R y1 R y2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, NHCH3, N(CH3)2, methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0042] In some implementation schemes, R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl or heterocycle is optionally surrounded by 1 to 4 R... k replace;

[0043] In some implementation schemes, R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl or 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl or heterocycle is optionally surrounded by 1 to 4 R... k replace;

[0044] In some implementation schemes, R y R 5 Each element is independently selected from H, deuterium, OH, or optionally coated with 1 to 4 R atoms. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxecyclopropyl; in some embodiments, R y R 5 Each is independently selected from H, methyl, CD3, CF3, CHF2, and CH2F;

[0045] In some implementations, Q is selected from NR. 5 R 6 or Or Q2;

[0046] In some implementations, Q is selected from -NH-R 6 or Or Q2;

[0047] In some implementations, Q is selected from... In this case, W is selected from W1, W1 is selected from 5-6 heteroaryl groups, and W1 is optionally surrounded by 1 to 4 R groups. w replace;

[0048] In some embodiments, Q1 is selected from nitrogen-containing 9- to 14-membered fused heterocyclic alkyl groups, nitrogen-containing 9- to 14-membered bridged heterocyclic alkyl groups, and nitrogen-containing 9- to 14-membered spirocyclic alkyl groups, wherein Q1 is optionally surrounded by 1 to 4 R groups. q replace;

[0049] In some implementations, Q1 is selected from , , , , , , , , , , , , , The Q1 is arbitrarily selected by 1 to 4 Rs q replace;

[0050] In some implementations, r1, r2, and r4 are each independently selected from 1 or 2; r5 is each independently selected from 3, 4, and 5; and r3 is selected from 2 or 3.

[0051] In some implementations, Q1 is selected from 1 to 4 Rs. q The following groups are substituted: , , , , , ;

[0052] In some embodiments, Q2 is selected from 4- to 9-membered heterocyclic groups, wherein Q2 is optionally divided by 1 to 4 R groups. q replace;

[0053] In some implementations, Q2 is selected from Q2 is selected from 4- to 9-membered heterocyclic groups, and Q2 is optionally divided by 1 to 4 R groups. q replace;

[0054] In some embodiments, Q2 is selected from aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, oxadiazine, tetrahydrofuranyl, etc. , , , , , , , The Q2 is arbitrarily divided by 1 to 4 Rs q replace;

[0055] In some implementations, Q2 is selected from 1 to 4 Rs. q The following substituents are substituted: , , , , , , , , , , ;

[0056] In some implementation schemes, R 6 Selected from , , , , , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R)6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-8 Carbon ring, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-6 alkyl)2, -C(R) 6c R 6d )-CONHC 1-6 Alkyl, -C 0-4 Alkylene-C 3-8 Carbon ring, -C 0-4 Alkylene-4 to 8-membered heterocycles, -C 0-4 Alkylene-C 3-8 Carbon ring-R q1 -C 0-4 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6 Choose from 1 to 4 Rs k replace;

[0057] In some implementation schemes, R 6 Selected from , R 6b The R 6 Choose from 1 to 4 Rs k replace;

[0058] In some implementation schemes, R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Carbon rings, 4- to 8-membered heterocycles, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 0-2 Alkylene-C 3-8 Carbon ring-R q1 -C 0-2 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6b Choose from 1 to 4 Rs k replace;

[0059] In some implementation schemes, R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d)-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 cycloalkyl, -C(R) 6c R 6d )-phenyl, -C(R 6c R 6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d )-C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic alkenyl, 4- to 8-membered heterocyclic alkyl, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 3-8 Carbon ring-R q1-4 to 8-membered heterocyclic -R q1 The R 6b Choose from 1 to 4 Rs k replace;

[0060] In some implementation schemes, R 6 Selected from or ;

[0061] In some implementation schemes, R 6b Selected from 1 to 4 Rs k The following groups are substituted: , , , , Azacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclohexyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, morpholinyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-cyclohexyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-morpholinyl, -C(R 6c R 6d )-phenyl, -C(R 6c R 6d )-pyridyl, -C(R 6c R 6d )-pyrrole, -C(R 6c R 6d )-pyrazolyl, -C(R 6c R 6d -imidazolium, -C(R) 6c R 6d )-triazolyl, -C(R 6c R 6d )-Tetrazolyl, -C(R 6c R 6d )-furanyl, -C(R 6c R 6d )-oxazolyl, -C(R 6c R 6d -isoxazole group, -C(R) 6c R 6d )-Oxadiazole group, -C(R 6c R 6d -thienyl, -C(R) 6c R 6d )-Thiazolyl, -C(R 6c R 6d -isothiazolyl, -C(R) 6c R 6d )-Thiadiazole group, , -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d -(C=O)N(methyl)2、-C(R) 6c R 6d )-(C=O)NH-methyl;

[0062] In some implementation schemes, R 6b Selected from , , , ;

[0063] In some implementation schemes, R 6b Selected from 1 to 3 Rs k The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0064] In some implementation schemes, R 6 Selected from , , , R 6b ;

[0065] In some implementation schemes, R 6a Selected from H, OH, CN, OC 1-6 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0066] In some implementation schemes, R 6a Selected from H, OH, CN, OC 1-4 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0067] In some implementation schemes, R 6a Each is independently selected from H, OH, CN, or arbitrarily selected by 1 to 4 Rs. k The following groups are substituted: methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl;

[0068] In some implementation schemes, R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6 Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0069] In some implementation schemes, R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-4 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6 Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0070] In some implementation schemes, R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxazolidine, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-aziridine, -CH2-oxazolidine, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-oxazolyl, -CH2CH2CH2-NH(C=NH)NH2, -CH2CH2-NH(C=O)NH2, -C H2-CONH2, -CH2-imidazolyl, -CH2-phenyl, -CH2NH(C=O)CH3, -CH2CH2-SCH3, -CH2SH, -CH2-OCH3, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxaziridine, imidazolyl, pyrazolyl, or oxazolyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0071] In some implementation schemes, R 6g R 6h Each independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0072] In some implementation schemes, R 6g R 6h Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0073] In some implementation schemes, R 6g R 6h Each of the following is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0074] In some implementation schemes, R 6c R 6d It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0075] In some implementation schemes, R 6c R 6d It forms C with the carbon atom it is attached to. 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0076] In some implementation schemes, R 6c R 6d The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0077] In some implementation schemes, R 6e R 6f It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0078] In some implementation schemes, R 6e R 6f And the atoms bonded to it form C 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0079] In some implementation schemes, R6e R 6f The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0080] In some implementation schemes, R 6g R 6h The atoms bonded to it form 4- to 10-membered heterocycles, which are optionally bonded by 1 to 4 R atoms. k replace;

[0081] In some implementation schemes, R 6g R 6h The carbon atom attached to it forms a 4- to 8-membered heterocycle, which is optionally surrounded by 1 to 4 R atoms. k replace;

[0082] In some implementation schemes, R 6g R 6h The atoms bonded to it form 4-, 5-, or 6-membered heterocyclic groups, wherein the heterocycle is optionally bonded by 1 to 4 R atoms. k replace;

[0083] In some implementation schemes, R 1 Selected from halogens, CN, OH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 3-6 cycloalkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)-C 3-10 Carbocyclic groups, -(C=O)-4 to 10-membered heterocyclic groups, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, R 1a The alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0084] In some implementation schemes, R 1 Selected from halogens, CN, OH, NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC3-6 cycloalkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)-C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)-C 3-6 Carbocyclic groups, -(C=O)-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, R 1a The alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0085] In some implementation schemes, R 1 Selected from F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, R 1a The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0086] In some implementation schemes, R 1 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, R 1a The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, and ethynyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0087] In some implementation schemes, R 1 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, CF3, CHF2, CH2F, CD3, R 1a ;

[0088] In some implementation schemes, R 1a Selected from 5-6 quinone heteroaryl groups, the R 1a Choose from 1 to 4 Rs k replace;

[0089] In some implementation schemes, R 1a Selected from 1 to 4 Rs kThe following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, isoxadiazolyl;

[0090] In some implementation schemes, R 1a Selected from 1 to 3 Rs k The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , ;

[0091] In some implementation schemes, R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl or -OC3-6 cycloalkyl or R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace;

[0092] In some implementation schemes, R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace;

[0093] In some implementation schemes, R 2 R 3 R 4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, or optionally under 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, R 1a ;

[0094] In some implementation schemes, R 2 R 3 R 4Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio;

[0095] In some implementation schemes, R 1 R 2 R 3 R 4 Each independently selected from R 1a ;

[0096] In some implementation schemes, R 2a Selected from R 2 ;

[0097] In some implementation schemes, R 3a Selected from R 3 ;

[0098] In some implementation schemes, R 4a Selected from R 4 ;

[0099] In some implementations, R in formula (IV) 2a R 3a R 4a R 1 At least one of the four is R. 1a ;

[0100] In some implementations, R in formula (IV) 2a R 3a R 4a R 1 One of the four is selected from R 1a The other three are selected from R 2 R 3 R 4 ;

[0101] In some implementation schemes, Selected from , , , Its right side is connected to X;

[0102] In some implementation schemes, R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-6Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0103] In some implementation schemes, R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0104] In some implementation schemes, R w R q R q1Each element is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)OCH3, or arbitrarily selected by 1 to 4 Rs. k The following groups are substituted: methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, -(C=O)NH-methyl, -(C=O)N(methyl)2;

[0105] In some implementation schemes, R w R q R q1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3, cyclopropyl, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH(CH3)2, -(C=O)OCH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, , , ;

[0106] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Cycloalkyl, -O-3 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0107] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-4 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Cycloalkyl, -O-4 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-4 to 7-membered heterocycles, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0108] In some implementation schemes, R k Each of the following groups is independently selected from: deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxygen Heterocyclic butyl, pyrrolyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxetanebutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxetanebutyl, pyrrolyl, piperidinyl, or morpholinyl group is optionally selected from 1 to 4 of the elements deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C. 1-4 Alkyl, C 1-4Substituents of alkoxy groups;

[0109] In some implementation schemes, R k Each of these compounds is independently selected from deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutylNHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCF3, -OCD3, -CH2OCH3, -CH2OH, -CH2CN, methyl, ethyl, propyl, isopropyl, methoxy The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, and methoxy groups;

[0110] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NO2, SF5, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, methoxy, ethoxy;

[0111] Optionally, general formula (I) must satisfy at least one of the following conditions:

[0112] 1) R 6 Selected from , , or ;

[0113] 2) Q is selected from In this case, W is selected from W1, W1 is selected from 5-6 heteroaryl groups, and W1 is optionally surrounded by 1 to 4 R groups. w replace;

[0114] 3) Y is selected from Y1, and Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-S-(CR y1 Ry2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -;

[0115] 4) X is selected from X1, and X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0116] 5) R 1 R 2 R 3 R 4 At least one of the four is selected from R. 1a ;

[0117] 6) R 6c R 4 The linked skeleton forms a ring B, which is selected from 6 to 20-membered heterocycles, wherein the heterocycle is optionally divided by 1 to 6 R... k replace.

[0118] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof...

[0119] W is selected from C 6-10 aryl, 5-10 heteroaryl, wherein W is optionally surrounded by 1 to 4 R w replace;

[0120] R 1 Selected from halogens, CN, OH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 3-6 cycloalkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)-C1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)-C 3-10 Carbocyclic groups, -(C=O)-4 to 10-membered heterocyclic groups, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, R 1a The alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0121] R 1a Selected from 5-6 quinone heteroaryl groups, the R 1a Choose from 1 to 4 Rs k replace;

[0122] X is selected from -(C=O)-, -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0123] Y is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-O-(CR y1 R y2 ) m -、-S-(CR y1 R y2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -O-、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -;

[0124] V is selected from -O-, -S-, -NR y -;

[0125] Q is selected from NR 5 R 6 , Or Q2;

[0126] Q1 is selected from nitrogen-containing 9- to 14-membered heterocyclic alkyl groups, nitrogen-containing 9- to 14-membered bridged heterocyclic alkyl groups, and nitrogen-containing 9- to 14-membered spirocyclic alkyl groups, wherein Q1 is optionally surrounded by 1 to 4 R groups. q replace;

[0127] Q2 is selected from 4- to 9-membered heterocyclic groups, wherein Q2 is optionally divided by 1 to 4 R groups. q replace;

[0128] R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace;

[0129] Ring A is selected from C 3-8 Carbon rings, 4- to 8-membered heterocycles, wherein ring A is optionally divided by 1 to 4 R... k replace;

[0130] R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0131] m is selected from 1, 2, 3, and 4;

[0132] R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl or heterocycle is optionally surrounded by 1 to 4 R... k replace;

[0133] R 6 Selected from , , , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R) 6c R 6d )-C(R 6c R 6d)-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-8 Carbon ring, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-6 alkyl)2, -C(R) 6c R 6d )-CONHC 1-6 Alkyl, -C 0-4 Alkylene-C 3-8 Carbon ring, -C 0-4 Alkylene-4 to 8-membered heterocycles, -C 0-4 Alkylene-C 3-8 Carbon ring-R q1 -C 0-4 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6 Choose from 1 to 4 Rs k replace;

[0134] R 6a Selected from H, OH, CN, OC 1-6 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0135] R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6 Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0136] As an option, R 6c R 6d It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0137] As an option, R 6e R 6f It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0138] R 6g R 6h Each independently selected from C 1-6 Alkyl, C 3-8Cycloalkyl or 4- to 10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0139] As an option, R 6g R 6h The atoms bonded to it form 4- to 10-membered heterocycles, which are optionally bonded by 1 to 4 R atoms. k replace;

[0140] As an option, R 6c R 4 The linked skeleton forms a 6- to 20-membered heterocycle, which is optionally divided by 1 to 6 R... k replace;

[0141] R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl or R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace;

[0142] R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-6 Alkyl, OC 1-6Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Cycloalkyl, -O-3 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0143] The condition is that general formula (I) satisfies at least one of the following conditions:

[0144] 1) R 6 Selected from , , or ;

[0145] 2) Q is selected from In this case, W is selected from W1, W1 is selected from 5-6 heteroaryl groups, and W1 is optionally surrounded by 1 to 4 R groups. w replace;

[0146] 3) Y is selected from Y1, and Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-S-(CR y1 R y2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -;

[0147] 4) X is selected from X1, and X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0148] 5) R 1 R 2 R 3 R 4 At least one of the four is selected from R. 1a ;

[0149] 6) R 6c R 4 The linked skeleton forms a ring B, which is selected from 6 to 20-membered heterocycles, wherein the heterocycle is optionally divided by 1 to 6 R... k replace.

[0150] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof...

[0151] W is selected from phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclic, benzo5- to 6-membered heteroaryl, wherein W is optionally surrounded by 1 to 4 R w replace;

[0152] Ring A is selected from C 3-6 Monocycloalkyl, C 4-8 cycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Spirocycloalkyl, 4- to 7-membered monoheterocyclic, 4- to 8-membered fused heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered spiroheterocyclic, wherein ring A is optionally surrounded by 1 to 4 R k replace;

[0153] R 1 Selected from halogens, CN, OH, NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 3-6 cycloalkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)-C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)-C 3-6 Carbocyclic groups, -(C=O)-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, R 1aThe alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace;

[0154] R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace;

[0155] R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0156] R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl or 3- to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, or heterocycle is optionally surrounded by 1 to 4 R...k replace;

[0157] R 6 Selected from , , , R 6b The R 6 Choose from 1 to 4 Rs k replace;

[0158] R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Carbon rings, 4- to 8-membered heterocycles, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 0-2 Alkylene-C 3-8 Carbon ring-R q1 -C 0-2 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6b Choose from 1 to 4 Rs k replace;

[0159] R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-4 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0160] As an option, R 6c R 6d It forms C with the carbon atom it is attached to. 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0161] As an option, R 6e R 6f And the atoms bonded to it form C 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace;

[0162] R 6g R 6h Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0163] As an option, R 6g R 6h The carbon atom attached to it forms a 4- to 8-membered heterocycle, which is optionally surrounded by 1 to 4 R atoms. k replace;

[0164] Alternatively, ring B is selected from 6- to 18-membered heterocycles, wherein the heterocycle is optionally bounded by 1 to 6 R... k replace;

[0165] R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace;

[0166] R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-4 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Cycloalkyl, -O-4 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-4 to 7-membered heterocycles, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-4Alkyl, C 1-4 Substituents of alkoxy groups;

[0167] The remaining definitions are the same as those in the first embodiment of the present invention.

[0168] As a third embodiment of the present invention, the compounds represented by the aforementioned general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, are used.

