Cyano-substituted heterocyclic derivative and pharmaceutical use thereof

Abstract

A cyano-substituted heterocyclic derivative and the pharmaceutical use thereof. The present invention relates to a compound of general formula (I) or (II), or a racemate, stereoisomer or pharmaceutically acceptable salt thereof, and an intermediate thereof and a preparation method therefor, and the use thereof in the preparation of a drug for growing hair.

Description

Cyanosubstituted heterocyclic derivatives and their use in medicine TECHNICAL FIELD

[0001] The present invention relates to a compound of general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediates and processes for the preparation thereof, and use in the manufacture of a medicament for treating hair loss or baldness. BACKGROUND

[0002] Hair loss is a very common health problem. 50% of men and 25% of women will have pattern hair loss by age 50. Minoxidil (Rogaine) and finasteride (Propecia) are two main FDA-approved drugs for treating hair loss, but only 30-40% of patients have hair growth with repeated treatment, and there are reports of serious side effects. Surgical treatment of hair loss is expensive and painful. Therefore, there is an urgent need for a better method of treating hair loss.

[0003] Hair follicle growth is cyclical. Each cycle consists of anagen (growth phase), catagen (regression phase) and telogen (resting phase). The ability of hair follicles to maintain this cycle depends on the presence of hair follicle stem cells (HFSC). Although hair follicle stem cells undergo telogen, they can be rapidly activated to divide in a new hair cycle, and in some cases they cannot be activated, which is the cause of hair loss. Hair follicle stem cells use glycolytic metabolism to produce more lactate in the epidermis than other cells, and lactate production is essential for the activation of hair follicle stem cells, while the absence of lactate dehydrogenase gene (Ldha) will hinder the activation of hair follicle stem cells; on the contrary, the absence of mitochondrial pyruvate carrier 1 (Mpc1) gene promotes the production of lactate by hair follicle stem cells, accelerating the activation of hair follicle stem cells and the hair cycle.

[0004] Mitochondrial pyruvate carrier (MPC) is located in the inner membrane of mitochondria, and is a transport protein that transports pyruvate from the cytoplasm to the mitochondria. When MPC is knocked down or inhibited by drugs, pyruvate in the cytoplasm cannot enter the mitochondria, but is converted into other metabolites such as lactate by lactate dehydrogenase (LDH), which leads to an increase in LDH activity and the activation of HFSC, thereby accelerating hair growth. Therefore, the development of new MPC inhibitors for treating hair loss has good application prospects. SUMMARY

[0005] The purpose of the present invention is to provide a compound of MPC inhibitor, which has good MPC inhibitory activity.

[0006] The present application provides a compound represented by general formula (I) or (II), or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

[0007] In some embodiments, the compound represented by general formula (I) is selected from general formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii),

[0008] In some embodiments, the compound represented by general formula (II) is selected from general formula (IIa), (IIb), or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, In some embodiments, k1 is selected from 1 or 2.

[0009] In some embodiments, ring AA is selected from which is connected to Y at its lower side, and AA and Y are not connected by heteroatom-heteroatom; represents an aromatic or non-aromatic ring.

[0010] In some embodiments, A1, A2, A3, A4 are each independently selected from a bond, C(=O), O, S, N, NR a3 , CR a1 or CR a1 R a2 , at most one of A1, A2, A3, A4 is a bond.

[0011] In some embodiments, any two of A1, A2, A3, A4 form a ring S with the connected skeleton, and ring S is selected from pyridyl, pyridinonyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, cyclopentenyl, cyclohexenyl, piperidinyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, isoxazolyl.

[0012] In some embodiments, at most two of A1, A2, A3, A4 are selected from O, S, N or NR a3 .

[0013] In some embodiments, ring W is selected from C 4-6 carbocyclyl or 4- to 6-membered heterocyclyl.

[0014] In some embodiments, ring W is selected from non-aromatic C 4-6 carbocyclyl or non-aromatic 4- to 6-membered heterocyclyl.

[0015] In some embodiments, ring W is selected from cyclobutenyl, cyclopentenyl, oxolobutenyl, oxolobutenyl, 1,3-dioxolobutenyl.

[0016] In some embodiments, ring AA is selected from

[0017] which is attached at its lower side to Y, and ring AA is not attached to Y by a heteroatom-heteroatom.

[0018] In some embodiments, ring AA is selected from which is attached at its lower side to Y, and ring AA is not attached to Y by a heteroatom-heteroatom.

[0019] In some embodiments, Y is selected from O, S, NR Y3 or CR Y1 R Y2 .

[0020] In some embodiments, Y is selected from O, S, NH, or CH2. In some embodiments, Y is selected from CH2.

[0021] In some embodiments, R 1 is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, said R 1 is optionally substituted with 1 to 4 R k .

[0022] In some embodiments, R 1 is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, said R 1 is optionally substituted with 1 to 4 R k .

[0023] In some embodiments, R 1 is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, said R 1 is optionally substituted with 1 to 4 R k .

[0024] In some embodiments, R 1 is selected from the following groups optionally substituted with 1 to 3 R k .

[0025] In some embodiments, R 1 is selected from

[0026] In some embodiments, R 2 is selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, and said substituents are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C

[0027] In some embodiments, R 2 is selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 7-membered heterocyclyl, -C 1-5 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and said substituents are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C

[0028] In some embodiments, R 2 is selected from H, deuterium, methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, - methylene-OH, -ethylene-OH, -propylene-OH, -butylene-OH, -pentylene-OH, - methylene-O-methylene-OH, -ethylene-O-methylene-OH, -ethylene-O-ethylene-OH, - propylene-O-ethylene-OH, -propylene-O-propylene-OH, said methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methylene, ethylene, propylene, butylene, pentylene being optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, =0, CN, OH, NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and said substituents are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C

[0029] In some implementation schemes, R 2 The methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, methylene, ethyl, propyl, butyl, and pentylene groups are selected from H, -methylene-OH, -ethylene-O-methylene-OH, -ethylene-O-ethylene-OH, -ethylene-O-ethylene-OH, -propylene-O-propylene-OH, and methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, methylene, ethylene, propylene, butylene, and pentylene groups are optionally selected from 1 to 4 of deuterium, F, Cl, Br, =O, CN, OH, NH2, and C. 1- 4-alkyl, halogen-substituted C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

[0030] In some implementation schemes, R 2 The CH2 group is selected from H, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -C(CH3)2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2OH, -CH2OCH2OH, and -CH2OCH2OH, wherein the CH2 group is optionally substituted by 1 to 3 substituents selected from deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, and methyl.

[0031] In some implementation schemes, R 5 R a1 R a2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace.

[0032] In some implementation schemes, R 5 R a1 R a2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups.k replace.

[0033] In some implementation schemes, R 5 R a1 R a2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. k replace.

[0034] In some implementation schemes, R 5 Each is independently selected from deuterium, F, Cl, Br, CN, OH, CD3, CHD2, CH2D, CF3, CHF2, CH2F, and methyl.

[0035] In some implementation schemes, R Y1 R Y2 Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace.

[0036] In some implementation schemes, R Y1 R Y2 Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace.

[0037] In some implementation schemes, R Y1 R Y2 Each alkyl group is independently selected from H, deuterium, F, Cl, Br, methyl, and ethyl, wherein the alkyl group is optionally surrounded by 1 to 4 R atoms. k replace.

[0038] In some implementation schemes, R Y3 R a3 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace.

[0039] In some implementation schemes, R Y3 R a3 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace.

[0040] In some implementation schemes, R Y3 R a3each independently selected from H, deuterium, methyl, ethyl, said alkyl is optionally substituted with 1 to 4 R k substituted.

[0041] In some embodiments, R Y1 , R Y2 and the carbon atom to which they are attached together form a C 3-6 carbocyclyl, said carbocyclyl is optionally substituted with 1 to 4 R k substituted.

[0042] In some embodiments, R Y1 , R Y2 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl, said cycloalkyl is optionally substituted with 1 to 4 R k substituted.

[0043] In some embodiments, R Y1 , R Y2 and the carbon atom to which they are attached together form a C k cycloalkyl, said cycloalkyl is optionally substituted with 1 to 4 R substituted.

[0044] In some embodiments, ring A is selected from

[0045] In some embodiments, ring A 1 is selected from

[0046] In some embodiments, ring A 2 is selected from

[0047] In some embodiments, Z is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and C 4-6 carbocyclyl.

[0048] In some embodiments, Z is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and C 4-6 carbocyclyl.

[0049] In some embodiments, Z is selected from phenyl, naphthyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroloyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indole, isoindole, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindole, benzothiophene, benzothiazolyl, benzofuranyl, benzooxazolyl, and benzene. Benzpyrrolyl, benzopyrazolyl, benzoimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrrolopyridinyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, imidazopyridyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyridazinyl, imidazopyridazinyl In some implementation schemes, Z is selected from

[0050] In some implementation schemes, Z 1 Selected from benzo[C] 4-6 Carbocyclic groups, benzo[4- to 6-membered heterocyclic groups.

[0051] In some implementation schemes, Z 1 Selected from

[0052] In some implementation schemes, Z 2 Selected from 5- to 10-membered heteroaryl groups, benzo[a]C 4-6 Carbocyclic, benzo4-6-membered heterocyclic, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, C 4-6 Carbon cyclic group.

[0053] In some implementation schemes, Z 3 Selected from pyridine.

[0054] In some implementation schemes, Z 4 Selected from thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0055] In some implementations, Q is selected from -C(R) q1 R q2 ) p - In some implementations, Q is selected from -CH2-.

[0056] In some implementation schemes, Q 1 Selected from C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace.

[0057] In some implementation schemes, Q 1 Selected from cyclopropyl, cyclobutyl, and cyclopentyl, the Q... 1 It may be optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, CF3, and methoxy.

[0058] In some implementation schemes, Selected from Preferred

[0059] In some implementations, p is selected from 1 or 2.

[0060] In some implementation schemes, R q1 R q2 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0061] As an option, any R q1 With R q2 Direct connection forms C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace.

[0062] In some implementation schemes, R q1 R q2 Each is independently selected from H, deuterium, or arbitrarily selected from 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, pyrrolidinyl, piperidinyl, morpholinyl;

[0063] As an option, any R q1 With R q2 Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl.

[0064] In some implementation schemes, R q1 R q2 Each is independently selected from H, deuterium, methyl, CF3, CD3, and CH2CF3;

[0065] As an option, any R q1 With R q2 Direct connection forms an optional 1 to 4 R ksubstituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C

[0066] In some embodiments, R 3 is selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 1- alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or halogen substituted C 1-6 alkyl.

[0067] In some embodiments, R 3 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, -C 1-5 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy.

[0068] In some embodiments, R 3Selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2C H2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH 2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, the R 3 It may be optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, and ethoxy.

[0069] In some implementation schemes, R 3a Selected from -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 alkylene-OH, wherein the alkylene group is optionally surrounded by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 Alkyl groups are substituted.

[0070] In some implementation schemes, R 3a-CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2CH2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, said CH2groups being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, ethoxy.

[0071] In some embodiments, R b each independently selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, optionally substituted with one to four R k one of the following groups: C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, SF5, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3 to 7 membered heterocyclyl;

[0072] as a single bond, or any R q1 is directly connected to R b to form a C 4-6 carbocyclyl or 4 to 7 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with one to four R kreplace.

[0073] In some implementation schemes, R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, or optionally coated by 1 to 4 R. k One of the following groups is substituted: C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, SF5, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, -CH2-C 3-6 Carbocyclic groups, -CH2-3 to 7-membered heterocyclic groups, -C 2-3 Iso-ynyl-C 3-6 carbonyl group, -C 2-3 Ethyne-3 to 7-membered heterocyclic groups;

[0074] As an option, any R q1 With R b Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the carbocyclic or heterocyclic group is optionally replaced by 1 to 4 R groups. k replace.

[0075] In some implementation schemes, R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, or optionally coated by 1 to 4 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, SF5, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroloyl, morpholinyl, phenyl, NHCH3, N(CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-aziridine Cyclobutyl, -O-oxetanebutyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azacyclobutyl, -NH-oxetanebutyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxetanebutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl

[0076] In some implementation schemes, R b Each is independently selected from F, Cl, Br, I, OH, CN, CF3, CHF2, CH2F, CD3, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, SF5, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, NHCH3, N(CH3)2, -O-cyclopropyl;

[0077] As an option, any R q1 With R b Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the carbocyclic or heterocyclic group is optionally replaced by 1 to 4 R groups. k replace.

[0078] In some implementation schemes, R b1 Selected from deuterium, NH2, SF5, C 1-6 Alkyl, -OC 1-6 Alkyl group, wherein the alkyl or alkoxy group is surrounded by 1 to 4 atoms selected from deuterium, Cl, Br, I, CN, OH, NH2, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl, 3- to 7-membered heterocyclic groups, or R b1 Selected from 1 to 4 Rs k One of the following groups is substituted: 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 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 0-4 Alkylene-C 3-6 carbonyl group, -C 0-4 alkylene-3 to 7-membered heterocyclic groups, -C 0-4 Alkylene-C 3-6 carbonyl group, -C 2-4 Iso-ynyl-C 3-6 carbonyl group, -C 2-4 Ethyne-3 to 7-membered heterocyclic groups.