[0169] R 2a Selected from R 2 ;

[0170] R 3a Selected from R 3 ;

[0171] R 4a Selected from R 4 ;

[0172] And R 2a R 3a R 4a R 1 At least one of the four is R. 1a ;

[0173] X is selected from -(C=O)-, X1; X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q;

[0174] Z is selected from -C 1-12 Alkylene, wherein the alkylene group is optionally replaced by 1 to 6 groups of the following: -(C=O)-, -O-, -S-, -NR- y - The Z is arbitrarily selected by 1 to 5 R k replace;

[0175] Y is selected from -O-(CR) y1 R y2 ) m -、-(CR y1 R y2 ) m -O-、Y1;

[0176] Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-S-(CR y1 R y2 )m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -;

[0177] W is selected from phenyl, W1, wherein the phenyl group is optionally surrounded by 1 to 4 R groups. w replace;

[0178] W1 is selected from 1 to 4 R's. w The following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0179] Cycle A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, aziridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, wherein cycle A is optionally surrounded by 1 to 4 R... k replace;

[0180] m is selected from 1 and 2;

[0181] R 1 Selected from F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, R 1a The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0182] R 1a Selected from 1 to 4 Rs k The following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, isoxadiazolyl;

[0183] R y1R y2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, NHCH3, N(CH3)2, methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0184] R w R q R q1 Each element is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)OCH3, or arbitrarily selected by 1 to 4 Rs. k The following groups are substituted: methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, -(C=O)NH-methyl, -(C=O)N(methyl)2;

[0185] R 2 R 3 R 4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, or optionally under 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, R 1a ;

[0186] R y R 5 Each element is independently selected from H, deuterium, OH, or optionally coated with 1 to 4 R atoms. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxecyclopropyl;

[0187] R 6a Selected from H, OH, CN, OC 1-4 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0188] R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 cycloalkyl, -C(R) 6c R 6d )-phenyl, -C(R 6c R 6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d )-C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic alkenyl, 4- to 8-membered heterocyclic alkyl, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 3-8 Carbon ring-R q1 -4 to 8-membered heterocyclic -R q1 The R 6b Choose from 1 to 4 Rs k replace;

[0189] Q1 is selected from , , , , , , , , , , , , , The Q1 is arbitrarily selected by 1 to 4 Rs q replace;

[0190] Q2 is selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxocyclic butyl, tetrahydrofuranyl, etc. , , , , , , , The Q2 is arbitrarily divided by 1 to 4 Rs q replace;

[0191] r1, r2, and r4 are each independently selected from 1 or 2;

[0192] r5 is selected independently from 3, 4, and 5;

[0193] r3 is selected from 2 or 3;

[0194] R k Each of the following groups is independently selected from: deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxygen Heterocyclic butyl, pyrrolyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxetanebutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxetanebutyl, pyrrolyl, piperidinyl, or morpholinyl group is optionally selected from 1 to 4 of the elements deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0195] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0196] As a fourth embodiment of the present invention, the compounds represented by the aforementioned general formulas (I), (II), (III), (IV), (V), (VII), (VIII), (Ia), and (IX), or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, are used.

[0197] Selected from , , , Its right side is connected to X;

[0198] W1 is selected from 1 to 4 R's. w The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , ;

[0199] Z is selected from -(CH2CH2)2-, -(CH2CH2)3-, -(CH2CH2)4-, -(CH2CH2)5-, -(CH2CH2)6-, -(CH2CH2CH2)3-, -(CH2CH2CH2)-, -(CH2)5-, -(CH2)7-, wherein CH2 is optionally replaced by 1 to 4 of the following groups: -(C=O)-, -O-, -S-, -NR. y - The Z is arbitrarily selected by 1 to 5 R k replace;

[0200] Y is selected from -O-(CR) y1 R y2 )-、-(CR y1 R y2 )-O-、Y1;

[0201] Y1 is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-S-(CR y1 R y2 )-、-NR y -(CR y1 R y2 )-、-(CR y1 R y2 )2-、 , , 、-(CR y1 R y2 )-S-、-(CR y1 R y2 )-NR y -;

[0202] R 6a Each is independently selected from H, OH, or optionally influenced by 1 to 4 R groups. k The following groups are substituted: methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl;

[0203] R 6b Selected from 1 to 4 Rs k The following groups are substituted: , , , , Azacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclohexyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, morpholinyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-cyclohexyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-morpholinyl, -C(R 6c R 6d )-phenyl, -C(R 6c R 6d )-pyridyl, -C(R 6c R 6d )-pyrrole, -C(R 6c R 6d )-pyrazolyl, -C(R 6c R 6d -imidazolium, -C(R) 6c R 6d )-triazolyl, -C(R 6c R 6d )-Tetrazolyl, -C(R 6c R 6d )-furanyl, -C(R 6c R 6d )-oxazolyl, -C(R 6c R 6d -isoxazole group, -C(R) 6c R 6d )-Oxadiazole group, -C(R 6c R 6d -thienyl, -C(R) 6c R 6d )-Thiazolyl, -C(R 6c R 6d -isothiazolyl, -C(R) 6c R 6d )-Thiadiazole group, , -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d -(C=O)N(methyl)2、-C(R) 6c R 6d )-(C=O)NH-methyl;

[0204] R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxazolidine, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-aziridine, -CH2-oxazolidine, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-oxazolyl, -CH2CH2CH2-NH(C=NH)NH2, -CH2CH2-NH(C=O)NH2, -C H2-CONH2, -CH2-imidazolyl, -CH2-phenyl, -CH2NH(C=O)CH3, -CH2CH2-SCH3, -CH2SH, -CH2-OCH3, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxaziridine, imidazolyl, pyrazolyl, or oxazolyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0205] As an option, R 6c R 6d The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0206] As an option, R 6e R 6f The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0207] R 6g R 6h Each of the following is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace;

[0208] As an option, R 6g R 6hThe atoms bonded to it form 4-, 5-, or 6-membered heterocyclic groups, wherein the heterocycle is optionally bonded by 1 to 4 R atoms. k replace;

[0209] Q1 is selected from 1 to 4 R's. q The following groups are substituted: , , , , , ;

[0210] R k Each of these compounds is independently selected from deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutylNHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCF3, -OCD3, -CH2OCH3, -CH2OH, -CH2CN, methyl, ethyl, propyl, isopropyl, methoxy The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, and methoxy groups;

[0211] The remaining definitions are the same as those in the first, second, or third embodiments of the present invention.

[0212] As a fifth embodiment of the present invention, the compounds represented by the aforementioned general formulas (I), (II), (III), (IV), (V), (VII), (VIII), (Ia), and (IX), or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts,

[0213] Y is selected from -O-CH2-, -CH2-O-, Y1, wherein the CH2 is optionally replaced by one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, CH2F;

[0214] Y1 is selected from -CH=CH-, -(C=O)-NH, -NH-(C=O)-, -S-CH2-, -NR y-CH2-, -CH2CH2-, , , -CH2-S-, -CH2NR y - The =CH- and CH2 groups are optionally substituted with one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, or CH2F;

[0215] Z is selected from -CH2OCH2CH2NR y CH2CH2NR y CH2-、-CH2OCH2CH2OCH2CH2NR y CH2-、-CH2OCH2CH2SCH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2CH2NR y CH2-,-CH2OCH2CH2CH2CH2CH2CH2NR y CH2-, -CH2OCH2CH2CH2CH2(C=O)-NR y CH2-, CH2OCH2CH2CH2CH2CH2(C=O)-NR y CH2-, wherein Z is optionally divided by 1 to 5 R k replace;

[0216] X1 is selected from -(C=S)-, -S(=O)2-, -NH-(C=O)-(C=O)-, its right end is connected to Q;

[0217] Selected from 1 to 4 Rs k The following groups are substituted: , , ;

[0218] R 1a Selected from 1 to 3 Rs k The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , ;

[0219] R y R 5 Each is independently selected from H, methyl, CD3, CF3, CHF2, and CH2F;

[0220] R w R q R q1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3, cyclopropyl, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH(CH3)2, -(C=O)OCH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, , , ;

[0221] Q2 is selected from any of the 1 to 4 R's. q The following substituents are substituted: , , , , , , , , , , ;

[0222] R 6 Selected from , , , , , R 6b ;

[0223] R 6b Selected from 1 to 3 Rs k The following groups are substituted: , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0224] R 2 、R 3 、R4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio;

[0225] R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, NO2, SF5, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, methoxy, ethoxy;

[0226] The remaining definitions are the same as those in the first, second, third, or fourth embodiments of this invention.

[0227] This invention relates to a compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the structures shown in Table E-1.

[0228] This invention relates to a pharmaceutical composition comprising the above-described compound or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0229] This invention relates to the use of the above-mentioned compounds or their stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of drugs that inhibit or antagonize TRPM3.

[0230] This invention relates to the use of the above-described compounds or their stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the above-described pharmaceutical compositions in the preparation of a treatment for pain disorders, preferably migraines.

[0231] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutical excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength").

[0232] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or pharmaceutical compositions. In some embodiments, the mammals described in the present invention include humans.

[0233] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will, to some extent, alleviate one or more symptoms of the disease or condition being treated (e.g., migraine). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg. 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-5 00mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 200-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30 -400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 150-400mg, 200-400mg, 250-400mg , 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75 -300mg, 80-300mg, 90-300mg, 125-300mg, 200-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30- 200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;

[0234] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-800 mg, 1-600 mg, 20-400 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, and 300 mg of the compound of the present invention or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0235] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably migraine.

[0236] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses, and in some embodiments, the daily dose including but not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, etc. 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, and 800mg / day.

[0237] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, wherein the amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is the same as the amount in the aforementioned pharmaceutical composition.

[0238] In this invention, the amount of the compound of the invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is converted in each case as a free base.

[0239] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0240] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0241] The compounds of this invention include their racemic, stereoisomer, tautomer, isotopic compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0242] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0243] “CN” refers to cyano.

[0244] "Halogen" refers to F, Cl, Br or I.

[0245] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0246] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0247] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2)d v - (dv is an integer from 1 to 10), alkylene examples include but are not limited to methylene, ethylene, propylene, and butylene.

[0248] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutylspirobutyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0249] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, S, and Se on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. , , , , , , , Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0250] "Cycloalkenyl" refers to a substituted or unsubstituted partially unsaturated carbocyclic hydrocarbon group, typically with 3 to 12 carbon atoms, and at least one carbon-carbon double bond within the ring, usually with 1, 2, or 3 carbon-carbon double bonds. Cycloalkenyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutyl-cyclobutenyl, cyclobutenylspirocyclobutyl, etc. Cycloalkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0251] "Heterocyclic alkenyl" refers to a substituted or unsubstituted partially unsaturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, S, and Se on the ring of the heterocyclic alkenyl can be oxidized to various oxidation states, and it has at least one, usually 1, 2, or 3, double bonds within the ring. Heterocyclic alkenyl can be monocyclic, fused, bridged, or spirocyclic. The heterocyclic alkenyl can be attached to a heteroatom or a carbon atom. Non-limiting examples include oxehexyl, oxehexenyl, oxehexenyl, azirhexenyl, azirhexenyl, etc. Heterocyclic alkenyl can be monovalent, divalent, trivalent, or tetravalent.

[0252] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0253] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0254] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0255] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. , , or "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0256] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, , , , , , , , , , , , , , , , , , , , , , , "Heterocyclic group" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0257] "Spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O, or S (=O). dn Heteroatoms (dn is 0, 1, or 2). Non-limiting embodiments include: "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0258] "Burying" or "burying group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in the burying system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). dn (Or O, dn is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: A "cyclic compound" or "cyclic base" can be monovalent, divalent, trivalent, or tetravalent.

[0259] A "bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain zero or more double bonds. Any ring in a bridged ring system may contain zero to five groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=O)). dn Or O, where dn is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0260] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0261] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0262] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0263] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0264] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0265] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0266] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0267] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linker site is located on the aryl ring.

[0268] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S (=O)). dn OrSe(=O) dn (dn is 0, 1, or 2), the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)). dm Se (=O) dm (dm is 1, 2), non-limiting embodiments of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: , , The definition of heteroaryl groups used in this paper is consistent with that in this paper. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When they are divalent, trivalent, or tetravalent, the linking site is located on an aromatic ring.

[0269] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2). dn -C(=O)-R da -O-(CH2) dn -C(=O)-R da -(CH2) dn -C(=O)-NR db R dc -(CH2) dn S(=O) dn R da -(CH2) dn -Alkenyl-R da OR dd Or -(CH2) dn -alkynyl-R da (where dn is 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR db R dc Groups, wherein R db With R dc Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R db With R dc It can form five- or six-membered cycloalkyl or heterocyclic groups, R da With R dd Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0270] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0271] The XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered elements. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0272] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …. C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0273] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes .For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula fragment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... , When X is selected from NH, the general formula fragment can be: .

[0274] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a solid line key (). ) and straight dashed line key ( ) indicates the relative configuration of the solid center.

[0275] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0276] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0277] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0278] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or their stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents. "Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound.

[0279] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0280] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0281] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0282] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers.

[0283] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0284] IC 50 "It refers to the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of that process, such as an enzyme, receptor, or cell) by half."

[0285] General formula synthesis method one:

[0286]

[0287] General formula compound Z-1 and Z-2 are reacted by condensation to prepare general formula compound Z-3; general formula compound Z-3 is reacted with Lawson's reagent to prepare general formula compound Z-4; general formula compound Z-4 is hydrolyzed to prepare general formula compound Z-5; general formula compound Z-5 is reacted by condensation or substitution to prepare general formula compound Z-6; general formula compound Z-6 is deprotected by a hydroxyl protecting group to prepare general formula compound Z-7.

[0288] General formula synthesis method two:

[0289]

[0290] The general formula compound Z-1 and Z-1-1 were combined by a condensation reaction to obtain the general formula compound Z-8;

[0291] General formula synthesis method three:

[0292]

[0293] General formula compound Z-9 was used to prepare general formula compound Z-10 via a coupling reaction;

[0294] General formula compound Z-12 was prepared by reacting general formula compound Z-10 and general formula compound Z-11 through an olefin metathesis reaction.

[0295] R m1 Selected from hydroxyl protecting groups such as TBS, TBDPS, and Bn, R m2 Selected from methyl, ethyl, isopropyl, etc., R m3 The groups are selected from OTf, Br, I, Cl, etc., and the definitions of the remaining groups are the same as those in the specification and claims. Detailed Implementation

[0296] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0297] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0298] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0299] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0300] Thin-layer chromatography silica gel plates used were from Yantai Huanghai HSGF. 254 Or Qingdao GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.20 mm, while the diameter used for TLC separation and purification of products is 0.4 mm to 0.5 mm.

[0301] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0302] The starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0303] Example 1: Preparation of Compound 1

[0304]

[0305] Step 1: Preparation of 1B

[0306] 1A (110 mg, 0.36 mmol) was dissolved in 8 mL of DMF, and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (120 mg, 0.54 mmol), HATU (0.27 g, 0.54 mmol), and diisopropylethylamine (0.14 g, 1.08 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with 20 mL of ethyl acetate, washed once with 20 mL of water, and extracted once with 20 mL of ethyl acetate. The organic phases were combined and washed twice with water (20 mL × 2), and once with a saturated NaCl aqueous solution (20 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 1B (75 mg, yield: 40.42%).

[0307] LCMS m / z = 512.3 [M+H] +

[0308] Step 2: Preparation of Compound 1

[0309] 1B (75 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to obtain target compound 1 (40 mg, yield: 66.31%).

[0310] LCMS m / z = 412.2 [M+H] +

[0311] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.46 (d, 1H), 7.01 – 6.91 (m, 2H), 5.31 (s, 2H), 3.64 – 3.31 (m, 9H), 2.42 (s, 3H), 2.40 (s, 3H), 1.78– 1.54 (m, 4H).

[0312] Example 2: Preparation of Compound 2

[0313]

[0314] The target compound 2 (43 mg) was prepared from tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate as a starting material, following the synthesis method of Example 1.

[0315] LCMS m / z = 412.2 [M+H] +

[0316] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.46 (d, 1H), 7.11 (d, 1H), 6.95 (dd, 1H), 5.33 (s, 2H), 3.83 – 3.58 (m, 4H), 2.70 – 2.54 (m, 4H), 2.51(s, 3H), 2.42 (s, 3H), 1.67 – 1.56 (m, 4H).

[0317] Example 3: Preparation of Compound 3

[0318]

[0319] Compound 3 (55 mg) was prepared using 3A as the raw material, following the preparation method in Example 1.

[0320] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 25% to 70% c. Flow rate: 12ml / min d. Elution time: 15min.

[0321] LCMS m / z = 409.2 [M+H] +

[0322] 1 H NMR (400 MHz, CD3OD) δ 7.55 – 7.47 (m, 1H), 7.41 – 7.31 (m, 2H), 7.22 – 7.08 (m, 2H), 7.02 – 6.93 (m, 2H), 5.16 (s, 2H), 3.86 – 3.39 (m, 8H), 2.45 (s, 3H), 2.03 – 1.62 (m, 4H).

[0323] Example 4: Preparation of Compound 4

[0324]

[0325] Compound 4 (53 mg, 52.79%) was prepared using 3A as the raw material, following the preparation method in Example 1.

[0326] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 25% to 70% c. Flow rate: 12ml / min d. Elution time: 15min.

[0327] LCMS m / z = 409.2 [M+H] +

[0328] 1 H NMR (400 MHz, CD3OD) δ 7.55 – 7.48 (m, 1H), 7.40 – 7.31 (m, 2H), 7.21 – 7.08 (m, 3H), 6.98 (dd, 1H), 5.18 (s, 2H), 4.02 – 3.69 (m, 4H), 2.97 –2.76 (m, 4H), 2.52 (s, 3H), 1.91 – 1.77 (m, 4H).

[0329] Example 5: Preparation of Compound 5

[0330]

[0331] Step 1: Preparation of 5A

[0332] 3A (110 mg, 0.36 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (100 mg, 0.54 mmol), HATU (0.27 g, 0.72 mmol), and diisopropylethylamine (93 mg, 0.72 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with 25 mL of ethyl acetate, washed once with 25 mL of water, and extracted once with 25 mL of ethyl acetate. The organic phases were combined and washed twice with water (25 mL × 2), and once with a saturated NaCl aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 5A (100 mg, yield: 58.48%).