[0079] In some implementation schemes, R b1SF5, SCF3, oxetanyl, ethynyl, propynyl, propargyl, the oxetanyl, ethynyl, propynyl, propargyl, optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =0, CN, OH, NH2, methyl.

[0080] In some embodiments, R b2 is selected from deuterium, NH2, SF5, or one of the following groups optionally substituted with 1 to 4 R k substituents: 1-6 alkyl,

[0081] vinyl, ethynyl, 3- to 7-membered heterocyclyl, -ethynyl-C 3-6 carbocyclyl, -ethynyl-3- to 7-membered heterocyclyl.

[0082] In some embodiments, R 4 , R a are each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents.

[0083] In some embodiments, R 4 , R a are each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, C 3-6carbocyclyl, 3- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-3- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents.

[0084] In some embodiments, R 4 , R a each independently is selected from H, deuterium, halogen, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, NHCH3, N(CH3)2, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, -O-cyclopropyl, -O-cyclobutyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azetidinyl, -NH-oxetanyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents.

[0085] In some embodiments, R k each independently is selected from deuterium, =O, halogen, CN, OH, COOH, NH2, SF5, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy.

[0086] In some embodiments, R k each independently is selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, or heterocyclyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy.

[0087] In some embodiments, R k each independently is selected from the group consisting of deuterium, =0, F, Cl, Br, I, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

[0088] In some embodiments, R kEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, SF5, -S-CHF2, -S-CF3, -SCH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0089] In some implementations, n is independently selected from 0, 1, 2, 3, 4, 5, or 6. In some implementations, n is independently selected from 0, 1, 2, 3, or 4. In some implementations, n is independently selected from 0, 1, or 2.

[0090] In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0, 1, or 2.

[0091] In some implementations, n1 is selected from 1, 2, 3 or 4.

[0092] In some implementations, n2 is selected from 0, 1, 2, or 3;

[0093] Choose any location, except for the area around AA.

[0094] Choose any location

[0095] 1) When ring A is selected Ring R q1 With R q2 Not directly connected to form a loop or R q1 With R b Instead of directly connecting to form a loop, Z is selected from C. 6-10 For aryl, n is selected from 1, 2, 3, or 4, and there is at least one R. b For R b1 R b1 Selected from deuterium, NH2, SF5, C 1-6 Alkyl, -OC 1-6 Alkyl group, wherein the alkyl or alkoxy group is surrounded by 1 to 4 atoms selected from deuterium, Cl, Br, I, CN, OH, NH2, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl, 3- to 7-membered heterocyclic groups, or R b1 Selected from 1 to 4 Rs k One of the following groups is substituted: SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3 to 7 membered heterocyclyl;

[0096] 2) ring A is selected from Q is selected from CH2and Z is selected from pyridyl, n is selected from 1, 2, 3 or 4;

[0097] 3) when ring A is selected from Z is selected from C 6-10 aryl, n is selected from 1, 2, 3 or 4, and at least one R b is R b2 , R b2 is selected from deuterium, NH2, SF5or one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, vinyl, ethynyl, 3 to 7 membered heterocyclyl, -ethynyl-C 3-6 carbocyclyl, -ethynyl-3 to 7 membered heterocyclyl;

[0098] 4) when ring A is selected from ring R q1 is not directly linked to ring R q2 or R q1 is not directly linked to ring R b , Z is selected from benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, R 3 is selected from R 3a , R 3a is selected from -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkylene-OH, said alkylene is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or halogen. 1- 6alkyl.

[0099] As a first embodiment of the present application, the above-mentioned compounds represented by the general formula (II), (I), (Ia), (Ib), (Ic) or (Id), or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, polymorphs, metabolites, prodrugs and isomers thereof,

[0100] Ring AA is selected from which is attached to Y at its lower side, and ring AA is not attached to Y by a heteroatom-heteroatom;

[0101] represents an aromatic or non-aromatic ring;

[0102] A1, A2, A3, A4are each independently selected from the group consisting of a bond, C(=O), O, S, N, NR a3 , CR a1 or CR a1 R a2 , at most one of A1, A2, A3, A4is a bond;

[0103] Ring W is selected from C 4-6 carbocyclyl or 4- to 6-membered heterocyclyl;

[0104] Y is selected from O, S, NR Y3 or CR Y1 R Y2 ;

[0105] R 1 is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, said R 1 is optionally substituted with 1 to 4 R k ;

[0106] R 5 , R a1 , R a2 are each independently selected from the group consisting of H, deuterium, halogen, CN, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R k ;

[0107] R 2 is selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C1-6 Alkylene-OH, wherein the alkylene group, alkyl group, heterocyclic group, or cycloalkyl group is optionally selected from one to four groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0108] R Y1 R Y2 Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0109] R Y3 R a3 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0110] As an option, R Y1 R Y2 Together with the carbon atoms attached to it, they form C 3-6 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0111] Ring A is selected from

[0112] Z is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, benzo[a]C 4-6 Carbocyclic, benzo4-6-membered heterocyclic, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, C 4-6 carbon cyclo group;

[0113] Q is selected from -C(R) q1 R q2 ) p -;

[0114] p is selected from 1 or 2;

[0115] R q1 R q2 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0116] As an option, any R q1 With R q2 Direct connection forms C 3-6cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 R k substituted;

[0117] R 3 selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or halogen; 1-6 substituted by 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C

[0118] R b each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, optionally substituted with 1 to 4 R k one of the following groups: C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, SF5, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3- to 7-membered heterocyclyl;

[0119] as an alternative, any R q1 is directly linked to form C b is directly linked to form C 4-6 carbocyclyl or 4- to 7-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituted;

[0120] R 4 , R aeach independently selected from the group consisting of H, deuterium, halogen, OH, CN, NH2, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 substituents independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC k ;

[0121] m is 0, 1, 2, 3 or 4;

[0122] R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 substituents independently selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0123] n is each independently selected from 0, 1, 2, 3, 4;

[0124] with the proviso that the ring AA of general formula (II) is not selected from

[0125] with the proviso that general formula (I):

[0126] 1 ) when the ring A is selected from ring Rq1 R q2 not directly connected to form a ring or R q1 R b not directly connected to form a ring, Z is selected from C 6-10 aryl, n is selected from 1, 2, 3 or 4, and at least one R b is R b1 , R b1 is selected from deuterium, NH2, SF5, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl or alkoxy is substituted with 1 to 4 substituents selected from deuterium, Cl, Br, I, CN, OH, NH2, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 7 membered heterocyclyl, or R b1 is selected from one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3 to 7 membered heterocyclyl;

[0127] 2) ring A is selected from Q is selected from CH2, and Z is selected from pyridyl, n is selected from 1, 2, 3 or 4;

[0128] 3) when ring A is selected from Z is selected from C 6-10 aryl, n is selected from 1, 2, 3 or 4, and at least one R b is R b2 , R b2 is selected from deuterium, NH2, SF5, or one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, vinyl, ethynyl, 3 to 7 membered heterocyclyl, -ethynyl-C 3-6 carbocyclyl, -ethynyl-3 to 7 membered heterocyclyl;

[0129] 4) When ring A is selected from Ring R q1 With R q2 Not directly connected to form a loop or R q1 With R b Z is selected from benzo[C] and does not directly form a ring. 4-6 When R is a carbocyclic group or a benzo[4] to 6-membered heterocyclic group, 3 Selected from R 3a R 3a Selected from -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 alkylene-OH, wherein the alkylene group is optionally surrounded by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 Alkyl groups are substituted.

[0130] As a second embodiment of the present invention, the compound represented by the above general formulas (II), (I), (Ia), (Ib), (Ic) or (Id), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is used.

[0131] Ring W is selected from non-aromatic C 4-6 Carbocyclic or non-aromatic 4- to 6-membered heterocyclic groups;

[0132] R 1 Selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo[C] 4-6 Carbocyclic, benzo4-6-membered heterocyclic, 5-6-membered heteroaryl, 5-6-membered heteroaryl, said R 1 Choose from 1 to 4 Rs k replace;

[0133] R 5 R a1 R a2 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0134] R 2 Selected from H, deuterium, and C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4 to 7-membered heterocyclic groups, -C1-5 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl are optionally substituted with one to four substituents independently selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, said substituents of alkyl, C

[0135] R Y3 , R a3 each independently selected from the group consisting of H, deuterium, C 1-4 alkyl, said alkyl is optionally substituted with one to four R k substituents;

[0136] R Y1 , R Y2 each independently selected from the group consisting of H, deuterium, halogen, C 1-4 alkyl, said alkyl is optionally substituted with one to four R k substituents;

[0137] R Y1 , R Y2 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl, said cycloalkyl is optionally substituted with one to four R k substituents;

[0138] R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, said substituents of alkyl, C

[0139] Z is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo[C] 4-6 Carbocyclic, benzo4-6-membered heterocyclic, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, C 4-6 carbon cyclo group;

[0140] R q1 R q2 Each is independently selected from H, deuterium, or arbitrarily selected from 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, pyrrolidinyl, piperidinyl, morpholinyl;

[0141] As an option, any R q1 With R q2 Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0142] R 3 Selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-5 alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkylene-OH, wherein the alkylene group, alkyl group, heterocyclic group, or cycloalkyl group is optionally selected from one to four groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0143] R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, or optionally coated by 1 to 4 R. k One of the following groups is substituted: C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, SF5, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6carbocyclyl, -NH-3- to 7-membered heterocyclyl, C 3-6 carbocyclyl, -CH2-3- to 7-membered heterocyclyl, -C 3-6 carbocyclyl, -CH2-3- to 7-membered heterocyclyl, -C 2-3 alkynylene-C 3-6 carbocyclyl, -C 2-3 alkynylene-3- to 7-membered heterocyclyl;

[0144] R q1 , R b directly linked to form an optionally substituted carbocyclyl or 3- to 7-membered heterocyclyl; k substituted with 1 to 4 R k ;

[0145] R 4 , R a each independently selected from the group consisting of H, deuterium, halogen, OH, CN, NH2, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 3- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-3- to 7-membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;

[0146] the remaining groups are defined as in the first embodiment of the present application.

[0147] as the third embodiment of the present application, the above-mentioned compounds of the general formula (II), (I), (Ia), (Ib), (Ic) or (Id) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

[0148] at most two of A1, A2, A3, A4are selected from the group consisting of O, S, N or NR a3 ;

[0149] W is selected from the group consisting of cyclobutenyl, cyclopentenyl, oxol enyl, oxol enyl, 1,3-dioxol enyl;

[0150] R 1 is selected from the group consisting of phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and said R 1 is optionally substituted with 1 to 4 R k ;

[0151] R 5 , R a1 , and R a2 are each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and said alkyl groups are optionally substituted with 1 to 4 R k ;

[0152] R Y3 , R a3 are each independently selected from the group consisting of H, deuterium, methyl, ethyl, and said alkyl groups are optionally substituted with 1 to 4 R k ;

[0153] R Y1 , R Y2 are each independently selected from the group consisting of H, deuterium, F, Cl, Br, methyl, ethyl, and said alkyl groups are optionally substituted with 1 to 4 R k ;

[0154] alternatively, R Y1 , R Y2 and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, and said cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 R k ;

[0155] Z is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridyl, pyrazolopyrimidyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridyl, imidazopyrimidyl, imidazopyrazinyl, imidazopyridazinyl,

[0156] R q1 , R q2 are each independently selected from H, deuterium, methyl, CF3, CD3, CH2CF3;

[0157] Alternatively, any R q1 is directly connected to R q2 to form the following group optionally substituted with 1 to 4 R k cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl;

[0158] R 3Selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-oxacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2C H2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH 2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, the R 3 It may be optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, and ethoxy;

[0159] R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, or optionally coated by 1 to 4 R. k The substitution may be made with one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, SF5, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, pyrazolyl, pyrroloyl, morpholinyl, phenyl, NHCH3, N(CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-aziridine Cyclobutyl, -O-oxetanebutyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azacyclobutyl, -NH-oxetanebutyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azacyclobutyl, -CH2-oxetanebutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl

[0160] As an option, any R q1 With R b Direct connection forms an optional 1 to 4 R ksubstituted with 1 to 4 R k substituted;

[0161] R 4 , R a each independently selected from H, deuterium, halogen, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, NHCH3, N(CH3)2, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, -O-cyclopropyl, -O-cyclobutyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azetidinyl, -NH-oxetanyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k substituted;

[0162] the remaining groups are defined as in the first or second embodiment of the application.

[0163] As a fourth embodiment of the application, the above-mentioned compounds of general formula (II), (IIa), (IIb) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, polymorph, ester, prodrug, or isotope thereof,

[0164] ring AA is selected from which is attached to Y at its lower side and which is not attached to Y via a heteroatom-heteroatom;

[0165] each n is independently selected from 0, 1, 2;

[0166] R 2H, deuterium, methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, -methylene-OH, -ethylene-OH, -propylene-OH, -butylene-OH, -pentylene-OH, -methylene-O-methylene-OH, -ethylene-O-methylene-OH, -ethylene-O-ethylene-OH, -propylene-O-ethylene-OH, -propylene-O-propylene-OH, said methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methylene, ethylene, propylene, butylene, pentylene optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, =O, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 1-4 halo-substituted C 1-4 halo-substituted C 1-4 halo-substituted C

[0167] R k each independently selected from the group consisting of deuterium, =O, F, Cl, Br, I, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 halo-substituted C 1-4 halo-substituted C

[0168] the remaining radicals are as defined for the first, second or third embodiment of the present application.