[0333] LCMS m / z = 469.1 [M+H] +

[0334] Step 2: Preparation of 5B

[0335] 5A (200 mg, 0.43 mmol) was dissolved in 15 mL of toluene, and Lawson's reagent (350 mg, 0.86 mmol) was added. The mixture was reacted at 100 °C for 2 hours. After cooling to room temperature, the residue was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 5B (70 mg, yield: 33.84%).

[0336] LCMS m / z = 485.1 [M+H] +

[0337] Step 3: Preparation of Compound 5

[0338] 5B (70 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to obtain target compound 5 (15 mg, yield: 27.01%).

[0339] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 25% to 70% c. Flow rate: 12ml / min d. Elution time: 15min.

[0340] LCMS m / z = 385.2 [M+H] +

[0341] 1 H NMR (400 MHz, CD3OD) δ 7.53 (t, 1H), 7.40 – 7.27 (m, 3H), 7.22 –7.08 (m, 2H), 6.94 (dd, 1H), 5.15 (s, 2H), 5.11 – 5.02 (m, 1H), 3.46 – 3.36(m, 1H), 3.18 – 2.90 (m, 3H), 2.55 (s, 3H), 2.40 – 2.27 (m, 1H), 1.99 – 1.88(m, 1H).

[0342] Example 6: Preparation of Compound 6

[0343]

[0344] Following the synthetic route of compound 5, target compound 6 (32 mg) was prepared.

[0345] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 25% to 70% c. Flow rate: 12ml / min d. Elution time: 15min.

[0346] LCMS m / z = 388.2 [M+H] +

[0347] 1 H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 7.40 – 7.30 (m, 2H), 6.93 (dd,1H), 5.29 (s, 2H), 5.14 – 5.02 (m, 1H), 3.46 – 3.36 (m, 1H), 3.17 – 2.91 (m,3H), 2.54 (s, 3H), 2.46 (s, 3H), 2.46 – 2.39 (m, 1H), 2.01 – 1.87 (m, 1H).

[0348] Example 7: Preparation of Compound 7

[0349]

[0350] Step 1 and Step 2: Preparation of 7c

[0351] The first and second steps of the synthetic route for compound 7 can be referred to the first and second steps of the synthetic route for compound 5, yielding compound 7c (100 mg, yield: 71.53%).

[0352] LCMS m / z = 468.1 [M+H] +

[0353] Step 3: Preparation of Compound 7

[0354] Compound 7c (100 mg, 0.21 mmol) was placed in a 12 mL sealed tube, and 3 mL of ammonia-methanol solution (7.0 mL Solution In MeOH, Water ≤ 0.1%, SpcSeal) was added. The reaction mixture was reacted overnight at 80 °C. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the residue was prepared by preparative liquid chromatography to give compound 7 (12 mg, 12.40%).

[0355] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: Water (containing 10 mmol / L ammonium bicarbonate); Mobile phase B: Acetonitrile b. Gradient elution, with mobile phase B content ranging from 35% to 65% c. Flow rate: 25 ml / min d. Elution time: 14 min.

[0356] LCMS m / z = 453.1 [M+H] +

[0357] 1 H NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 7.54 (t, 1H), 7.39 – 7.33 (m,2H), 7.30 (d, 1H), 7.19 (t, 1H), 7.16 – 7.09 (m, 1H), 6.96 (s, 1H), 6.91 (dd,1H), 5.57 (dd, 1H), 5.09 (s, 2H), 3.29 – 3.20 (m, 2H), 2.48 (s, 3H).

[0358] Example 8: Preparation of Compound 8

[0359]

[0360] Step 1: Preparation of Compound 8A

[0361] 5B (160 mg, 0.33 mmol) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (10 / 1), and then 50 mg of solid sodium bicarbonate was added and stirred for 20 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 8A (130 mg, crude).

[0362] LCMS m / z = 385.2 [M+H]+

[0363] Step 2: Preparation of Compound 8

[0364] Dissolve 8A (130 mg, 0.34 mmol) in 4 mL of DMF, then add 2,2-difluorocyclopropanecarboxylic acid (50 mg, 0.41 mmol), HATU (190 mg, 0.51 mmol), and DIPEA (130 mg, 1.02 mmol) sequentially. React at room temperature for 2 hours. Dilute with 20 mL of ethyl acetate, wash once with 20 mL of water, and extract the aqueous phase once with 20 mL of ethyl acetate. Combine the organic phases, and wash twice with water (20 mL × 2), and once with 20 mL of saturated NaCl aqueous solution. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase reaction to obtain compound 8, which was then chirally resolved to obtain compounds 8-P1 (39 mg, yield: 23.61%; analytical retention time Rt = 1.704 min) and 8-P2 (43 mg, yield: 26.03%; analytical retention time Rt = 2.974 min). One of compounds 8-P1 and 8-P2 is structure 8-a, and the other is structure 8-b.

[0365] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 5 mmol / L ammonium bicarbonate) b. Gradient elution, with mobile phase A content ranging from 45% to 85% c. Flow rate: 15 ml / min d. Elution time: 16 min.

[0366] Chiral analysis method: 1. Instrument: CAS-05-ANA-HPLC-E; Column: IH column; 2. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: n-hexane; Mobile phase B: a mixture of ethanol and acetonitrile (containing 0.1% IPAm); Flow rate: 1 ml / min; Column temperature: 35℃; Detection wavelength: 220 nm.

[0367] Chiral preparation method: 1. Instrument: CAS-05-Prep-NPLC-D; Column: IH column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 5 mg / ml. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: n-hexane; Mobile phase B: a mixture of ethanol and acetonitrile (v / v = 4 / 1) (containing 0.1% ammonia); b. Flow rate: 90 ml / min.

[0368] Compound 8-P1: LCMS m / z = 489.2 [M+H] +

[0369] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (dd, 1H), 7.57 (t, 1H), 7.46 (dd,1H), 7.44 – 7.38 (m, 1H), 7.34 – 7.29 (m, 1H), 7.28 – 7.19 (m, 2H), 7.00 –6.94 (m, 1H), 5.14 (d, 2H), 5.10 – 4.94 (m, 1H), 3.98 – 3.84 (m, 1H), 3.83 –3.74 (m, 1H), 3.74 – 3.56 (m, 1H), 3.55 – 3.47 (m, 1H), 3.02 – 2.91 (m, 1H),2.53 (s, 3H), 2.44 – 2.10 (m, 2H), 1.98 – 1.76 (m, 2H).

[0370] Compound 8-P2:

[0371] LCMS m / z = 489.2 [M+H] +

[0372] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (dd, 1H), 7.57 (dd, 1H), 7.46 (d,1H), 7.44 – 7.39 (m, 1H), 7.29 (t, 1H), 7.27 – 7.21 (m, 2H), 6.99 – 6.94 (m,1H), 5.13 (d, 2H), 5.08 – 4.96 (m, 1H), 4.09 – 3.80 (m, 1H), 3.78 – 3.71 (m,1H), 3.68 – 3.44 (m, 2H), 3.01 – 2.87 (m, 1H), 2.49 (s, 3H), 2.40 – 2.07 (m,2H), 1.97 – 1.74 (m,2H).

[0373] Example 9: Preparation of Compound 9

[0374]

[0375] Step 1: Preparation of 9C

[0376] (S)-3-tert-butoxycarbonylaminopyrrolidine 9B (300 mg, 1.61 mmol) was dissolved in 6 mL of DMF. Sodium hydride (60%) (84 mg, 2.09 mmol) was added under ice bath conditions, replacing the atmosphere with nitrogen. After 15 minutes, a DMF solution of 9A (920 mg, 2.42 mmol) (3 mL) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 5 hours. The reaction was quenched with 20 mL of water, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then separated by silica gel column chromatography to obtain 9C (184 mg, yield: 42.58%).

[0377] LCMS m / z = 269.1 [M+H] +

[0378] Step 2: Preparation of compound 9D

[0379] 9C (183 mg, 0.68 mmol) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (10 / 1), and then 50 mg of solid sodium bicarbonate was added and stirred for 20 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 9D (120 mg, crude product).

[0380] LCMS m / z = 169.0 [M+H] +

[0381] Step 3: Preparation of 9E

[0382] 9D (120 mg, 0.71 mmol) was dissolved in 4 mL of DMF, and intermediate 3A (210 mg, 0.71 mmol), HATU (400 mg, 1.06 mmol), and DIPEA (280 mg, 2.13 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with 20 mL of ethyl acetate and washed once with 20 mL of water. The aqueous phase was extracted once with 20 mL of ethyl acetate. The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 9E (147 mg, yield: 45.73%).

[0383] LCMS m / z = 450.9 [M+H] +

[0384] Step 4: Preparation of Compound 9

[0385] 9E (147 mg, 0.33 mmol) was dissolved in 6 mL of toluene, and Lawson's reagent (270 mg, 0.66 mmol) was added. The mixture was reacted at 100 °C for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted three times with 20 mL of ethyl acetate. The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated aqueous solution of NaCl (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was prepared by reverse phase reaction and lyophilized to give trifluoroacetate of compound 9 (99 mg, yield: 65.03%).

[0386] Preparation Method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 10% to 70% c. Flow rate: 15 ml / min d. Elution time: 25 min.

[0387] LCMS m / z = 467.2 [M+H] +

[0388] 1H NMR (400 MHz, CD3OD) δ 7.57 – 7.50 (m, 2H), 7.41 – 7.34 (m, 1H), 7.24 – 7.16 (m, 2H), 7.16 – 7.10 (m, 2H), 5.20 (s, 2H), 4.41 – 4.13 (m, 2H), 4.09 – 3.83 (m, 3H), 3.05 – 2.85 (m, 2H), 2.57 (d, 3H), 2.45 – 2.21 (m, 2H).

[0389] Example 10: Preparation of Compound 10

[0390]

[0391] Step 1: Preparation of 10A

[0392] 3A (250 mg, 0.83 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and (2R,4S)-1-tert-butyl-2-methyl-4-aminopyrrolidine-1,2-dicarboxylate (240 mg, 1.0 mmol), HATU (0.38 g, 1.0 mmol), and DIPEA (320 mg, 2.49 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. The solution was diluted with 100 mL of ethyl acetate, washed once with 100 mL of water, and extracted once with 100 mL of ethyl acetate. The organic phases were combined and washed twice with water (100 mL × 2), and once with saturated NaCl aqueous solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 10A (0.41 g, yield: 93.53%).

[0393] LCMS m / z = 527.2 [M+H] +

[0394] Step 2: Preparation of 10B

[0395] 10A (0.35 g, 0.66 mmol) was dissolved in 15 mL of toluene, and Lawson's reagent (0.53 g, 1.32 mmol) was added. The mixture was reacted at 100 °C for 0.5 h. After cooling to room temperature, the residue was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 10B (0.21 g, yield: 58.22%).

[0396] LCMS m / z = 543.2 [M+H] +

[0397] Step 3: Preparation of 10C

[0398] 10B (0.21 g, 0.39 mmol) was dissolved in 6 mL of THF and 2 mL of water, and lithium hydroxide (19 mg, 0.78 mmol) was added. The reaction was carried out at room temperature for 12 hours. The pH was adjusted to approximately 5 with 1N hydrochloric acid, diluted with 100 mL of ethyl acetate, washed once with 100 mL of water, and extracted once with 100 mL of ethyl acetate. The organic phases were combined and washed twice with water (100 mL × 2), and once with 100 mL of saturated NaCl aqueous solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was separated by silica gel column chromatography to obtain the target compound 10C (180 mg, yield: 87.99%).

[0399] LCMS m / z = 529.0 [M+H] +

[0400] Step 4: Preparation of 10D

[0401] 10C (0.17 g, 0.32 mmol) was dissolved in 8 mL of N,N-dimethylformamide, followed by the addition of ammonium chloride (0.17 g, 3.2 mmol), HATU (0.15 g, 0.38 mmol), and DIPEA (0.12 g, 0.96 mmol). The reaction was carried out at room temperature for 2 hours. The solution was diluted with 100 mL of ethyl acetate, washed once with 100 mL of water, and extracted once with 100 mL of ethyl acetate. The organic phases were combined and washed twice with water (100 mL × 2), and once with a saturated NaCl aqueous solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 10D (0.15 g, yield: 88.40%).

[0402] LCMS m / z = 528.0 [M+H] +

[0403] Step 5: Preparation of Compound 10

[0404] 10D (0.15 g, 0.28 mmol) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure, and the crude product was prepared by lyophilization to give compound 10 (35 mg, yield: 28.80%).

[0405] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 30% to 70%; c. Flow rate: 15ml / min; d. Elution time: 15min.

[0406] LCMS m / z = 428.1 [M+H] +

[0407] 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (d, 1H), 7.60 – 7.54 (m, 1H), 7.46(d, 1H), 7.44 – 7.35 (m, 2H), 7.32 (d, 1H), 7.29 – 7.21 (m, 2H), 7.04 (s,1H), 6.97 (dd, 1H), 5.15 (s, 2H), 4.91 – 4.82 (m, 1H), 3.68 (t, 1H), 3.19(dd, 1H), 3.09 – 2.77 (m, 2H), 2.52 (s, 3H), 2.21 – 2.07 (m, 2H).

[0408] Example 11: Preparation of Compound 11

[0409]

[0410] Following the synthetic route of compound 5, compound 11 (35 mg) was prepared.

[0411] LCMS m / z = 413.3 [M+H] +

[0412] 1H NMR (400 MHz, CD3OD) δ 7.51 (t, 1H), 7.39 – 7.30 (m, 2H), 7.21 – 7.09 (m, 2H), 7.05 – 6.83 (m, 2H), 5.19 – 5.12 (m, 2H), 4.78 – 4.51 (m, 1H),4.11 – 3.75 (m, 1H), 3.72 – 3.57 (m, 1H), 3.45 – 3.34 (m, 2H), 3.10 – 2.99(m, 1H), 2.43 (d, 3H), 1.25 – 1.18 (m, 3H), 0.92 (dd, 3H).

[0413] Example 12: Preparation of Compound 12

[0414]

[0415] Step 1: Preparation of 12A

[0416] 3A (500 mg, 1.67 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and tert-butyl 4-amino-3,3-difluoro-1-piperidinecarboxylate (510 mg, 2.17 mmol), HATU (0.95 g, 2.50 mmol), and DIPEA (0.65 g, 5.01 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with 40 mL of ethyl acetate, washed once with 40 mL of water, and extracted once with 40 mL of ethyl acetate. The organic phases were combined and washed twice with water (40 mL × 2), and once with a saturated NaCl aqueous solution (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 12A (510 mg, yield: 59.07%).

[0417] LCMS m / z = 463.2 [M+H-56] +

[0418] Step 2: Preparation of 12B

[0419] 12A (500 mg, 0.96 mmol) was dissolved in 40 mL of toluene, and Lawson's reagent (0.58 g, 1.44 mmol) was added. The mixture was reacted at 100 °C for 15 min. After cooling to room temperature, the residue was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 12B (415 mg, yield: 80.50%).

[0420] LCMS m / z = 535.1 [M+H] +

[0421] Step 3: Preparation of Compound 12

[0422] 12B (415 mg, 0.78 mmol) was dissolved in 15 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure. The residue was separated by silica gel column chromatography to obtain 220 mg of crude compound 12. The crude product was purified by SFC to obtain compound 12-P1 (68.9 mg, yield: 20.43%; analytical retention time: Rt = 1.447 min) and compound 12-P2 (70.3 mg, yield: 20.84%; analytical retention time: Rt = 1.733 min). One of the compounds 12-P1 is structure 12-a, and the other is structure 12-b.

[0423] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-C; Column: AD column; 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: Ethanol containing 0.5% DEA b. Flow rate: 3 mL / min, Column temperature: 35℃; Detection wavelength: 220 nm.

[0424] Preparation method: 1. Instrument: CAS-05-Prep-SFC-C; Column: AD column; 2. The sample was dissolved in acetonitrile and methanol to a concentration of 20 mg / ml, and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: Ethanol containing 0.1% ammonia; b. Flow rate: 100 mL / min.

[0425] Compound 12-P1: LCMS m / z = 435.1 [M+H] +

[0426] 1H NMR (400 MHz, CD3OD) 6.94 (dd, 1H), 5.47 – 5.33 (m, 1H),5.14 (s, 2H), 3.29 – 3.22 (m, 1H), 3.15 – 3.06 (m, 1H), 2.98 (dd, 1H), 2.83 –2.73 (m, 1H), 2.58 (s, 3H), 2.20 – 2.10 (m, 1H), 1.90 – 1.76 (m, 1H).

[0427] Compound 12-P2: LCMS m / z = 435.1 [M+H] +

[0428] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.48 (t, 1H), 7.41 (d, 1H), 7.39 –7.28 (m, 2H), 7.17 (t, 1H), 7.15 – 7.09 (m, 1H), 6.94 (dd, 1H), 5.54 – 5.42(m, 1H), 5.14 (s, 2H), 3.52 – 3.41 (m, 1H), 3.26 – 3.12 (m, 2H), 3.00 – 2.90(m, 1H), 2.58 (s, 3H), 2.29 – 2.21 (m, 1H), 1.97 – 1.85 (m, 1H).

[0429] Example 13: Preparation of Compound 13

[0430]

[0431] Following the synthetic route of compound 5, the trifluoroacetate of compound 13 (110 mg) was prepared.

[0432] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 15% to 60%; c. Flow rate: 15 ml / min; d. Elution time: 14 min.

[0433] LCMS m / z = 425.1 [M+H] +

[0434] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.49 (m, 1H), 7.40 – 7.31 (m, 2H), 7.23 – 7.09 (m, 3H), 7.01 – 6.94 (m, 1H), 5.16 (s, 2H), 4.23 (s, 2H), 3.92(s, 2H), 3.27 – 3.07 (m, 4H), 2.52 (s, 3H), 2.16 – 1.95 (m, 4H).

[0435] Example 14: Preparation of Compound 14

[0436]

[0437] Following the synthetic route of compound 5, crude compound 14 (150 mg) was prepared. This crude compound was chirally resolved by SFC to yield compound 14-P1 (48.2 mg, analytical retention time: Rt = 1.433 min) and compound 14-P2 (46.7 mg, analytical retention time: Rt = 1.793 min). One of compounds 14-P1 and 14-P2 is structure 14-a, and the other is structure 14-b.

[0438] Chiral analysis method: Instrument: CAS-05-ANA-SFC-D; Column: IK column; Mobile phase: A is CO2; B is 0.05% M ammonia in ethanol solution; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0439] Preparation method: Instrument: CAS-05-Prep-SFC-G; Column: IK column; Mobile phase: A is CO2; B is ethanol solution; Flow rate: 120 mL / min; Column temperature: room temperature; Wavelength: 220 nm

[0440] 14-P1: LCMS m / z = 421.1 [M+H] +

[0441] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.50 (m, 1H), 7.43 – 7.31 (m, 3H), 7.21 – 7.08 (m, 2H), 6.95 (dd, 1H), 5.65 – 5.52 (m, 1H), 5.15 (s, 2H), 3.67 – 3.59 (m, 1H), 3.49 – 3.36 (m, 1H), 3.25 – 3.11 (m, 1H), 2.96 – 2.88 (m, 1H), 2.59 (s, 3H).

[0442] 14-P2: LCMS m / z = 421.1 [M+H] +

[0443] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.50 (m, 1H), 7.44 – 7.29 (m, 3H), 7.21 – 7.09 (m, 2H), 6.95 (dd, 1H), 5.66 – 5.52 (m, 1H), 5.15 (s, 2H), 3.67 – 3.59 (m, 1H), 3.49 – 3.34 (m, 1H), 3.26 – 3.11 (m, 1H), 2.96 – 2.87 (m, 1H), 2.59 (s, 3H).

[0444] Example 15: Preparation of Compound 15

[0445]

[0446] Compound 5 (85 mg, 0.22 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and cyclopropionic acid (38 g, 0.44 mmol), HATU (0.17 g, 0.44 mmol), and DIPEA (85 mg, 0.66 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The mixture was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL × 2), once with a saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative treatment and lyophilized to give compound 15 (20 mg, yield: 19.99%).

[0447] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 30% to 80%; c. Flow rate: 12 ml / min; d. Elution time: 15.8 min.

[0448] LCMS m / z = 453.2 [M+H] +

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (dd, 1H), 7.62 – 7.51 (m, 1H), 7.50 – 7.36 (m, 2H), 7.34 – 7.19 (m, 3H), 6.96 (dd, 1H), 5.19 – 4.91 (m, 3H), 4.09– 3.73 (m, 2H), 3.72 – 3.39 (m, 2H), 2.42 – 2.03 (m, 2H), 1.82 – 1.68 (m,1H), 0.80 – 0.60 (m, 4H).

[0450] Example 16: Preparation of Compound 16

[0451]

[0452] Following the synthetic route of compound 15, compound 16 (14 mg) was prepared.

[0453] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 30% to 80%; c. Flow rate: 12 ml / min; d. Elution time: 16.72 min.

[0454] LCMS m / z = 471.2 [M+H] +

[0455] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.49 (m, 1H), 7.39 – 7.28 (m, 3H), 7.22 – 7.08 (m, 2H), 6.96 – 6.90 (m, 1H), 5.21 – 5.10 (m, 3H), 4.98 – 4.74(m, 1H), 4.15 – 3.97 (m, 1H), 3.93 – 3.59 (m, 3H), 2.57 – 2.13 (m, 5H), 2.07– 1.97 (m, 1H), 1.75 – 1.62 (m, 1H), 1.13 – 0.97 (m, 1H).

[0456] Example 17: Preparation of Compound 17

[0457]

[0458] Step 1: Preparation of 17B

[0459] 3A (350 mg, 1.17 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by the addition of (S)-cyclopropylalanine methyl ester hydrochloride (320 mg, 1.75 mmol), HATU (0.67 g, 1.75 mmol), and DIPEA (0.45 g, 3.51 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with 25 mL of ethyl acetate, washed once with 25 mL of water, and extracted once with 25 mL of ethyl acetate. The organic phases were combined and washed twice with water (30 mL × 2), and once with a saturated NaCl aqueous solution (30 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 17B (370 mg, yield: 74.61%).

[0460] LCMS m / z = 426.2 [M+H] +

[0461] Step 2: Preparation of 17C

[0462] 17B (370 mg, 0.87 mmol) was dissolved in 25 mL of toluene, and Lawson's reagent (0.70 g, 1.74 mmol) was added. The mixture was reacted at 100 °C for 15 min. After cooling to room temperature and concentrating under reduced pressure, the residue was separated by silica gel column chromatography to obtain 17C (280 mg, yield: 72.92%).

[0463] LCMS m / z = 442.1[M+H] +

[0464] Step 3: Preparation of Compound 17

[0465] 17C (100 mg, 0.23 mmol) was dissolved in 3 mL of ammonia-methanol solution (7.0 mol / L in MeOH) and reacted at 80 °C for 4 hours. After cooling to room temperature, the residue was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 45 mg of crude compound 17. The crude product was then chirped by SFC to prepare compounds 17-P1 (13 mg, yield: 13.46%; analytical retention time: Rt = 0.705 min) and 17-P2 (32 mg, yield: 33.13%; analytical retention time: Rt = 1.341 min), one of which is structure 17-a and the other is structure 17-b.

[0466] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: IG column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is a methanol solution of 0.05% M ammonia; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0467] Chiral preparation method: 1. Instrument: CAS-05-Prep-SFC-E; Column: IG column; 2. The sample was dissolved in acetonitrile and methanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / mL. 3. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.1% ammonia-methanol solution; b. Flow rate: 100 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0468] Compound 17-P1: LCMS m / z = 427.1 [M+H]+

[0469] 1 H NMR (400 MHz, CD3OD) δ 7.57 – 7.51 (m, 1H), 7.48 (d, 1H), 7.39 – 7.30 (m, 2H), 7.21 – 7.09 (m, 2H), 6.94 (dd, 1H), 5.37 – 5.31 (m, 1H), 5.15(s, 2H), 2.63 (s, 3H), 1.98 – 1.79 (m, 2H), 0.95 – 0.83 (m, 1H), 0.58 – 0.47(m, 2H), 0.25 – 0.17 (m, 2H).

[0470] Compound 17-P2: LCMS m / z = 427.1 [M+H] +

[0471] 1 H NMR (400 MHz, CD3OD) δ 7.57 – 7.51 (m, 1H), 7.48 (d, 1H), 7.39 – 7.31 (m, 2H), 7.21 – 7.09 (m, 2H), 6.94 (dd, 1H), 5.37 – 5.31 (m, 1H), 5.15(s, 2H), 2.63 (s, 3H), 1.97 – 1.81 (m, 2H), 0.96 – 0.83 (m, 1H), 0.59 – 0.46(m, 2H), 0.26 – 0.16 (m, 2H).

[0472] Example 18: Preparation of Compound 18

[0473]

[0474] Following the synthetic route of compound 15, compound 18 (16 mg) was prepared.

[0475] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 40% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0476] LCMS m / z = 471.2 [M+H] +

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (dd, 1H), 7.61 – 7.54 (m, 1H), 7.50– 7.38 (m, 2H), 7.30 (t, 1H), 7.28 – 7.20 (m, 2H), 6.97 (dd, 1H), 5.14 (d,2H), 5.11 – 4.67 (m, 2H), 4.09 – 4.06 (m, 1H), 3.85 – 3.79 (m, 1H), 3.71 –3.45 (m, 2H), 2.51 (d, 3H), 2.42 – 2.07 (m, 3H), 1.49 – 1.32 (m, 1H), 1.20 –1.07 (m, 1H).

[0478] Example 19: Preparation of Compound 19

[0479]

[0480] Following the synthetic route of compound 15, compound 19 (23 mg) was prepared.

[0481] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 40% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0482] LCMS m / z = 471.2 [M+H] +

[0483] 1H NMR (400 MHz, DMSO- d6) δ 10.34 (dd, 1H), 7.61 – 7.54 (m, 1H), 7.50– 7.38 (m, 2H), 7.33 – 7.20 (m, 3H), 7.00 – 6.94 (m, 1H) 5.13 (d, 2H), 5.10 –4.65 (m, 2H), 4.14 – 3.77 (m, 2H), 3.74 – 3.42 (m, 2H), 2.52 (d, 3H), 2.44 –2.10 (m, 3H), 1.49 – 1.29 (m, 1H), 1.20 – 1.06 (m, 1H).

[0484] Example 20: Preparation of Compound 20

[0485]

[0486] Following the synthetic route of compound 15, compound 20 (21 mg) was prepared.

[0487] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 30% to 90%; c. Flow rate: 12 ml / min; d. Elution time: 15 min.

[0488] LCMS m / z = 471.2 [M+H] +

[0489] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (dd, 1H), 7.60 – 7.54 (m, 1H), 7.49– 7.38 (m, 2H), 7.32 (dd, 1H), 7.28 – 7.20 (m, 2H), 7.00 – 6.93 (m, 1H), 5.14(d, 2H), 5.10 – 4.78 (m, 2H), 4.04 – 3.73 (m, 3H), 3.54 – 3.46 (m, 1H), 2.52(d, 3H), 2.44 – 2.00 (m, 3H), 1.62 – 1.42 (m, 1H), 1.07 – 0.94 (m, 1H).

[0490] Example 21: Preparation of compound 21

[0491]

[0492] Following the synthetic route of compound 5, trifluoroacetate of compound 21 (30 mg) was prepared.

[0493] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm × 250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 40% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 15 min.

[0494] LCMS m / z = 397.1[M+H] +

[0495] 1 H NMR (400 MHz, CD3OD) δ 7.57 – 7.46 (m, 1H), 7.42 – 7.30 (m, 2H), 7.28 – 6.82 (m, 4H), 5.74 – 4.36 (m, 4H), 4.21 – 3.99 (m, 1H), 3.88 – 3.35(m, 2H), 3.30 – 3.22 (m, 1H), 2.61 – 2.32 (m, 4H), 2.22 – 1.98 (m, 1H).

[0496] Example 22: Preparation of compound 22

[0497]

[0498] Compound 22 (20 mg) was prepared by following the synthetic route of compound 10.

[0499] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: Xbridge C18 (19mm × 250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: water (containing 5 mmol / L ammonium bicarbonate); Mobile phase B: acetonitrile; b. Gradient elution, with mobile phase B gradient from 10% to 65%; c. Flow rate: 15 mL / min; d. Elution time: 20 min.

[0500] LCMS m / z = 428.1 [M+H] +

[0501] 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (d, 1H), 7.60 – 7.54 (m, 1H), 7.51 –7.38 (m, 3H), 7.36 (d, 1H), 7.29 – 7.20 (m, 2H), 7.07 (s, 1H), 6.95 (dd, 1H),5.15 (s, 2H), 4.92 – 4.83 (m, 1H), 3.62 – 3.53 (m, 1H), 3.17 (dd, 1H), 2.98(brs, 1H), 2.90 (dd, 1H), 2.51 (s, 3H), 2.48 – 2.44 (m, 1H), 1.91 – 1.80 (m, 1H).

[0502] Example 23: Preparation of compound 23

[0503]

[0504] The synthetic route of compound 23 can be referred to the first and second steps of the synthetic route of compound 5 to obtain compound 23 (15 mg).

[0505] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: Xbridge C18 (19mm × 250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: water (containing 5mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; b. Gradient elution, with mobile phase B gradient from 40% to 82.5%; c. Flow rate: 15mL / min; d. Elution time: 17min.

[0506] LCMS m / z = 386.1 [M+H] +

[0507] 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (d, 1H), 7.60 – 7.54 (m, 1H), 7.48 –7.38 (m, 2H), 7.31 (d, 1H), 7.28 – 7.20 (m, 2H), 6.97 (dd, 1H), 5.14 (s, 2H),5.04 – 4.95 (m, 1H), 3.99 – 3.92 (m, 1H), 3.91 – 3.84 (m, 1H), 3.81 – 3.72(m, 2H), 2.51 (s, 3H), 2.35 – 2.23 (m, 1H), 2.06 – 2.00 (m, 1H).

[0508] Example 24: Preparation of compound 24

[0509]

[0510] Following the synthetic route of compound 17, compound 24-P1 (4 mg; analytical retention time (Rt = 0.899 min) and compound 24-P2 were prepared.

[0511] (4 mg; analytical retention time Rt = 1.388 min), in which one of compounds 24-P1 and 24-P2 is structure 24-a and the other is structure 24-b.

[0512] HPLC preparation method:

[0513] 1. Instrument: CAS-05-Prep-HPLC-O preparative liquid chromatograph; column: C18; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / ml. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: water (containing 0.1% trifluoroacetic acid); Mobile phase B: acetonitrile; b. Gradient elution, with mobile phase A content ranging from 20% to 50%; c. Flow rate: 25 ml / min; column temperature: room temperature; wavelength: 220 nm; d. Elution time: 14 min.

[0514] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: OX column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M ammonia in methanol-acetonitrile solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0515] Chiral decomposition method:

[0516] 1. Instrument: CAS-05-Prep-SFC-E; Column: OX column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / ml; 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: a mixture of ethanol and acetonitrile (v / v = 4 / 1) (containing 0.1% ammonia); b. Flow rate: 130 ml / min; Column temperature: room temperature; Wavelength: 220 nm.

[0517] Compound 24-P1:

[0518] LCMS m / z = 472.2 [M+H] +

[0519] 1 H NMR (400 MHz, CD3OD) δ 7.58 – 7.52 (m, 1H), 7.49 (d, 1H), 7.40 –7.30 (m, 2H), 7.23 – 7.09 (m, 2H), 6.96 (dd, 1H), 5.39 (dd, 1H), 5.20 – 5.11(m, 2H), 3.26 (t, 2H), 2.63 (s, 3H), 2.18 – 2.06 (m, 1H), 2.02 – 1.92 (m,1H), 1.82 – 1.72 (m, 2H).

[0520] Compound 24-P2:

[0521] LCMS m / z = 472.2 [M+H] +

[0522] 1 H NMR (400 MHz, CD3OD) δ 7.58 – 7.52 (m, 1H), 7.49 (d, 1H), 7.40 –7.30 (m, 2H), 7.23 – 7.09 (m, 2H), 6.96 (dd, 1H), 5.39 (dd, 1H), 5.20 – 5.10(m, 2H), 3.26 (t, 2H), 2.63 (s, 3H), 2.17 – 2.06 (m, 1H), 2.03 – 1.93 (m,1H), 1.83 – 1.72 (m, 2H).

[0523] Example 25: Preparation of Compound 25

[0524]

[0525] Compound 1-methoxycyclopropanecarboxylic acid (25 mg, 0.22 mmol) was dissolved in 10 mL of N,N-dimethylformamide. HATU (0.1 g, 0.26 mmol), DIPEA (85 mg, 0.66 mmol), and compound 11 (109 mg, 0.26 mmol) were added sequentially, and the reaction was carried out at room temperature for 16 hours. The mixture was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL × 2), once with a saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative treatment and lyophilized to give compound 25 (25 mg, yield: 22.74%).

[0526] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE @ Prep C18 (19mm × 250 mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 50% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0527] LCMS m / z = 511.3 [M+H]+

[0528] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.45 (m, 2H), 7.44 – 7.36 (m, 1H), 7.27 – 7.18 (m, 2H), 7.09 – 6.79 (m, 2H), 5.15 (d, 2H), 4.42 – 4.26 (m, 2H),4.09 – 3.59 (m, 4H), 3.22 (d, 3H), 2.42 (d, 3H), 1.40 (d, 3H), 1.12 – 0.83(m, 7H).

[0529] Example 26: Preparation of Compound 26

[0530]

[0531] Compound 11 (80 mg, 0.19 mmol) was dissolved in 10 mL of dichloromethane. DIPEA (74 mg, 0.57 mmol) and isobutyryl chloride (40 mg, 0.38 mmol) were added sequentially at 0 °C, and the reaction was carried out at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative treatment and lyophilized to give compound 26 (22 mg, yield: 23.51%).

[0532] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19 mm × 250 mm); 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 45% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0533] LCMS m / z = 483.2[M+H] +

[0534] 1H NMR (400 MHz, DMSO-d6) δ 7.57 – 7.45 (m, 2H), 7.43 – 7.34 (m, 1H), 7.26 – 7.18 (m, 2H), 7.09 – 6.76 (m, 2H), 5.21 – 5.10 (d, 2H), 4.58 – 4.29(m, 2H), 4.07 – 3.90 (m, 2H), 3.70 – 3.55 (m, 2H), 2.85 – 2.65 (m, 1H), 2.42(d, 3H), 1.49 – 1.23 (m, 3H), 1.14 – 0.90 (m, 9H).

[0535] Example 27: Preparation of Compound 27

[0536]

[0537] Following the synthetic route of compound 5, compound 27 (25 mg) was prepared.