[0169] As a fifth embodiment of the present application, the above-mentioned compounds of the general formula (II), (Ila), (lib) or racemates, stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, polymorphs, tautomers, prodrugs, metabolites, isomers, hydrates and optical isomers thereof,

[0170] Y is selected from O, S, NH or CH2; preferably CH2; R 1 selected from optionally 1 to 3 R k substituted with the following groups: preferably R 1 selected from

[0171] R 2H, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -C(CH3)2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2OH, -CH2OCH2OH, said CH2groups being optionally substituted with 1 to 3 substituents selected from the group consisting of deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, methyl;

[0172] R 5 each independently selected from the group consisting of deuterium, F, Cl, Br, CN, OH, CD3, CHD2, CH2D, CF3, CHF2, CH2F, methyl;

[0173] R k each independently selected from the group consisting of deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, SF5, -S-CHF2, -S-CF3, -SCH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably, R k each independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH2, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, SF5, -S-CHF2, -S-CF3, -SCH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, methoxy, ethoxy;

[0174] the remaining groups are defined as in the first, second, third or fourth embodiment of the present application.

[0175] As a sixth embodiment of the present application, the above-mentioned compounds of general formula (I), (la), (lb), (lc), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

[0176] R b1 selected from the group consisting of deuterium, NH2, SF5, C 1-6 alkyl, -OC 1-6alkyl, said alkyl or alkoxy is substituted with one to four substituents selected from the group consisting of deuterium, CI, Br, I, CN, OH, NH2, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with one to four substituents selected from the group consisting of deuterium, F, CI, Br, I, CN, OH, NH2, C

[0177] or R b1 is selected from one of the following groups, which is optionally substituted with one to four R k substituents: SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3- 6carbocyclyl, -C 0-4 alkylene-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3- to 7-membered heterocyclyl;

[0178] R b2 is selected from one of the following groups, which is optionally substituted with one to four R k substituents: SC 1-6 alkyl, vinyl, ethynyl, 3- to 7-membered heterocyclyl, -ethynyl-C 3-6 carbocyclyl, -ethynyl-3- to 7-membered heterocyclyl;

[0179] Q 1 is selected from C 3-6 cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with one to four R k substituents;

[0180] Ring B is selected from C 4-6 cycloalkyl or 4- to 7-membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being optionally substituted with one to four R k substituents;

[0181] Z 1 is selected from benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl;

[0182] R 3a is selected from -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C1-6 alkylene-OH, said alkylene is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or halogen substituted C 1-6 alkyl, or is unsubstituted;

[0183] n1 is selected from 1, 2, 3 or 4;

[0184] n2 is selected from 0, 1, 2 or 3;

[0185] the remaining group definitions are identical with the first, second or third embodiment of the present application.

[0186] As a seventh embodiment of the present application, the above-mentioned compounds of general formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

[0187] R b1 is selected from SF5, SCF3, oxetanyl, ethynyl, propynyl, propargyl, said oxetanyl, ethynyl, propynyl, propargyl, optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, =0, CN, OH, NH2, methyl;

[0188] R b2 is selected from NH2, SF5 or one of the following groups optionally substituted with 1 to 4 R k SCF3, oxetanyl, ethynyl, propynyl, propargyl,

[0189] Q 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, said Q 1 optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, =0, CN, OH, NH2, methyl, CF3, methoxy;

[0190] Q is selected from -CH2-;

[0191] is selected from is preferably

[0192] R 3a-CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2CH2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, said CH2groups being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, ethoxy;

[0193] Z is selected from the group consisting of

[0194] Z 1 is selected from the group consisting of

[0195] R k each independently selected from the group consisting of deuterium, F, Cl, Br, CN, OH, CD3, CHD2, CH2D, CF3, CHF2, CH2F, methyl;

[0196] the remaining group definitions are the same as in the first, second, third, sixth embodiment of the present application.

[0197] As an eighth embodiment of the present application, the following compounds of the general formula (IIa), (IIb) or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof,

[0198] R 5 each independently selected from the group consisting of deuterium, F, Cl, Br, CN, OH, CD3, CHD2, CH2D, CF3, CHF2, CH2F, methyl;

[0199] Ring AA is selected from

[0200] R 2 selected from H, -methylene-OH, -ethyl ene-OH, -propylene-OH, -butylene-OH, -pentylene-OH, -methylene-O-methylene-OH, -ethyl ene-O-methylene-OH, -ethyl ene-O-ethyl ene-OH, -propylene-O-ethyl ene-OH, -propylene-O-propylene-OH, said methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, methylene, ethylene, propylene, butylene, pentylene groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, CI, Br, =0, CN, OH, NH2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy; preferably, R 2 selected from H, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -C(CH3)2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2OH, -CH2OCH2OH, said CH2groups are optionally substituted with 1 to 3 substituents selected from deuterium, F, CI, Br, CN, OH, CF3, CHF2, CH2F, methyl;

[0201] m is 0, 1, 2;

[0202] k1 is selected from 1, 2;

[0203] the remaining group definitions are the same as in the first, second, third, fourth, or fifth embodiment of the invention.

[0204] The present invention relates to a compound as shown below or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown below in Table E.

[0205] Table E

[0206] The present application relates to a pharmaceutical composition comprising any of the above-mentioned compounds, racemates, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0207] The present application relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds of the present application, racemates, stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0208] In some embodiments, the pharmaceutical composition of the present application can be in the form of a unit dosage formulation (the amount of the main drug in the unit dosage formulation is also referred to as "formulation specification").

[0209] "Effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., one or more symptoms selected from conditions affecting hair growth, preferably hair loss or baldness). In some embodiments, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein that is required to provide a clinically significant decrease in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 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, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 80-1000 mg, 80-800 mg.

[0210] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 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, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present application or a stereoisomer, pharmaceutically acceptable salt, or co-crystal thereof.

[0211] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of the compound of the present application or a stereoisomer, pharmaceutically acceptable salt, or co-crystal thereof, the disease selected from the group consisting of conditions affecting hair growth (preferably hair loss or baldness).

[0212] A method for treating or alleviating a disease in a mammal, the method comprising administering to the subject a pharmaceutical compound of the present application or a stereoisomer, pharmaceutically acceptable salt, or co-crystal thereof in a daily dose of 1-1000 mg / day, the daily dose can be in a single dose or in divided doses, in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0213] The present application relates to a kit which can include a composition in single or multiple dose form, comprising a compound of the present application or a stereoisomer, a pharmaceutically acceptable salt thereof, a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt of a compound of the present application in the same amount as in the above pharmaceutical composition.