[0538] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19 mm × 250 mm); 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50 mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 40% to 80%; c. Flow rate: 12 ml / min; d. Elution time: 15.5 min.

[0539] LCMS m / z = 411.1[M+H] +

[0540] 1 H NMR (400 MHz, DMSO-d6) δ 7.60 – 7.53 (m, 1H), 7.50 – 7.37 (m, 2H), 7.29 – 7.19 (m, 2H), 7.02 – 6.91 (m, 2H), 5.15 (s, 2H), 4.56 – 4.12 (m, 2H),3.60 – 3.33 (m, 2H), 3.02 – 2.64 (m, 3H), 2.40 (d, 3H), 0.78 – 0.32 (m, 3H),0.27 – 0.07 (m, 1H).

[0541] Example 28: Preparation of compound 28

[0542]

[0543] Following the synthetic route of the first two steps of compound 5, compound 28 (15 mg) was prepared.

[0544] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, with mobile phase A content ranging from 25% to 70%; c. Flow rate: 15 ml / min; d. Elution time: 15 min.

[0545] LCMS m / z = 429.1 [M+H] +

[0546] 1 H NMR (400 MHz, CD3OD) δ 7.57 – 7.51 (m, 1H), 7.40 – 7.30 (m, 3H), 7.22 – 7.10 (m, 2H), 6.94 (dd, 1H), 5.16 (s, 2H), 5.02 – 4.93 (m, 1H), 3.55 –3.39 (m, 3H), 2.89 (dd, 1H), 2.56 (s, 3H), 2.40 – 2.32 (m, 1H), 2.01 – 1.90 (m, 1H).

[0547] Example 29: Preparation of compound 29

[0548]

[0549] Following the synthetic route of compound 17, compounds 29-P1 (20 mg, yield: 12.88%; analytical retention time (Rt = 1.588 min) and 29-P2 (6 mg, yield: 3.68%; analytical retention time Rt = 2.268 min) were prepared. One of compounds 29-P1 and 29-P2 is structure 29-a, and the other is structure 29-b.

[0550] HPLC Preparation Method: 1. Instrument: CAS-05-Prep-HPLC-O; Column: C18 column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / mL. 3. Preparative Chromatographic Conditions: a. Mobile phase: A is water (containing 10 mmol / L NH4HCO3); B is acetonitrile; b. Flow rate: 25 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0551] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: IK column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is a methanol solution of 0.05% M ammonia; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0552] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-A; Column: IK column; 2. The sample was dissolved in acetonitrile and methanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / mL. 3. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.1% ammonia-methanol solution; b. Flow rate: 110 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0553] Compound 29-P1: LCMS m / z = 415.1 [M+H] +

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (d, 1H), 7.64 – 7.54 (m, 2H), 7.47 – 7.38 (m, 3H), 7.28 – 7.20 (m, 3H), 6.95 (dd, 1H), 5.18 – 5.07 (m, 3H), 2.57(s, 3H), 2.30 – 2.20 (m, 1H), 1.00 (t, 6H).

[0555] Compound 29-P2: LCMS m / z = 415.1 [M+H] +

[0556] 1H NMR (400 MHz, DMSO-d6) δ 9.85 (d, 1H), 7.63 – 7.54 (m, 2H), 7.47 – 7.38 (m, 3H), 7.28 – 7.19 (m, 3H), 6.95 (dd, 1H), 5.18 – 5.07 (m, 3H), 2.57(s, 3H), 2.29 – 2.20 (m, 1H), 1.00 (t, 6H).

[0557] Example 30: Preparation of compound 30

[0558]

[0559] Following the synthetic route of compound 5, trifluoroacetate of compound 30 (89 mg) was prepared.

[0560] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 10% to 70%; c. Flow rate: 15 ml / min; d. Elution time: 15 min.

[0561] LCMS m / z = 397.2 [M+H] +

[0562] 1 H NMR (400 MHz, CD3OD) δ 7.58 – 7.45 (m, 1H), 7.43 – 7.31 (m, 2H), 7.27 – 6.83 (m, 4H), 5.75 – 4.36 (m, 4H), 4.19 – 4.01 (m, 1H), 3.88 – 3.35(m, 2H), 3.29 – 3.18 (m, 1H), 2.61 – 2.33 (m, 4H), 2.22 – 1.95 (m, 1H).

[0563] Example 31: Preparation of compound 31

[0564]

[0565] Following the synthetic route of compound 7, compounds 31-P1 (10 mg, yield: 5.26%; analytical retention time Rt = 1.993 min) and 31-P2 (35 mg, yield: 18.18%; analytical retention time Rt = 2.414 min) were prepared, with one of compounds 31-P1 and 31-P2 being structure 31-a and the other being structure 31-b.

[0566] HPLC Preparation Method: Instrument: CAS-05-Prep-HPLC-O Preparative Liquid Chromatography; Column: C18 column; Sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / ml. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: Water (containing 10 mmol / L ammonium bicarbonate); Mobile phase B: Acetonitrile; Flow rate: 25 ml / min; Column temperature: Room temperature; Detection wavelength: 220 nm.

[0567] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D, chromatographic column: IG column; 2. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: Ethanol (containing 0.05% M NH3); Flow rate: 3 ml / min; Column temperature: 35℃; Detection wavelength: 220 nm.

[0568] Chiral preparation method: Instrument: CAS-05-Prep-SFC-G; Column: IG column; The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / ml; Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: ethanol; Flow rate: 120 ml / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0569] Compound 31-P1: LCMS m / z = 387.2 [M+H] +

[0570] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (d, 1H), 7.61 – 7.56 (m, 2H), 7.54(d, 1H), 7.47 – 7.39 (m, 2H), 7.28 – 7.21 (m, 2H), 7.18 (s, 1H), 6.95 (dd,1H), 5.21 – 5.09 (m, 3H), 2.60 (s, 3H), 1.45 (d, 3H).

[0571] Compound 31-P2: LCMS m / z = 387.2 [M+H] +

[0572] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (d, 1H), 7.61 – 7.55 (m, 2H), 7.54(d, 1H), 7.47 – 7.39 (m, 2H), 7.28 – 7.20 (m, 2H), 7.18 (s, 1H), 6.95 (dd,1H), 5.21 – 5.10 (m, 3H), 2.60 (s, 3H), 1.45 (d, 3H).

[0573] Example 32: Preparation of compound 32

[0574]

[0575] Following the synthetic route of compound 27, trifluoroacetate of compound 32 (31 mg) was prepared.

[0576] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 20% to 60%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0577] LCMS m / z = 411.2[M+H] +

[0578] 1 H NMR (400 MHz, CD3OD) δ 7.53 – 7.47 (m, 1H), 7.41 – 7.33 (m, 2H), 7.22 – 7.11 (m, 2H), 7.03 – 6.88 (m, 2H), 5.17 (s, 2H), 4.25 – 3.85 (m, 2H), 3.80 – 3.35 (m, 2H), 3.27 – 3.02 (m, 2H), 2.53 (s, 3H), 1.55 – 1.10 (d, 4H).

[0579] Example 33: Preparation of compound 33

[0580]

[0581] Following the synthetic route of compound 11, the trifluoroacetate of compound 33 (27 mg) was prepared.

[0582] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 15% to 55%; c. Flow rate: 12 ml / min; d. Elution time: 15.7 min.

[0583] LCMS m / z = 411.3[M+H] +

[0584] 1 H NMR (400 MHz, CD3OD) δ 7.56 – 7.48 (m, 1H), 7.40 – 7.31 (m, 2H), 7.21 – 7.11 (m, 2H), 7.10 – 6.84 (m, 2H), 6.02 – 5.82 (m, 1H), 5.16 (d, 2H),4.38 – 4.28 (m, 1H), 4.15 – 3.90 (m, 2H), 3.86 – 3.72 (m, 1H), 3.66 – 3.46(m, 1H), 2.44 (d, 3H), 2.28 – 1.91 (m, 3H), 1.86 – 1.58 (m, 1H).

[0585] Example 34: Preparation of compound 34

[0586]

[0587] Following the synthetic route of compound 11, trifluoroacetate of compound 34 (35 mg) was prepared.

[0588] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SUNFIRE@ Prep C18 (19mm×250mm);

[0589] 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 15% to 60%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0590] LCMS m / z = 413.1 [M+H] +

[0591] 1 H NMR (400 MHz, CD3OD) 6.38 – 5.50 (m, 1H), 5.16 (s, 2H),4.70 – 3.94 (m, 1H), 3.70 – 3.40 (m, 2H), 3.38 – 3.34 (m, 1H), 3.29 – 3.20(m, 1H), 2.53 – 2.32 (m, 3H), 1.65 – 1.08 (m, 6H).

[0592] Example 35: Preparation of compound 35

[0593]

[0594] Step 1: Preparation of Compound 35

[0595] Compound 11 (170 mg, 0.41 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and anhydrous acetic acid (0.12 g, 2.05 mmol), HATU (0.23 g, 0.61 mmol), and N,N-diisopropylethylamine (0.16 g, 1.23 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (25 mL), washed once with water (25 mL), and the aqueous phase was extracted once with ethyl acetate (25 mL). The organic phases were combined and washed twice with water (25 mL × 2), once with a saturated NaCl aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative treatment and lyophilized to give compound 35 (25 mg, yield: 13.35%).

[0596] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SUNFIRE@ Prep C18 (19mm×250mm);

[0597] 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 20% to 60%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0598] LCMS m / z = 455.2 [M+H] +

[0599] 1 H NMR (400 MHz, CD3OD) δ 7.53 – 7.42 (m, 1H), 7.41 – 7.29 (m, 2H), 7.20 – 7.09 (m, 2H), 7.09 – 6.70 (m, 2H), 5.23 – 5.11 (m, 2H), 4.71 – 4.40(m, 2H), 4.34 – 3.84 (m, 3H), 3.82 – 3.56 (m, 1H), 2.44 (d, 3H), 2.13 (d,3H), 1.58 – 1.01 (m, 6H).

[0600] Example 36: Synthesis of Compound 36

[0601]

[0602] Following the synthetic route of compound 11, trifluoroacetate (5 mg) of target compound 36 was prepared.

[0603] LCMS m / z = 410.2[M+H]+

[0604] Preparation method: 1. Instruments: Waters 3767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 5% to 50%; c. Flow rate: 12 ml / min; d. Elution time: 18 min.

[0605] 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, 1H), 7.60 – 7.54 (m, 1H), 7.48 –7.40 (m, 1H), 7.29 – 7.22 (m, 3H), 7.18 (s, 1H), 7.11 (dd, 1H), 5.14 (s, 2H), 4.37 – 4.26 (m, 4H), 3.55 – 3.45 (m, 3H), 2.56 (s, 3H).

[0606] Example 37: Synthesis of Compound 37

[0607]

[0608] Following the synthetic route of compound 11, compound 37 (10 mg) was prepared.

[0609] LCMS m / z = 413.1[M+H]+

[0610] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50 mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 40% to 97%; c. Flow rate: 12 ml / min; d. Elution time: 16 min.

[0611] Example 38: Preparation of compound 38

[0612]

[0613] Step 1: Synthesis of Compound 38

[0614] Compound 38 (0.20 g, 0.48 mmol) was dissolved in 8 mL of N,N-dimethylformamide, and (1R,2R)-2-fluorocyclopropanecarboxylic acid (0.075 g, 0.72 mmol), HATU (0.37 g, 0.96 mmol), and DIPEA (0.25 g, 1.92 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. The solution was diluted with 100 mL of ethyl acetate, washed once with 100 mL of water, and extracted once with 100 mL of ethyl acetate. The organic phases were combined and washed twice with water (100 mL × 2), and once with saturated NaCl aqueous solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then used to prepare compound 38 (20 mg, yield 8.27%).

[0615] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter with a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 5mM ammonium bicarbonate); b. Gradient elution: Mobile phase A content from 40% to 90%, flow rate 12ml / min, elution time 15.5min.

[0616] LCMS m / z = 499.2 [M+H] +

[0617] 1 H NMR (400 MHz, CD3OD) δ 7.54 – 7.23 (m, 3H), 7.21 – 6.63 (m, 4H), 5.27 – 5.12 (m, 2H), 5.04 – 4.88 (m, 1H), 4.78 – 4.70 (m, 1H), 4.64 – 4.22(m, 2H), 4.17 – 3.53 (m, 3H), 2.45 (d, 3H), 2.32 – 2.10 (m, 1H), 1.84 – 1.71(m, 1H), 1.63 – 1.03 (m, 7H).

[0618] Example 39: Preparation of compound 39

[0619]

[0620] Following the synthetic route of compound 17, 115 mg of crude compound 39 was obtained by silica gel column purification. SFC was used for resolution to obtain compounds 39-P1 (39.5 mg, yield: 14.83%; analytical retention time: Rt = 0.584 min) and 39-P2 (35.3 mg, yield: 13.25%; analytical retention time: Rt = 1.492 min). One of compounds 39-P1 and 39-P2 is structure 39-a, and the other is 39-b.

[0621] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-C; Column: IC column; 2. Preparative chromatographic conditions: Mobile phase: A is CO2; B is 0.05% M ethylenediamine-methanol solution; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0622] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-G; Column: IC column; 2. The sample was dissolved in acetonitrile and methanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 5 mg / mL; 3. Preparative chromatographic conditions: Mobile phase: A was CO2; B was 0.1% ammonia-ethanol solution; Flow rate: 120 mL / min; Column temperature: room temperature; Wavelength: 220 nm

[0623] Compound 39-P1: LCMS m / z = 439.0 [M+Na] +

[0624] 1 H NMR (400 MHz, CD3OD) δ 7.59 – 7.52 (m, 2H), 7.39 – 7.32 (m, 2H), 7.21 – 7.09 (m, 2H), 6.95 (dd, 1H), 5.48 (t, 1H), 5.16 (s, 2H), 3.94 – 3.85(m, 2H), 3.43(s, 3H), 2.66(s, 3H).

[0625] Compound 39-P2: LCMS m / z = 439.0 [M+Na] +

[0626] 1H NMR (400 MHz, CD3OD) δ 7.58 – 7.52 (m, 2H), 7.39 – 7.31 (m, 2H), 7.22 – 7.09 (m, 2H), 6.95 (dd, 1H), 5.48 (t, 1H), 5.16 (s, 2H), 3.95 – 3.85(m, 2H), 3.43(s, 3H), 2.66(s, 3H).

[0627] Example 40: Preparation of Compound 40

[0628]

[0629] Step 1: Preparation of 40B

[0630] 40A (0.25 g, 1.14 mmol) was dissolved in 15 mL of tetrahydrofuran, and pyridine (0.14 g, 1.71 mmol) was added. Trifluoromethanesulfonic anhydride (0.42 g, 1.48 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 40B (0.31 g, yield: 77.52%).

[0631] LCMS m / z = 353.0 [M+H] +

[0632] Step 2: Preparation of 40C

[0633] 40B (310 mg, 0.88 mmol) was dissolved in a mixed solvent of 12 mL of 1,4-dioxane and 1.5 mL of water. Vinylboronic acid pinacol ester (0.27 g, 1.76 mmol), potassium carbonate (0.36 g, 2.64 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (72 mg, 0.088 mmol) were added. The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL). The organic phase was washed once with water (20 mL) and once with a saturated aqueous solution of NaCl (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 40C (200 mg, yield: 98.70%).

[0634] LCMS m / z = 231.1 [M+H] +

[0635] Step 3: Preparation of 40D

[0636] 40C (0.2 g, 0.87 mmol) was dissolved in 30 mL of dichloromethane, and 2-fluorostyrene (0.21 g, 1.74 mmol) and HOVEYDA-GRUBBS catalyst (0.27 g, 0.43 mmol) were added sequentially. The reaction was carried out at 40 °C for 16 hours. The reaction solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 40D (168 mg, yield: 59.63%).

[0637] LCMS m / z = 325.1 [M+H] +

[0638] Step 4: Preparation of 40E

[0639] 40D (168 mg, 0.52 mmol) was dissolved in a mixture of 12 mL anhydrous ethanol and 2 mL water, and lithium hydroxide (120 mg, 5.20 mmol) was added. The mixture was reacted at 40 °C for 2 hours. The reaction solvent was removed by concentration under reduced pressure. The crude product was adjusted to pH 2-3 with 1N HCl and extracted twice with dichloromethane (20 mL × 2). The organic phases were combined and washed once with a saturated aqueous solution of NaCl (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 40E (150 mg, yield: 97.74%).

[0640] LCMS m / z = 297.1 [M+H] +

[0641] Step 5: Preparation of Compound 40

[0642] 40E (150 mg, 0.51 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by the addition of L-serineamide hydrochloride (80 mg, 0.77 mmol), HATU (0.39 g, 1.02 mmol), and DIPEA (0.20 g, 1.53 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (25 mL × 2), once with a saturated NaCl aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain compound 40 (140 mg, yield: 72.32%).

[0643] LCMS m / z = 383.1 [M+H] +

[0644] 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.72 (t, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.43 – 7.21 (m, 3H), 7.21 – 7.05 (m, 2H), 4.72 (t, 1H), 4.03 –3.92 (m, 2H), 2.71 (s, 3H).

[0645] Example 41: Preparation of compound 41

[0646]

[0647] Step 1: Preparation of 41B

[0648] 41A (900 mg, 2.65 mmol) was dissolved in 35 mL of N,N-dimethylformamide, and (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (0.74 g, 3.97 mmol), HATU (2.02 g, 5.30 mmol), and DIPEA (1.03 g, 7.95 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (50 mL), washed once with water (50 mL), and extracted once with ethyl acetate (50 mL). The organic phases were combined and washed twice with water (50 mL × 2), once with a saturated NaCl aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 41B (705 mg, yield: 52.37%).

[0649] LCMS m / z = 508.1 [M+H] +

[0650] Step 2: Preparation of 41C

[0651] 41B (550 mg, 1.08 mmol) was dissolved in 30 mL of toluene, and Lawson's reagent (0.87 g, 2.16 mmol) was added. The mixture was reacted at 100 °C for 2 hours. After cooling to room temperature, the crude product was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 41C (450 mg, yield: 79.31%).

[0652] LCMS m / z = 524.2 [M+H] +

[0653] Step 3: Preparation of Compound 41

[0654] 41C (450 mg, 0.86 mmol) was dissolved in 15 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure. The crude product was separated by silica gel column chromatography, concentrated, and sent to the preparation section. The product was lyophilized to give compound 41 (30 mg, yield: 8%).

[0655] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution: Mobile phase A content from 10% to 50%, flow rate 12ml / min, elution time 15min.

[0656] 1 H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.54 (d, 1H), 7.34 (d, 1H), 7.32 – 7.03 (m, 2H), 5.33 (s, 2H), 5.24 – 5.16 (m, 1H), 3.94 – 3.85 (m, 1H), 3.55 – 3.39 (m, 3H), 2.70 (s, 3H), 2.62 – 2.51 (m, 1H), 2.32 – 2.21 (m, 1H).

[0657] LCMS m / z = 424.1 [M+H] +

[0658] Example 42: Preparation of compound 42

[0659]

[0660] Step 1: Preparation of Compound 42

[0661] Compound 41 (130 mg, 0.31 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of (1R,2R)-2-fluoro-cyclopropionic acid (97 mg, 0.93 mmol), HATU (0.24 g, 0.62 mmol), and N,N-diisopropylethylamine (0.12 g, 0.93 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL × 2), once with a saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified to obtain compound 42 (30 mg, yield: 19%).

[0662] LCMS m / z = 510.1 [M+H] + 1 H NMR (400 MHz, CD3OD) δ 7.84 (d, 1H), 7.53(dd, 1H), 7.34 – 6.98 (m, 3H), 5.31 (d, 2H), 5.19 – 5.10 (m, 1H), 5.00 – 4.76(m, 1H), 4.15 – 4.04 (m, 1H), 3.93 – 3.64 (m, 3H), 2.79 (d, 3H), 2.55 – 2.17(m, 2H), 2.09 – 1.98 (m, 1H), 1.76 – 1.64 (m, 1H), 1.16 – 1.01 (m, 1H).

[0663] Example 43: Preparation of compound 43

[0664]

[0665] Following the synthetic route of compound 42, compound 43 (30 mg) was prepared.

[0666] LCMS m / z = 528.1 [M+H] +

[0667] Example 44: Preparation of compound 44

[0668]

[0669] Following the synthetic route of compound 41, compound 44 (30 mg) was prepared.

[0670] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution: Mobile phase A content from 15% to 50%, flow rate 12 ml / min, elution time 14 min.

[0671] LCMS m / z = 452.1 [M+H] +

[0672] 1 H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.60 – 7.51 (m, 1H), 7.32 – 6.88 (m, 3H), 5.41 – 5.30 (m, 2H), 5.20 – 3.55 (m, 4H), 3.78 – 3.55 (m, 2H), 2.69 (s, 3H), 1.53 – 1.44 (m, 3H), 1.28 – 1.12 (m, 3H).

[0673] Example 45: Preparation of compound 45

[0674]

[0675] Following the synthetic route of compound 42, compound 45 (25 mg) was prepared.

[0676] LCMS m / z = 538.1 [M+H] +

[0677] 1H NMR (400 MHz, CD3OD) δ 7.64 – 7.50 (m, 2H), 7.25 – 7.08 (m, 2H), 7.01 – 6.83 (m, 1H), 5.40 – 5.24 (m, 2H), 5.01 – 4.74 (m, 2H), 4.70 – 4.54(m, 1H), 4.45 – 4.34 (m, 1H), 4.15 – 3.93 (m, 2H), 3.77 – 3.63 (m, 1H), 2.67(d, 3H), 2.37 – 2.05 (m, 1H), 1.84 – 1.72 (m, 1H), 1.68 – 1.38 (m, 4H), 1.21– 1.05 (m, 2H), 0.99 – 0.92 (m, 1H).

[0678] Example 46: Preparation of Compound 46

[0679]

[0680] Following the synthetic route of compound 42, compound 46 (10 mg) was prepared.

[0681] LCMS m / z = 556.1 [M+H] + .

[0682] Example 47: Preparation of Compound 47

[0683]

[0684] Step 1: Preparation of 47A

[0685] 41A (330 mg, 0.97 mmol) was dissolved in 12 mL of N,N-dimethylformamide, followed by the addition of (S)-cyclopropylalanine methyl ester hydrochloride (210 mg, 1.26 mmol), HATU (0.74 g, 1.94 mmol), and DIPEA (0.38 g, 2.91 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (25 mL), washed once with water (25 mL), and extracted once with ethyl acetate (25 mL). The organic phases were combined and washed twice with water (25 mL × 2), and once with a saturated NaCl aqueous solution (25 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 47A (280 mg, yield: 61.98%).

[0686] LCMS m / z = 465.1 [M+H]+

[0687] Step 2: Preparation of 47B

[0688] 47A (280 mg, 0.60 mmol) was dissolved in 20 mL of toluene, and Lawson's reagent (0.49 g, 1.20 mmol) was added. The mixture was reacted at 100 °C for 30 min. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 47B (270 mg, yield: 93.20%).

[0689] LCMS m / z = 481.1[M+H] +

[0690] Step 3: Preparation of Compound 47

[0691] 47B (150 mg, 0.31 mmol) was dissolved in 3 mL of ammonia-methanol solution (7.0 mol / L in MeOH) and reacted at 80 °C for 4 hours. After cooling to room temperature, the solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain compound 47 (26 mg, 18%).

[0692] LCMS m / z = 466.1[M+H] + .

[0693] Example 48: Synthesis of Compound 48

[0694]

[0695] Following the synthetic route of compound 5, 25 mg of trifluoroacetate of target compound 48 was prepared.

[0696] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution, with mobile phase A content ranging from 15% to 40% c. Flow rate: 12 mL / min d. Elution time: 14 min.

[0697] LCMS m / z = 388.1 [M+H] +

[0698] 1H NMR (400 MHz, DMSO-d6) δ 10.29 (d, 1H), 8.89 (s, 1H), 7.69 (s, 1H), 7.48 (d, 1H), 7.32 (d, 1H), 6.98 (dd, 1H), 5.31 (s, 2H), 5.11 – 5.01 (m, 1H), 3.72 – 3.62 (m, 1H), 3.41 – 3.25 (m, 3H), 2.63 (s, 3H), 2.56 (s, 3H), 2.41 – 2.30 (m, 1H), 2.18 – 2.07 (m, 1H).

[0699] Example 49: Synthesis of Compound 49

[0700]

[0701] Following the synthetic route of compound 14, target compound 49-P1 (25 mg; analytical retention time Rt = 0.507) was obtained.

[0702] (min) and 49-P2 (21 mg; analytical retention time Rt = 1.304 min), wherein one of compounds 49-P1 and 49-P2 is structure 49-a and the other is structure 49-b.

[0703] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm) 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 5 mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 20% to 80%; c. Flow rate: 12 mL / min; d. Elution time: 16 min.

[0704] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-C; Column: AD column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M ammonia in ethanol solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0705] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-C; Column: AD column; 2. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / mL; 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: 0.1% ammonia-ethanol solution; b. Flow rate: 120 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0706] Compound 49-P1: LCMS m / z = 424.1 [M+H] +

[0707] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (d, 1H), 7.68 (s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 6.97 (dd, 1H), 5.50 – 5.36 (m, 1H), 5.29 (s, 2H), 3.44 (dd,1H), 3.38 – 3.26 (m, 1H), 3.18 – 2.98 (m, 2H), 2.92 (dd, 1H), 2.63 (s, 3H), 2.54 (s, 3H).

[0708] Compound 49-P2: LCMS m / z = 424.1 [M+H] +

[0709] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (d, 1H), 7.68 (s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 6.97 (dd, 1H), 5.49 – 5.36 (m, 1H), 5.29 (s, 2H), 3.44 (dd,1H), 3.38 – 3.26 (m, 1H), 3.18 – 2.98 (m, 2H), 2.92 (dd, 1H), 2.63 (s, 3H), 2.54 (s, 3H).

[0710] Example 50: Preparation of Compound 50

[0711]

[0712] Following the synthetic route of compound 17, compound 50-P1 (10 mg; analytical retention time Rt = 0.631 min) was prepared.

[0713] And 50-P2 (15 mg; analytical retention time Rt = 2.501 min), wherein one of compounds 50-P1 and 50-P2 is structure 50-a and the other is structure 50-b.

[0714] HPLC Preparation Method: 1. Instrument: CAS-05-Prep-HPLC-O; Column: C18 column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / mL. 3. Preparative Chromatographic Conditions: a. Mobile phase: A is water (containing 0.1% TFA); B is acetonitrile; b. Flow rate: 25 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0715] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: OX column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M ammonia in ethanol solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0716] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-E; Column: OX column; 2. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 6 mg / mL. 3. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.1% ammonia-ethanol solution; b. Flow rate: 120 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0717] Compound 50-P1: LCMS m / z = 447.1 [M+H] +

[0718] 1 H NMR (400 MHz, CD3OD) δ 7.54 (td, 1H), 7.49 (d, 1H), 7.39 – 7.30 (m,2H), 7.22 – 7.09 (m, 2H), 6.94 (dd, 1H), 5.43 (dd, 1H), 5.16 (s, 2H), 2.69 –2.63 (m, 2H), 2.62 (s, 3H), 2.37 – 2.15 (m, 2H), 2.12 (s, 3H).

[0719] Compound 50-P2: LCMS m / z = 447.1 [M+H] +

[0720] 1 H NMR (400 MHz, CD3OD) δ 7.54 (td, 1H), 7.49 (d, 1H), 7.39 – 7.30 (m,2H), 7.22 – 7.09 (m, 2H), 6.94 (dd, 1H), 5.43 (dd, 1H), 5.16 (s, 2H), 2.69 –2.63 (m, 2H), 2.62 (s, 3H), 2.36 – 2.15 (m, 2H), 2.12 (s, 3H).

[0721] Example 51: Preparation of compound 51

[0722]

[0723] Following the synthetic route of compound 10, compound 51 (20 mg) was prepared.

[0724] HPLC Preparation Method: 1. Instruments: Waters 2767 preparative HPLC; Column: SUNFIRE@ Prep C18 (19mm × 250mm) 2. Dissolve the sample in DMF and filter through a 0.45 μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 5 mM ammonium bicarbonate) b. Gradient elution: Mobile phase A content from 15% to 60%, flow rate 12 mL / min, elution time 15 min.

[0725] LCMS m / z = 431.1 [M+H] +

[0726] 1 H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 7.40 (d, 1H), 7.31 (d, 1H), 6.91 (dd, 1H), 5.30 (s, 2H), 5.13 – 5.06 (m, 1H), 3.81 (dd, 1H), 3.37 – 3.33(m, 1H), 3.14 – 3.08 (m, 1H), 2.73 – 2.63 (m, 4H), 2.55 (s, 3H), 2.07 – 1.98(m, 1H).

[0727] Example 52: Preparation of compound 52

[0728]

[0729] Following the synthetic route of compound 47, compound 52-P1 (20 mg; analytical retention time Rt = 0.657 min) was prepared.

[0730] And 52-P2 (33 mg; analytical retention time Rt = 1.425 min), wherein one of compounds 52-P1 and 52-P2 is structure 52-a and the other is structure 52-b.

[0731] HPLC Preparation Method: 1. Instrument: CAS-05-Prep-HPLC-J; Column: C18 column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / mL. 3. Preparative Chromatographic Conditions: a. Mobile phase: A is water (10 mmol / L NH4HCO3); B is acetonitrile; b. Flow rate: 75 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0732] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: IK column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M ammonia in ethanol solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0733] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-G; Column: IK column; 2. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / mL. 3. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.1% ammonia-ethanol solution; b. Flow rate: 100 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0734] Compound 52-P1: LCMS m / z = 430.1 [M+H] +

[0735] 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.50 (d, 1H), 7.33 (d, 1H), 6.91 (dd, 1H), 5.36 (t, 1H), 5.29 (s, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 1.97 –1.82 (m, 2H), 0.94 – 0.83 (m, 1H), 0.59 – 0.46 (m, 2H), 0.26 – 0.15 (m, 2H).

[0736] Compound 52-P2: LCMS m / z = 430.1 [M+H] +

[0737] 1 H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.50 (d, 1H), 7.33 (d, 1H), 6.91 (dd, 1H), 5.36 (t, 1H), 5.29 (s, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 1.97 –1.82 (m, 2H), 0.94 – 0.83 (m, 1H), 0.58 – 0.47 (m, 2H), 0.26 – 0.15 (m, 2H).

[0738] Example 53: Preparation of compound 53

[0739]

[0740] Following the synthetic route of compound 47, compound 53-P1 (10 mg; analytical retention time Rt = 1.553 min) was prepared.

[0741] And 53-P2 (23 mg; analytical retention time Rt = 1.955 min), wherein one of compounds 53-P1 and 53-P2 is structure 53-a and the other is structure 53-b.

[0742] HPLC Preparation Method: 1. Instrument: CAS-05-Prep-HPLC-O; Column: C18 column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / mL. 3. Preparative Chromatographic Conditions: a. Mobile phase: A is water (10 mmol / L NH4HCO3); B is acetonitrile; b. Flow rate: 25 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0743] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-C; Column: AD column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M diethylamine in ethanol solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0744] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-F; Column: AD column; 2. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 2 mg / mL. 3. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.1% ammonia-ethanol solution; b. Flow rate: 120 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0745] Compound 53-P1: LCMS m / z = 463.0 [M+H] +

[0746] 1 H NMR (400 MHz, CD3OD) δ 7.57 – 7.50 (m, 2H), 7.49 (d, 1H), 7.45 – 7.29 (m, 2H), 7.22 – 7.09 (m, 3H), 5.31 (dd, 1H), 5.22 – 5.14 (m, 2H), 1.98 –1.77 (m, 2H), 0.96 – 0.84 (m, 1H), 0.59 – 0.46 (m, 2H), 0.27 – 0.15 (m, 2H).

[0747] Compound 53-P2: LCMS m / z = 463.0 [M+H] +

[0748] 1H NMR (400 MHz, CD3OD) δ 7.57 – 7.50 (m, 2H), 7.49 (d, 1H), 7.45 – 7.29 (m, 2H), 7.23 – 7.09 (m, 3H), 5.31 (dd, 1H), 5.23 – 5.13 (m, 2H), 1.98 –1.80 (m, 2H), 0.97 – 0.84 (m, 1H), 0.59 – 0.46 (m, 2H), 0.27 – 0.16 (m, 2H).

[0749] Example 54: Preparation of compound 54

[0750]

[0751] Following the synthetic route of compound 41, the trifluoroacetate of compound 54 (25 mg) was prepared.

[0752] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 30% to 60%; c. Flow rate: 12 mL / min; d. Elution time: 16 min.

[0753] LCMS m / z = 421.1 [M+H] +

[0754] 1 H NMR (400 MHz, CD3OD) δ 7.58 – 7.51 (m, 2H), 7.42 – 7.31 (m, 2H), 7.24 – 7.03 (m, 4H), 5.24 – 5.16 (m, 3H), 3.88 (dd, 1H), 3.55 – 3.39 (m, 3H), 2.62 – 2.50 (m, 1H), 2.32 – 2.19 (m, 1H).

[0755] Example 55: Preparation of compound 55

[0756]

[0757] Step 1: Preparation of 55B

[0758] 55A (5 g, 35.66 mmol) was dissolved in 75 mL of acetonitrile under nitrogen protection. In an ice bath, pyridine 4-methylbenzenesulfonic acid (9.86 g, 39.23 mmol) and NBS (6.98 g, 39.23 mmol) were added sequentially. The mixture was then slowly brought back to room temperature, and the reaction was continued for 16 hours. The solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 55B (3.43 g, yield: 43.90%).

[0759] 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.19 (dd, 1H), 6.95 (d, 1H), 5.44 (br.s, 1H), 2.44 (s, 3H).

[0760] Step 2: Preparation of 55C

[0761] Using a sealed tube, 55B (2 g, 9.13 mmol) was dissolved in 40 mL of acetonitrile, followed by the sequential addition of ethyl 2-butynedoate (1.64 g, 14.61 mmol) and potassium carbonate (6 g, 43.41 mmol). The mixture was then purged under nitrogen protection and reacted at 120 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 55C (2.93 g, yield: 96.91%).

[0762] LCMS m / z = 331.0 [M+H] +

[0763] Step 3: Preparation of 55D

[0764] 55C (600 mg, 1.81 mmol) was added to a microwave-safe tube and dissolved in 6 mL of acetonitrile. Triethylamine (1.26 mL, 9.05 mmol) was added sequentially, and the mixture was purged under nitrogen protection. Then, di(tri-tert-butylphosphine)palladium (93 mg, 0.18 mmol) was added, and the mixture was microwaved at 125 °C for 35 min. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 55D (310 mg, yield: 68.37%).