[0214] The present application relates to the use of any of the above-mentioned compounds or a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof for the manufacture of a medicament for growing hair.

[0215] The present application relates to the use of the above-mentioned pharmaceutical composition for the manufacture of a medicament for growing hair.

[0216] The amount of the compound of the present application, a racemate, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof is in each case calculated as the free base.

[0217] Synthesis method one:

[0218] X is selected from halogen or OTf, OTs, OMs, preferably from Br, I, OTf, OMS;

[0219] The remaining groups are defined as in the specification.

[0220] The compound of general formula (C1-1) is reacted by Vilsmeier reaction to obtain the compound of general formula (C1-2);

[0221] The compound of general formula (C1-2) is reacted by substitution reaction with the compound of general formula (C1-3) to obtain the compound of general formula (C1-4);

[0222] The compound of general formula (C1-4) is reacted by condensation reaction with methyl cyanoacetate to obtain the compound of general formula (C1-5);

[0223] The compound of general formula (C1-5) is reacted by hydrolysis to obtain the compound of general formula (C1-6);

[0224] The compound of general formula (C1-6) is reacted by condensation with the compound of general formula (C1-7) to obtain the compound of general formula (C1).

[0225] Synthesis method two:

[0226] X is selected from halogen or OTf, OTs, OMs, preferably from Br, I, OTf, OMS;

[0227] The remaining groups are defined as in the specification.

[0228] The compound of general formula (B1-1) is reacted by Vilsmeier reaction to obtain the compound of general formula (B1-2);

[0229] The compound of general formula (B1-4) is obtained from the compound of general formula (B1-2) and the compound of general formula (B1-3) through a substitution reaction;

[0230] The compound of general formula (B1-4) is obtained from the compound of general formula (B1-2) and the compound of general formula (B1-3) through a substitution reaction;

[0231] The compound of general formula (B1-5) is obtained from the compound of general formula (B1-4) through a condensation reaction;

[0232] The compound of general formula (B1) is obtained from the compound of general formula (B1-6) and the compound of general formula (B1-7) through a condensation reaction.

[0233] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0234] The compounds of the present application include racemates, stereoisomers, tautomers, isotopically substituted compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof.

[0235] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present application include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present application is optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C、 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O、 17 O and 18 O, the isotopes of sulfur include 32 S、 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0236] “CN” refers to a cyano group.

[0237] “Halogen” refers to F, Cl, Br or I.

[0238] "Halo" means F, Cl, Br or I substitution, 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, 1 to 4 substituents selected from F, Cl, Br or I. "Halo" is a short form for "halogen substituted."

[0239] "Alkyl" means a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neopentyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0240] "Heteroalkyl" means 1 or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms in an alkyl group are replaced by a heteroatom (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-H (v is an integer from 1 to 5, and each X is independently selected from a bond or a heteroatom, including but not limited to N, O or S, and at least one X is selected from a heteroatom, and N or S in the heteroatom can be oxidized to various oxidation states). Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0241] "Alkylene" means a substituted or unsubstituted straight chain and branched chain divalent saturated hydrocarbon group, including -(CH2) v (v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene, etc.

[0242] "Heteroalkylene" means 1 or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms in an alkylene group are replaced by a heteroatom (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-, v is an integer from 1 to 5, and each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0243] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms, cycloalkyl groups can be monocyclic, fused, bridged and spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl fused cyclobutyl, cyclobutyl spirocyclobutyl, adamantyl, etc. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0244] "Heterocycloalkyl" refers to substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon groups, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se, the C, N, S of the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be monocyclic, annulated, bridged, and spirocyclic. Heterocycloalkyl groups can be attached at a heteroatom or carbon atom, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, Heterocycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0245] "Alkenyl" refers to substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon groups having at least one, usually one, two, or three carbon-carbon double bonds, the main chain including but 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 ethenyl, 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, and the like; alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0246] "Alkynyl" refers to substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon groups having at least one, usually one, two, or three carbon-carbon triple bonds, the main chain including 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonyl, 3-nonyl, 1-decynyl, 4-decynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0247] "Alkoxy" means a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy.

[0248] "Carbocyclyl" or "carbocyclic" means a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic ring system, which can be attached to the rest of the molecule at a carbon atom of the ring, and which optionally is mono-, bi-, or spiro-cyclic. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-l-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene, naphthalene, indane, tetralin, biphenyl, terphenyl, and the like. "Carbocyclyl" or "carbocyclic" can be monovalent, divalent, trivalent, or tetravalent.

[0249] "Heterocyclyl" or "heterocyclic" means a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic ring system, which contains 1 or more (including, but not limited to, 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se, and which optionally is mono-, bi-, or spiro-cyclic. The ring of a heterocyclyl group optionally has one or more (including, but not limited to, 2, 3, 4, or 5) ring carbon atoms oxidized to form various oxidized states of carbonyl, epoxide, or other ring-oxidized states. The heterocyclyl group can be attached to the rest of the molecule at any heteroatom or carbon atom, and can be attached to the rest of the molecule through a ring carbon or a ring heteroatom. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantanyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0250] "Spirocycle" or "spirocyclyl" refers to a polycyclic group sharing one atom (referred to as the spiro atom) between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings can contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, S(=0)n or O, wherein n is 0, 1, or 2). n

[0251] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0252] "Fused cycle" or "fused cyclyl" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings can contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and can be substituted or unsubstituted, each ring in the fused system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, S(=0)n or O, wherein n is 0, 1, or 2). The number of ring atoms in the fused system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: n

[0253] "Fused cycle" or "fused cyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0254] "Bridge cycle" or "bridge cyclyl" refers to a polycyclic group containing any two non-adjacent atoms, which can contain 0 or more double bonds, substituted or unsubstituted, any ring in the bridge system can contain 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, S(=0)n or O, wherein n is 0, 1, 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.

[0255] Non-limiting examples include Cubane, adamantane. "Bridge cycle" or "bridge cyclyl" can be monovalent, divalent, trivalent, or tetravalent.

[0256] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl", or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0257] "Carbofused cycle", "fused carbocyclyl", "fused carbocyclyl", or "carbofused cyclyl" refers to a "fused cycle" in which the ring system consists only of carbon atoms. ​​

[0258] "Carbocyclo", "carbocyclo ring", "carbocyclo ring group", "carbocyclo ring group" or "carbocyclo ring group" means a "bridged ring" consisting of only carbon atoms.

[0259] "Heteromonocyclo", "monocyclo heterocyclo group" or "heteromonocyclo group" means a "heterocyclo group" or "heterocyclo" of a monocyclo system,

[0260] "Heteronuclear", "heteronuclear", "heteronuclear" or "heteronuclear" means a "nuclear ring" containing heteroatoms.