[0765] LCMS m / z = 251.1 [M+H] +

[0766] Step 4: Preparation of 55E

[0767] 55D (1.45 g, 5.79 mmol) was dissolved in 25 mL of dichloromethane. Under ice bath conditions, m-chloroperoxybenzoic acid (1.20 g, 6.95 mmol) was added in portions, and the mixture was slowly brought to room temperature for 4 hours. The reaction was quenched with sodium thiosulfate solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 55E (1.37 g, yield: 88.81%).

[0768] LCMS m / z = 267.0 [M+H] +

[0769] Step 5: Preparation of 55F

[0770] 55E (1.37 g, 5.14 mmol) was dissolved in 18 mL of dichloromethane. Trifluoroacetic anhydride (2.16 g, 10.28 mmol) was slowly added under ice bath conditions, followed by slow return to room temperature. The reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol. Triethylamine (3 mL, 21.58 mmol) was slowly added under ice bath conditions, followed by reaction at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was quenched with saturated ammonium chloride solution. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 55F (380 mg, yield: 31.26%).

[0771] LCMS m / z = 237.1 [M+H] +

[0772] Step 6: Preparation of 55G

[0773] 55F (250 mg, 1.06 mmol) was dissolved in 30 mL of tetrahydrofuran, and 2-fluorobenzyl alcohol (270 mg, 2.12 mmol) and ADDP (500 mg, 1.59 mmol) were added sequentially. Tributylphosphine (430 mg, 2.12 mmol) was slowly added dropwise under a nitrogen atmosphere at room temperature. After the addition was complete, the reaction was carried out at room temperature for 16 hours. The crude product was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 55G (265 mg, yield: 72.73%).

[0774] LCMS m / z = 345.1 [M+H] +

[0775] Step 7: Preparation of 55H

[0776] 55g (265 mg, 0.77 mmol) was dissolved in a mixed solvent of 10 mL anhydrous ethanol and 2 mL water, and lithium hydroxide (180 mg, 7.70 mmol) was added. The mixture was reacted at 40 °C for 2 hours. After cooling to room temperature, the reaction solvent was removed by concentration under reduced pressure. The crude product was adjusted to pH 2-3 with 1N HCl and extracted twice with dichloromethane (15 mL × 2). The organic phases were combined and washed once with a saturated aqueous solution of NaCl (15 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 55H (190 mg, yield: 78.06%).

[0777] LCMS m / z = 317.1 [M+H] +

[0778] Step 8: Preparation of Compound 55

[0779] 55H (190 mg, 0.60 mmol) was dissolved in 12 mL of N,N-dimethylformamide, followed by the addition of L-serineamide hydrochloride (130 mg, 0.90 mmol), HATU (0.46 g, 1.20 mmol), and DIPEA (0.23 g, 1.80 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL × 2), once with a saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified to give compound 55 (30 mg, yield: 12.41%).

[0780] Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 30% to 60%; c. Flow rate: 12 mL / min; d. Elution time: 16 min.

[0781] LCMS m / z = 403.1 [M+H] +

[0782] 1H NMR (400 MHz, CD3OD) δ 7.85 (d, 1H), 7.36 (d, 1H), 7.28 – 7.13 (m,3H), 7.04 – 6.95 (m, 2H), 4.67 (t, 1H), 4.15 (s, 2H), 3.98 – 3.87 (m, 2H),2.69 (s, 3H).

[0783] Example 56: Preparation of Compound 56

[0784]

[0785] Step 1: Preparation of 56A

[0786] 55F (200 mg, 0.85 mmol) was dissolved in 30 mL of tetrahydrofuran, and (2-methyl-1,3-thiazolyl-5-yl)methanol (220 mg, 1.70 mmol) and ADDP (320 mg, 1.27 mmol) were added sequentially. Tributylphosphine (520 mg, 2.55 mmol) was slowly added dropwise at room temperature under a nitrogen atmosphere. After the addition was complete, the reaction was carried out at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 56A (241 mg, yield: 81.60%).

[0787] LCMS m / z = 348.1 [M+H] +

[0788] Step 2: Preparation of 56B

[0789] 56A (241 mg, 0.69 mmol) was dissolved in a mixed solvent of 10 mL anhydrous ethanol and 2 mL water, and lithium hydroxide (170 mg, 6.90 mmol) was added. The mixture was reacted at 40 °C for 2 hours. After cooling to room temperature, the reaction solvent was removed by concentration under reduced pressure. The crude product was adjusted to pH 2-3 with 1N HCl and extracted twice with dichloromethane (15 mL × 2). The organic phases were combined and washed once with a saturated aqueous solution of NaCl (15 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 56B (200 mg, yield: 90.28%).

[0790] LCMS m / z = 320.1 [M+H] +

[0791] Step 3: Preparation of Compound 56

[0792] 56B (200 mg, 0.63 mmol) was dissolved in 12 mL of N,N-dimethylformamide, followed by the addition of L-serineamide hydrochloride (130 mg, 0.95 mmol), HATU (0.48 g, 1.26 mmol), and DIPEA (0.24 g, 1.89 mmol). The reaction was carried out at room temperature for 16 hours. The solution was diluted with ethyl acetate (20 mL), washed once with water (20 mL), and extracted once with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL × 2), once with a saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified to obtain compound 56 (45 mg, yield: 17.72%).

[0793] Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; Column: SUNFIRE@ Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, with mobile phase A content ranging from 10% to 40%; c. Flow rate: 12 mL / min; d. Elution time: 13 min.

[0794] LCMS m / z = 406.1 [M+H] +

[0795] 1 H NMR (400 MHz, CD3OD) δ 7.88 (d, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 7.23 (s, 1H), 4.68 (t, 1H), 4.33 (s, 2H), 3.99 – 3.89 (m, 2H), 2.69 (s, 3H),2.58 (s, 3H).

[0796] Example 57: Synthesis of Compound 57

[0797]

[0798] Step 1: Synthesis of Compound 57B

[0799] 57A (1 g, 2.77 mmol) was dissolved in 20 mL of THF, and DIPEA (1.07 g, 8.31 mmol) and benzyl bromide (0.71 g, 4.16 mmol) were added sequentially. The reaction was carried out at 80 °C for 12 hours. After cooling to room temperature, the mixture was diluted with 100 mL of ethyl acetate, washed once with 100 mL of water, and extracted once with 100 mL of ethyl acetate. The organic phases were combined and washed twice with water (100 mL × 2), and once with a saturated NaCl aqueous solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 57B (1.1 g, yield: 88.04%).

[0800] LCMS m / z = 452.1 [M+H] +

[0801] Step 2: Synthesis of compound 57C

[0802] 57B (1.1 g, 2.44 mmol) was dissolved in 10 mL of THF, and diethylamine (1.42 g, 19.41 mmol) was added. The mixture was reacted at room temperature for 4 hours. The residue was concentrated under reduced pressure and purified by C18 reversed-phase column chromatography to give 57C (0.51 g, yield: 91.23%).

[0803] LCMS m / z = 230.3 [M+H] +

[0804] Step 3: Synthesis of Compound 57D

[0805] 3A (250 mg, 0.83 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 57C (190 mg, 0.83 mmol), HATU (0.38 g, 1.0 mmol), and DIPEA (320 mg, 2.49 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. The solution was diluted with 50 mL of ethyl acetate, washed once with 50 mL of water, and extracted once with 50 mL of ethyl acetate. The organic phases were combined and washed twice with water (50 mL × 2), and once with a saturated NaCl aqueous solution (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 57D (0.31 g, yield: 72.80%).

[0806] LCMS m / z = 512.2 [M+H] +

[0807] Step 4: Synthesis of compound 57E

[0808] 57D (300 mg, 0.43 mmol) was dissolved in 10 mL of toluene, and Lawson's reagent (480 mg, 1.18 mmol) was added. The mixture was reacted at 100 °C for 0.5 h. After cooling to room temperature, the residue was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 57E (110 mg, yield: 35.55%).

[0809] LCMS m / z = 528.2 [M+H] +

[0810] Step 5: Synthesis of Compound 57

[0811] Compound 57E (100 mg, 0.19 mmol) was placed in a 12 mL sealed tube, and 3 mL of ammonia-methanol solution (7.0 M Solution In MeOH, Water ≤ 0.1%, SpcSeal) was added. The reaction mixture was reacted overnight at 80 °C. The reaction solution was concentrated under reduced pressure to remove excess solvent. The residue was prepared by preparative liquid chromatography and chiral resolution to give compounds 57-P1 (8 mg, 9.67%; analytical retention time Rt = 1.476 min) and 57-P2 (10 mg, 12.09%; analytical retention time Rt = 2.419 min). One of compounds 57-P1 and 57-P2 is structure 57-a, and the other is structure 57-b.

[0812] HPLC Preparation Method: 1. Instrument: CAS-05-Prep-HPLC-O; Column: C18 column; 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 20 mg / ml. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: 10 mmol / L NH4HCO3; Mobile phase B: ACN; Flow rate: 25 ml / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0813] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: OX column; 2. Preparative chromatographic conditions: a. Mobile phase: A is CO2; B is 0.05% M ammonia in ethanol solution; b. Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0814] Chiral preparation method: 1. Instrument: CAS-05-Prep-SFC-E; Column: OX column; 2. The sample was dissolved in acetonitrile and ethanol, filtered through a 0.45 μm filter to prepare a sample solution with a concentration of 1 mg / ml. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: 0.1% ammonia-ethanol solution; b. Flow rate: 100 ml / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0815] Compound 57-P1: LCMS m / z = 435.0 [MH] -

[0816] 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (d, 1H), 7.68 (s, 1H), 7.58 (dd,1H), 7.52 (d, 1H), 7.48 – 7.39 (m, 2H), 7.33 (s, 1H), 7.29 – 7.19 (m, 2H),6.97 (dd, 1H), 6.34 – 5.98 (m, 1H), 5.44 – 5.35 (m, 1H), 5.18 – 5.09 (m, 2H), 2.59 (s, 3H), 2.54 – 2.42 (m, 2H).

[0817] Compound 57-P2: LCMS m / z = 435.0 [MH] -

[0818] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (d, 1H), 7.69 (s, 1H), 7.58 (dd,1H), 7.52 (d, 1H), 7.48 – 7.39 (m, 2H), 7.34 (s, 1H), 7.28 – 7.20 (m, 2H),6.96 (dd, 1H), 6.34 – 5.99 (m, 1H), 5.43 – 5.35 (m, 1H), 5.18 – 5.09 (m, 2H), 2.59 (s, 3H), 2.55 – 2.40 (m, 2H).

[0819] Biological test cases

[0820] 1. Manual patch-clamp test for TRPM3 antagonism

[0821] (1) Cell Culture

[0822] HEK293 cell lines stably expressing human TRPM3 were cultured in DMEM medium containing 10% fetal bovine serum and 2 μg / mL puromycin. The cell culture temperature was 37 ºC and the carbon dioxide concentration was 5%. After removing the old medium and washing once with PBS, 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37 ºC for approximately 1.5 min. Once the cells detached from the bottom of the dish, pre-warmed complete medium (37 ºC) was added. The cell suspension was gently pipetted to separate aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 1000 rpm for 5 min to collect the cells. Cells were seeded in 6 cm cell culture dishes at a density of 3 × 10⁶ cells per dish. 5 Cells (final volume 5 mL) were used for expansion or maintenance culture. To maintain cell electrophysiological activity, cell density should not exceed 80%. Before patch-clamp detection, cells were separated with 0.25% Trypsin-EDTA, and 6.5 × 10⁶ cells were cultured. 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume 500 µL), and analyzed after 18 hours.

[0823] (2) Compound preparation

[0824] The compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 30 mM stock solution. The stock solution was then diluted with DMSO to prepare intermediate dilutions of different concentrations. The intermediate dilutions were then prepared into the final working solution of the compound using extracellular fluid containing 10 μM CIM0216 agonist. The final DMSO concentration of all test samples was 0.1%.

[0825] (3) Electrophysiological tests

[0826] First, a capillary glass tube was drawn into a recording electrode using a microelectrode drawing device. Then, the electrode, filled with intracellular fluid (140 mM sCl, 2 mM MgCl2•6H2O, 5 mM NaCl, 5 mM CaCl2•2H2O, 10 mM EGTA, 10 mM HEPES, and 1 mM Mg-ATP; pH adjusted to 7.2 with CsOH), was placed into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator was manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) was recorded. Next, the electrode was slowly brought into contact with the cell surface, and negative pressure was applied to aspirate and form a GΩ seal. Fast capacitance compensation was then performed, and negative pressure was continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was applied. Once the current amplitude stabilized in the extracellular fluid containing the agonist 10 μM CIM-0216, drug administration began. After the current reached equilibrium at each drug concentration, elution was performed. Blank control solution, agonist working solution, and mixed working solution of the test compound and agonist were sequentially administered to the cells via gravity perfusion through a recording bath, while a peristaltic pump was used for fluid replacement during recording. All electrophysiological experiments were performed at room temperature.

[0827] The voltage stimulation protocol for whole-cell patch-clamp recording of TRPM3 currents was as follows: After whole-cell sealing, the cell membrane voltage was clamped at -80 mV. During recording, the voltage was changed to 0 mV, then stepped from 0 mV to -100 mV and held for 5 ms. This was followed by a ramp-up to 100 mV, held for 300 ms. Data was collected every 5 seconds to observe the effect of the drug on TRPM3 currents. Experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0828] The test results are shown in Table 1:

[0829] Table 1

[0830] Compound numbering <![CDATA[TRPM3 Manual Patch-Clamp IC 50 (nM)]]> Compound numbering <![CDATA[TRPM3 Manual Patch-Clamp IC 50 (nM)]]> Compound 5 < 30 nM Compound 36 < 30 nM Compound 6 < 30 nM Compound 37 < 30 nM Compound 7 < 30 nM Compound 39-P1 < 30 nM Compound 8-P2 < 30 nM Compound 39-P2 < 30 nM Compound 11 < 30 nM Compound 41 < 30 nM Compound 12-P2 < 30 nM Compound 44 < 30 nM Compound 14-P1 < 30 nM Compound 47-P1 < 30 nM Compound 14-P2 < 30 nM Compound 48 < 30 nM Compound 16 < 30 nM Compound 49-P1 < 30 nM Compound 17-P2 < 30 nM Compound 49-P2 < 30 nM Compound 22 < 30 nM Compound 55 < 30 nM Compound 27 < 30 nM Compound 56 < 30 nM Compound 29-P2 < 30 nM

[0831] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against human TRPM3.

[0832] 2. FLIPR test for TRPM3 antagonism

[0833] The FLIPR Calcium 6 Assay Kit (Molecular Devices, R8191) and FLIPR Pentainstrument (Molecular Devices, 5) were used for assays. HEK cells stably transfected with the human TRPM3 receptor (adherent cells) were cultured and passaged in 10 cm culture dishes. Approximately 24 hours before the experiment, the cells were digested, collected, centrifuged, resuspended in plating medium (DMEM + 10% FBS), and counted. Cells were seeded at 1.2 × 10⁶ cells per well in 384-well plates (Corning, 3764). 4 Cells, 25 μL in volume, were incubated in a 5% CO2, 37°C incubator for 16-20 hours. Assay Buffer was prepared according to the FLIPR Calcium 6 Assay Kit instructions, and Component A was diluted with Assay Buffer to a final 2× loading buffer. The culture medium in the 384-well plate was removed by inverted centrifugation, and 20 μL of Assay Buffer was added. 20 μL / well of the prepared 2× loading buffer was added to the corresponding wells, centrifuged, and incubated at 37°C in the dark for 2 hours. A 5× mixture of Isosakuranetin or the test compound and the agonist CIM-0216 was prepared. Using an ECHO apparatus (LABCYTE, 655), 100 nL / well of the 5× test compound and 2.5 mM CIM-0216 were dispensed into a source plate (Nunc, 264573). Then, 20 μL of Assay Buffer was added to each well. After incubation, 10 μL of the prepared compound and agonist mixture was added to each well using a FLIPR Penta instrument, and fluorescence signals were detected (excitation wavelength 470 nm - 495 nm, emission wavelength 515 nm - 575 nm). The highest concentration of Isosakuranetin (15 μM) was used as the 100% inhibition rate, and DMSO data as the 0% inhibition rate. A curve was plotted between the signal value and the compound concentration, and curve fitting and IC50 analysis were performed using the nonlinear regression method in XLFit software. 50 calculate.

[0834] The test results are shown in Table 2:

[0835] Table 2

[0836] Compound numbering <![CDATA[TRPM3 FLIPR test IC 50 (nM)]]> Compound 55 < 100 nM Compound 56 < 100 nM

[0837] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against human TRPM3.

Claims

1. A compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from compounds represented by general formula (I), wherein, (I) W is selected from C 6-10 aryl, 5-10 heteroaryl, wherein W is optionally surrounded by 1 to 4 R w replace; R 1 Selected from halogens, CN, OH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 3-6 cycloalkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)-C 3-10 Carbocyclic groups, -(C=O)-4 to 10-membered heterocyclic groups, C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, R 1a The alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace; R 1a Selected from 5-6 quinone heteroaryl groups, the R 1a Choose from 1 to 4 Rs k replace; X is selected from -(C=O)-, -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q; Y is selected from -CR y1 =CR y2 -、-(C=O)-NR y -、-NR y -(C=O)-、-O-(CR y1 R y2 ) m -、-S-(CR y1 R y2 ) m -、-NR y -(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -、-(CR y1 R y2 ) m -O-、 、-(CR y1 R y2 ) m -S-、-(CR y1 R y2 ) m -NR y -; V is selected from -O-, -S-, -NR y -; Q is selected from NR 5 R 6 , Or Q2; Q1 is selected from nitrogen-containing 9- to 14-membered heterocyclic alkyl groups, nitrogen-containing 9- to 14-membered bridged heterocyclic alkyl groups, and nitrogen-containing 9- to 14-membered spirocyclic alkyl groups, wherein Q1 is optionally surrounded by 1 to 4 R groups. q replace; Q2 is selected from 4- to 9-membered heterocyclic groups, wherein Q2 is optionally divided by 1 to 4 R groups. q replace; R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, SC 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace; Ring A is selected from C 3-8 Carbon rings, 4- to 8-membered heterocycles, wherein ring A is optionally divided by 1 to 4 R... k replace; R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; m is selected from 1, 2, 3, and 4; R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl or heterocycle is optionally surrounded by 1 to 4 R... k replace; R 6 Selected from , , , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-8 Carbon ring, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-8 Carbon ring, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-6 Alkyl)2, -C(R) 6c R 6d )-CONHC 1-6 Alkyl, -C 0-4 Alkylene-C 3-8 Carbon ring, -C 0-4 Alkylene-4 to 8-membered heterocycles, -C 0-4 Alkylene-C 3-8 Carbon ring-R q1 -C 0-4 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6 Choose from 1 to 4 Rs k replace; R 6a Selected from H, OH, CN, OC 1-6 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-3 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6 Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 6c R 6d It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; As an option, R 6e R 6f It forms C with the carbon atom it is attached to. 3-10 Carbon rings, 3- to 10-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; R 6g R 6h Each independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace; As an option, R 6g R 6h The atoms bonded to it form 4- to 10-membered heterocycles, which are optionally bonded by 1 to 4 R atoms. k replace; As an option, R 6c R 4 The linked skeleton forms a 6- to 20-membered heterocycle, which is optionally divided by 1 to 6 R... k replace; R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, SC 1-6 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-6 Alkyl, -(C=O)N(C 1-6 Alkyl)2、-NHC(=O)-C 1-6 Alkyl, -(C=O)C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl or R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace; R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Cycloalkyl, -O-3 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; The condition is that general formula (I) satisfies at least one of the following conditions: 1) R 6 Selected from or ; 2) Q is selected from In this case, W is selected from W1, W1 is selected from 5-6 heteroaryl groups, and W1 is optionally surrounded by 1 to 4 R groups. w replace; 3) Y is selected from Y1, and Y1 is selected from -CR y1 =CR y2 -, -(C=O)-NR y -, -NR y -(C=O)-, -S-(CR y1 R y2 ) m -, -NR y -(CR y1 R y2 ) m -, -(CR y1 R y2 ) m -, , -(CR y1 R y2 ) m -S-, -(CR y1 R y2 ) m -NR y -; 4) X is selected from X1, and X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q; 5) R 1 R 2 R 3 R 4 At least one of the four is selected from R. 1a ; 6) R 6c R 4 The linked skeleton forms a ring B, which is selected from 6 to 20-membered heterocycles, wherein the heterocycle is optionally divided by 1 to 6 R... k replace.

2. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, W is selected from phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclic, benzo5- to 6-membered heteroaryl, wherein W is optionally surrounded by 1 to 4 R w replace; Ring A is selected from C 3-6 Monocycloalkyl, C 4-8 cycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Spirocycloalkyl, 4- to 7-membered monoheterocyclic, 4- to 8-membered fused heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered spiroheterocyclic, wherein ring A is optionally surrounded by 1 to 4 R k replace; R 1 Selected from halogens, CN, OH, NH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 3-6 cycloalkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)-C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)-C 3-6 Carbocyclic groups, -(C=O)-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, R 1a The alkyl, alkenyl, alkynyl, alkylene, carbocyclic, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. k replace; R y1 R y2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, SC 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, or cycloalkyl group is optionally prefixed with 1 to 4 R groups. k replace; R w R q R q1 Each element is independently selected from deuterium, halogens, CN, OH, NH2, NO2, SF5, =O, =S, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-(C=O)NHC 3-6 cycloalkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)-4 to 7-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, C 3-6 cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R y R 5 Each element is independently selected from H, deuterium, OH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl or 3- to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, or heterocycle is optionally surrounded by 1 to 4 R... k replace; R 6 Selected from , R 6b The R 6 Choose from 1 to 4 Rs k replace; R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 Carbon ring, -C(R) 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic rings, -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 Alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Carbon rings, 4- to 8-membered heterocycles, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 0-2 Alkylene-C 3-8 Carbon ring-R q1 -C 0-2 Alkylene-4 to 8-membered heterocyclic-R q1 The R 6b Choose from 1 to 4 Rs k replace; R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 Alkylene-4 to 7-membered heterocycles, -C 1-4 alkylene-5 to 6-membered heteroaryl, -C 1-4 Alkylene-NH(C=O)C 1-6 Alkyl, -C 1-4 Alkylene-NH(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene -NH(C=NH)NH2, -C 1-4 Alkylene -NH(C=O)NH2, -C 1-4 Alkylene -CONH2, -C 1-4 Alkylene -NH2, -C 1-4 Alkylene-NH(C=O)C 1-4 Alkyl, -C 1-4 Alkylene-N(C=O)C 3-6 cycloalkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -SH, -C 1-4 alkylene-OH, wherein the alkyl, alkylene, alkenyl, alkynyl, heteroaryl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 6c R 6d It forms C with the carbon atom it is attached to. 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; As an option, R 6e R 6f And the atoms bonded to it form C 3-8 Carbon rings, 3- to 8-membered heterocycles, wherein the carbon rings or heterocycles are optionally surrounded by 1 to 4 R... k replace; Alternatively, ring B is selected from 6- to 18-membered heterocycles, wherein the heterocycle is optionally bounded by 1 to 6 R... k replace; R 6g R 6h Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace; As an option, R 6g R 6h The carbon atom attached to it forms a 4- to 8-membered heterocycle, which is optionally surrounded by 1 to 4 R atoms. k replace; R 2 R 3 R 4 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, SC 1-4 Alkyl group, COOH, -(C=O)NH2, -(C=O)NHC 1-4 Alkyl, -(C=O)N(C 1-4 Alkyl)2、-NHC(=O)-C 1-4 Alkyl, -(C=O)C 1-4 Alkyl, -(C=O)OC 1-4 Alkyl, -(C=O)C 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, R 1a The alkyl, alkylene, alkenyl, ynyl or cycloalkyl, R 1a Choose from 1 to 4 Rs k replace; R k Each element is independently selected from deuterium, halogens, OH, =O, =S, CN, NH2, COOH, -(C=O)NH2, and -(C=O)C. 1-4 Alkyl, -(C=O)C 3-6 cycloalkyl, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Cycloalkyl, -O-4 to 7-membered heterocycles, -NH-C 3-6 Cycloalkyl, -NH-4 to 7-membered heterocycles, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, or heterocycle is optionally composed of 1 to 4 elements selected from deuterium, halogen, =O, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, General formula (I) is selected from compounds represented by general formulas (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX). (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) R 2a Selected from R 2 ; R 3a Selected from R 3 ; R 4a Selected from R 4 ; And R 2a R 3a R 4a R 1 At least one of the four is R. 1a ; X is selected from -(C=O)- and X1; X1 is selected from -(C=S)-, -S(=O)2-, -NR y -(C=O)-(C=O)-, its right end is connected to Q; Z is selected from -C 1-12 Alkylene, wherein the alkylene group is optionally replaced by 1 to 6 groups of the following: -(C=O)-, -O-, -S-, -NR- y - The Z is arbitrarily selected by 1 to 5 R k replace; Y is selected from -O-(CR y1 R y2 ) m -, -(CR y1 R y2 ) m -O-, Y1; Y1 is selected from -CR y1 =CR y2 -, -(C=O)-NR y -, -NR y -(C=O)-, -S-(CR y1 R y2 ) m -, -NR y -(CR y1 R y2 ) m -, -(CR y1 R y2 ) m -, , -(CR y1 R y2 ) m -S-, -(CR y1 R y2 ) m -NR y -; W is selected from phenyl, W1, wherein the phenyl group is optionally surrounded by 1 to 4 R groups. w replace; W1 is selected from 1 to 4 R's. w The following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl; Cycle A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, aziridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, wherein cycle A is optionally surrounded by 1 to 4 R... k replace; m is selected from 1 and 2; R 1 Selected from F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, R 1a The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k replace; R 1a Selected from 1 to 4 Rs k The following groups are substituted: thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, isoxadiazolyl; R y1 R y2 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, NHCH3, N(CH3)2, methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace; R w R q R q1 Each element is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)OCH3, or arbitrarily selected by 1 to 4 Rs. k The following groups are substituted: methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, -(C=O)NH-methyl, -(C=O)N(methyl)2; R 2 R 3 R 4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, or optionally under 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, R 1a ; R y R 5 Each element is independently selected from H, deuterium, OH, or optionally coated with 1 to 4 R atoms. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxecyclopropyl; R 6a Selected from H, CN, OH, OC 1-4 Alkyl, -OC 3-8 cycloalkyl, wherein the alkyl group or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 6b Selected from , , , , -C(R) 6c R 6d -SO2NH2, -C(R) 6c R 6d )-SO2-C 1-4 Alkyl, C(R) 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-S(=O)(=NH)-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d -SO2NH2, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-SO2-C 3-6 cycloalkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)NH2、-C(R 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 1-4 Alkyl, -C(R) 6c R 6d )-C(R 6c R 6d )-S(=O)(=NH)C 3-6 cycloalkyl, -C(R) 6c R 6d )-C 3-8 cycloalkyl, -C(R) 6c R 6d )-phenyl, -C(R 6c R 6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R 6d -4 to 8-membered heterocyclic alkyl groups, -C(R 6c R 6d )-C(R 6c R 6d -5 to 6-membered heteroaryl, -C(R 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d )-CON(C 1-4 Alkyl)2, -C(R) 6c R 6d )-CONHC 1-4 Alkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic alkenyl, 4- to 8-membered heterocyclic alkyl, -C 1-2 Alkylene-C 3-8 cycloalkyl, -C 1-2 Alkylene - 4 to 8-membered heterocyclic alkyl, -C 1-2 alkylene-phenyl, -C 1-2 alkylene-5 to 6-membered heteroaryl, -C 3-8 Carbon ring-R q1 -4 to 8-membered heterocyclic -R q1 The R 6b Choose from 1 to 4 Rs k replace; Q1 is selected from , , , , , , , , , , , , , The Q1 is arbitrarily selected by 1 to 4 Rs q replace; Q2 is selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxocyclic butyl, tetrahydrofuranyl, etc. , , , , , , , The Q2 is arbitrarily divided by 1 to 4 Rs q replace; r1, r2, and r4 are each independently selected from 1 or 2; r5 is selected independently from 3, 4, and 5; r3 is selected from 2 or 3; R k Each of the following groups is independently selected from: deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxygen Heterocyclic butyl, pyrrolyl, piperidinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxetanebutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxetanebutyl, pyrrolyl, piperidinyl, or morpholinyl group is optionally selected from 1 to 4 of the elements deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

4. The compound according to claim 3, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof. Selected from , , , Its right side is connected to X; W1 is selected from 1 to 4 R's. w The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , ; Z is selected from -(CH2CH2)2-, -(CH2CH2)3-, -(CH2CH2)4-, -(CH2CH2)5-, -(CH2CH2)6-, -(CH2CH2CH2)3-, -(CH2CH2CH2)-, -(CH2)5-, -(CH2)7-, wherein CH2 is optionally replaced by 1 to 4 of the following groups: -(C=O)-, -O-, -S-, -NR. y - The Z is arbitrarily selected by 1 to 5 R k replace; Y is selected from -O-(CR y1 R y2 )-, -(CR y1 R y2 )-O-, Y1; Y1 is selected from -CR y1 =CR y2 -, -(C=O)-NR y -, -NR y -(C=O)-, -S-(CR y1 R y2 )-, -NR y -(CR y1 R y2 )-, -(CR y1 R y2 )2-, , , , -(CR y1 R y2 )-S-, -(CR y1 R y2 )-NR y -; R 6a Each is independently selected from H, OH, CN, or arbitrarily selected by 1 to 4 Rs. k The following groups are substituted: methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl; R 6b Selected from 1 to 4 Rs k The following groups are substituted: , , , , Azacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclohexyl, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, morpholinyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-cyclohexyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-morpholinyl, -C(R 6c R 6d )-phenyl, -C(R 6c R 6d )-pyridyl, -C(R 6c R 6d )-pyrrole, -C(R 6c R 6d )-pyrazolyl, -C(R 6c R 6d -imidazolium, -C(R) 6c R 6d )-triazolyl, -C(R 6c R 6d )-Tetrazolyl, -C(R 6c R 6d )-furanyl, -C(R 6c R 6d )-oxazolyl, -C(R 6c R 6d -isoxazole group, -C(R) 6c R 6d )-Oxadiazole group, -C(R 6c R 6d )-Thiophene group, -C(R 6c R 6d )-Thiazolyl, -C(R 6c R 6d -isothiazolyl, -C(R) 6c R 6d )-Thiadiazole group, , -C(R) 6c R 6d )-C(R 6c R 6d -CONH2, -C(R) 6c R 6d -(C=O)N(methyl)2、-C(R) 6c R 6d )-(C=O)NH-methyl; R 6c R 6d R 6e R 6f Each element is independently selected from H, deuterium, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxazolidine, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-aziridine, -CH2-oxazolidine, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-oxazolyl, -CH2CH2CH2-NH(C=NH)NH2, -CH2CH2-NH(C=O)NH2, -C H2-CONH2, -CH2-imidazolyl, -CH2-phenyl, -CH2NH(C=O)CH3, -CH2CH2-SCH3, -CH2SH, -CH2-OCH3, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, aziridine, oxaziridine, imidazolyl, pyrazolyl, or oxazolyl groups are optionally surrounded by 1 to 4 R groups. k replace; As an option, R 6c R 6d The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace; As an option, R 6e R 6f The carbon atom bonded thereto forms a cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group, wherein the cyclopropyl, cyclobutyl, aziridine, oxadiazine, tetrahydrofuranyl, or pyrrolidinyl group is optionally surrounded by 1 to 4 R atoms. k replace; R 6g R 6h Each of the following is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. k replace; As an option, R 6g R 6h The atoms bonded to it form 4-, 5-, or 6-membered heterocyclic groups, wherein the heterocycle is optionally bonded by 1 to 4 R atoms. k replace; Q1 is selected from 1 to 4 R's. q The following groups are substituted: , , , , , ; R k Each of these compounds is independently selected from deuterium, F, Cl, Br, I, OH, =O, =S, CN, NH2, COOH, CONH2, -(C=O)CH3, -(C=O)CH2CH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutylNHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCF3, -OCD3, -CH2OCH3, -CH2OH, -CH2CN, methyl, ethyl, propyl, isopropyl, methoxy The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azacyclobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, methoxy.

5. The compound according to claim 4, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, Y is selected from -O-CH2-, -CH2-O-, Y1, wherein the CH2 is optionally replaced by one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, CH2F; Y1 is selected from -CH=CH-, -(C=O)-NH, -NH-(C=O)-, -S-CH2-, -NR y -CH2-, -CH2CH2-, , , -CH2-S-, -CH2NR y - The =CH- and CH2 groups are optionally substituted with one or two substituents of deuterium, F, Cl, Br, methyl, CD3, CF3, CHF2, or CH2F; Z is selected from -CH2OCH2CH2NR y CH2CH2NR y CH2-、-CH2OCH2CH2OCH2CH2NR y CH2-、-CH2OCH2CH2SCH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2NR y CH2-、-CH2OCH2CH2CH2CH2CH2NR y CH2-,-CH2OCH2CH2CH2CH2CH2CH2NR y CH2-, -CH2OCH2CH2CH2CH2(C=O)-NR y CH2-, -CH2OCH2CH2CH2CH2CH2(C=O)-NR y CH2-, wherein Z is optionally divided by 1 to 5 R k replace; X1 is selected from -(C=S)-, -S(=O)2-, -NH-(C=O)-(C=O)-, its right end is connected to Q; Selected from 1 to 4 Rs k The following groups are substituted: , , ; R 1a Selected from 1 to 3 Rs k The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , ; R y R 5 Each is independently selected from H, methyl, CD3, CF3, CHF2, and CH2F; R w R q R q1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3, cyclopropyl, =O, =S, NHCH3, N(CH3)2, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -(C=O)CH3, -(C=O)CH(CH3)2, -(C=O)OCH3, -(C=O)-cyclopropyl, -(C=O)-cyclobutyl, , , ; Q2 is selected from any of the 1 to 4 R's. q The following substituents are substituted: , , , , , , , , , , ; R 6 Selected from , , , R 6b ; R 6b Selected from 1 to 3 Rs k The following groups are substituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R 2 R 3 R 4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, SF5, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio.

6. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table E-1: Table E-1 7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition containing 1-1500 mg of the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts.

8. The use of the compound or its stereoisomer, tautomer, racemate, pharmaceutically acceptable salt, or composition of claim 7 in the preparation of a medicament for treating diseases related to TRPM3 activity or expression levels.

9. The use of the compound or its stereoisomer, tautomer, racemate, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating a pain disorder, preferably migraine.

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