[0261] "Heterospiro", "heterospiro", "heterospiro" or "heterospiro" means a "spiro ring" containing heteroatoms.

[0262] "Heterobridging", "heterobridging", "heterobridging" or "heterobridging" means a "bridged ring" containing heteroatoms.

[0263] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, the number of ring atoms in the aromatic ring including but 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 carbocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0264] "Heteroaryl" or "heteroaromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S ( = O) n or Se ( = O) n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring including but not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S on the ring are optionally oxidized (i.e. C ( = O), NO, S ( = O) n, Se ( = O) n, n is 1, 2), non-limiting examples of heteroaryl groups include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include The heteroaryl appearing herein is defined in accordance with the present definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the connection site is on the ring with aromaticity.

[0265] "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, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) m S(=O) n R a -(CH2) m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0266] "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.

[0267] A ring of X-Y members (X, Y are integers, and 3 < X < Y, X < Y < 20 is selected from any integer between 4 and 20) includes a ring of X, X+1, X+2, X+3, X+4,... Y members. A ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heteroannular ring, a heterospiro ring, or a heterobridged ring. For example, "4-7 membered heteromonocyclic ring" means a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heteroannular ring" means a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroannular ring.

[0268] C x-y A carbocyclic ring (including an aryl group, a cycloalkyl group, a monocyclic carbocyclic ring, a spiro carbocyclic ring, an annular carbocyclic ring, or a bridged carbocyclic ring) includes a ring of C x , C x+1 , C x+2 , C x+3 , C x+4 ... C y members (x is an integer, and 3 < x < y, y is selected from any integer between 4 and 20), for example. For example, a "C3-C10 cycloalkyl group" means a C3, C4, C5, C6, C7, C8, C9, or C10 cycloalkyl group. 3-6 A cycloalkyl group" means a C3, C4, C5, or C6 cycloalkyl group.

[0269] When a group has one or more available sites for connection, any one or more sites of the group can be connected to other groups by a chemical bond. When the connection mode of the chemical bond is not fixed, and there is a hydrogen atom at the available site, the number of H atoms at the site will be reduced to the corresponding valence number of groups corresponding to the number of chemical bonds connected. For example indicates that any available site on the piperidyl group can be connected to other groups by 1 chemical bond, at least including The 4 connection modes, even if H atoms are drawn on -N- also include For example indicates that the R group on the piperidyl group can be on C or on N, at least including

[0270] When the connection group listed does not indicate its connection direction, its connection direction includes the direction of reading from left to right and from right to left, for example A-L-B, L is selected from -M-W-, including A-M-W-B and A-W-M-B.

[0271] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and the description includes the event or circumstance occurring or not occurring. For example, "an alkyl group optionally substituted with F" means that the alkyl group can or can not 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.

[0272] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases, and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0273] "Pharmaceutical composition" means a mixture of one or more compounds of the present application, or stereoisomers, tautomers, deuterated analogs, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, where the "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0274] "Dosage form" means the weight of the main drug contained in each bottle, tablet or other unit of preparation.

[0275] "Carrier" means a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of an administered compound.

[0276] "Animal" means an organism including mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0277] "Stereoisomer" means isomers that have the same molecular formula but different three-dimensional structures due to the spatial arrangement of atoms. This includes enantiomers, diastereomers, and conformers.

[0278] "Tautomer" means isomers that differ in the position of a proton but not in the structure of the molecule, such as keto-enol isomers and amide-imidol isomers. DETAILED DESCRIPTION

[0279] The following examples illustrate the technical solutions of the present application, but the scope of protection of the present application includes but is not limited to this.

[0280] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shift (δ) is given in units of 10 6 (ppm). NMR is measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0281] MS is measured by Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0282] The determination of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0283] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.20mm. The specification of the product used in thin layer chromatography separation and purification is 0.4mm-0.5mm.

[0284] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0285] In order to achieve the purpose of the present application, the compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature according to the organic synthesis techniques known to those skilled in the art. The "commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aldrin Biochemical Technology Co., Ltd., Shanghai Macklin Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anjieke Chemical, Shanghai Titan Science and Technology Co., Ltd., Kelong Chemical, Bailingwei Technology Co., Ltd., etc.

[0286] TCFH: tetramethylchloroformamidinium hexafluorophosphate; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1

[0287] Retention time: if no special instructions are given in the examples, it represents the retention time corresponding to the analysis method.

[0288] Example 1: Preparation of compound 1

[0289] First step: synthesis of 1B

[0290] Under nitrogen protection, dry tetrahydrofuran (50mL) was added to 1A (5g, 51.50mmol), dry ice ethanol was cooled to about-60℃, then 2.0mol / L lithium diisopropylamide cyclohexane solution (7.17g, 66.95mmol) was slowly added to the reaction liquid, after adding, the reaction was stirred for 1.5 hours, then 2,2-diethoxyethyl acetate (9.98g, 56.65mmol) was slowly added to the reaction, after adding, the reaction was continued for 2 hours. The reaction liquid was added with water, extracted with ethyl acetate three times, dried, concentrated, and 1B (11g) was obtained.

[0291] Second step: synthesis of 1C

[0292] Dissolve 1B (10 g, 44.01 mmol) in 100 mL of tetrahydrofuran, then slowly add hydrazine hydrate (5.51 g, 88.02 mmol) into the reaction solution. After the addition, raise the temperature to 55 °C and react overnight. Cool the reaction solution to room temperature, then add water and extract with ethyl acetate three times. Dry the organic phase, then concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to obtain 1C (7.4 g, yield: 76%).

[0293] LCMS m / z = 222.1 [M+1] +

[0294] Third step: synthesis of 1D

[0295] Dissolve 1C (1.0 g, 4.52 mmol) in 10 mL of tetrahydrofuran, then slowly add concentrated hydrochloric acid (1.13 mL, 13.56 mmol). After the addition, raise the temperature to 55 °C and react overnight. Cool the reaction solution to room temperature, then add water and extract with ethyl acetate three times. Dry the organic phase, then concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain 1D (0.4 g, yield: 60%).

[0296] Fourth step: synthesis of 1E

[0297] Dissolve 1D (0.2 g, 1.36 mmol) in 10 mL of tetrahydrofuran, then add 3,5-bistrifluoromethylbenzyl bromide (0.50 g, 1.63 mmol) and cesium carbonate (0.66 g, 2.04 mmol). After the addition, react at room temperature overnight. Add 30 mL of saturated brine and 30 mL of ethyl acetate, stir and separate the layers. Collect the organic phase, wash with saturated brine twice, then dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to obtain 1E (0.27 g, yield: 53%).

[0298] Fifth step: synthesis of 1F

[0299] Dissolve 1E (0.27 g, 0.72 mmol) in 6 mL of ethanol, then add tert-butyl cyanoacetate (132.14 mg, 0.94 mmol) and L-proline (33.16 mg, 0.29 mmol) successively. After the addition, stir at room temperature under nitrogen protection overnight. During the reaction, yellow solids gradually precipitate. After the reaction is complete, add ice water to the mixture, stir for 5 min, filter, wash the filter cake with water, and dry to obtain 1F (280 mg, yield: 78%).

[0300] Sixth step: synthesis of compound 1

[0301] Compound 1 was prepared according to the following procedure: 1F (280 mg, 0.56 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to give Compound 1 (100 mg, yield: 40%).

[0302] LCMS m / z = 441.0 [M+1] +

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.70 (m, 2H), 8.67 - 8.59 (m, 1H), 8.24 - 8.12 (m, 2H), 8.11 - 8.03 (m, 1H), 7.56 - 7.45 (m, 1H), 6.09 (s, 2H).

[0304] Example 2: Preparation of Compound 2

[0305] First Step: Synthesis of 2A

[0306] 1D (0.2 g, 1.36 mmol) was dissolved in 10 mL of tetrahydrofuran, 3- (trifluoromethyl)benzyl bromide (0.39 g, 1.63 mmol) and cesium carbonate (0.66 g, 2.04 mmol) were added, and the mixture was stirred at room temperature overnight. 30 mL of saturated brine and 30 mL of ethyl acetate were added, the mixture was stirred to separate the layers, and the organic phase was collected. After washing with saturated brine twice, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to give 2A (0.17 g, yield: 41%).

[0307] Second Step: Synthesis of 2B

[0308] 2A (0.17 g, 0.56 mmol) was dissolved in 6 mL of ethanol, tert-butyl cyanoacetate (102.77 mg, 0.73 mmol) and L-proline (25.79 mg, 0.22 mmol) were added successively, and the mixture was stirred at room temperature overnight under nitrogen protection. During the reaction, yellow solids gradually precipitated. After the reaction was completed, ice water was added to the mixture, which was stirred for 5 min, filtered, and the filter cake was washed with water and dried to give 2B (165 mg).

[0309] Third Step: Synthesis of Compound 2

[0310] Compound 2 (60 mg, yield: 42%) was obtained by dissolving 2B (165 mg, 0.39 mmol) in 5 mL of dichloromethane, adding 1 mL of trifluoroacetic acid, stirring at room temperature for 1 hour, concentrating under vacuum, purifying the residue by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and lyophilizing the preparative liquid.

[0311] LCMS m / z = 373.0 [M+1] +

[0312] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 - 8.68 (m, 2H), 8.60 (s, 1H), 7.88 - 7.79 (m, 1H), 7.71 - 7.53 (m, 3H), 7.51 - 7.42 (m, 1H), 5.94 (s, 2H).

[0313] Example 3: Preparation of compound 3

[0314] First step: synthesis of 3A

[0315] Dissolve 3-formylindazole (0.2 g, 1.37 mmol) in 10 mL of tetrahydrofuran, add 3,5-bistrifluoromethylbenzyl bromide (0.50 g, 1.63 mmol) and cesium carbonate (0.66 g, 2.04 mmol), after adding, react at room temperature overnight. Add 30 mL of saturated brine and 30 mL of ethyl acetate, stir to separate the layers, collect the organic phase, wash with saturated brine twice, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to obtain 3A (0.23 g, yield: 45%).

[0316] Second step: synthesis of 3B

[0317] Dissolve 3A (0.23 g, 0.62 mmol) in 3 mL of ethanol, add tert-butyl cyanoacetate (113.78 mg, 0.81 mmol) and L-proline (28.55 mg, 0.25 mmol) in sequence, after adding, stir at room temperature under nitrogen protection overnight. Yellow solid gradually precipitates during the reaction, after the reaction is completed, add ice water to it, stir for 5 min, filter, wash the filter cake with water, and dry to obtain 3B (160 mg, yield: 52%).

[0318] Third step: synthesis of compound 3

[0319] Compound 3 (60 mg, yield: 42%) was obtained by dissolving 3B (160 mg, 0.32 mmol) in 5 mL of dichloromethane, adding 1 mL of trifluoroacetic acid, stirring at room temperature for 1 hour, concentrating under vacuum, purifying the residue by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and freeze-drying the preparative liquid.

[0320] LCMS m / z = 440.1 [M+1] +

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.26-8.14 (m, 3H), 8.11-8.03 (m, 2H), 7.63-7.50 (m, 1H), 7.45-7.33 (m, 1H), 6.04 (s, 2H).

[0322] Example 4: Preparation of compound 4

[0323] First step: synthesis of 4A

[0324] Dissolve 3-formylindazole (0.3 g, 2.05 mmol) in 10 mL of tetrahydrofuran, add 3-(trifluoromethyl)benzyl bromide (0.588 g, 2.46 mmol) and cesium carbonate (1.00 g, 3.07 mmol), add, and react at room temperature overnight. Add 30 mL of saturated brine and 30 mL of ethyl acetate, stir to separate the layers, collect the organic phase, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to obtain 4A (0.55 g, yield: 88%).

[0325] Second step: synthesis of 4B

[0326] Dissolve 4A (0.55 g, 1.81 mmol) in 6 mL of ethanol, add tert-butyl cyanoacetate (332.17 mg, 2.35 mmol) and L-proline (83.35 mg, 0.72 mmol) in sequence, add, stir at room temperature under nitrogen protection overnight. Yellow solid gradually precipitates during the reaction. After the reaction is completed, add ice water to it, stir for 5 min, filter, wash the filter cake with water, and dry to obtain 4B (770 mg).

[0327] Third step: synthesis of compound 4

[0328] Compound 4 (150 mg, yield: 22%) was obtained by the following procedure. Compound 4B (770 mg, 1.80 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and stirred at room temperature for 1 hour. Concentrated in vacuum, the residue was purified by preparative HPLC (Instrument: waters 2767 preparative liquid; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparative liquid was lyophilized to obtain compound 4 (150 mg, yield: 22%).

[0329] LCMS m / z = 372.3 [M+1] +

[0330] Example 5: Preparation of compound 5

[0331] First step: synthesis of 5B

[0332] Compound 5B (1.6 g, 3.72 mmol) was dissolved in 5 mL of trifluoroacetic acid, 5 mL of triethylsilane was slowly added dropwise, and the temperature was raised to 75°C for reaction for 2 hours. Concentrated, the residue was dissolved in dichloromethane, and then a proper amount of silica gel was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to obtain 5C (1.4 g, yield: 90%).

[0333] LCMS m / z = 431.1 [M+1] +

[0334] Second step: synthesis of 5C

[0335] Compound 5B (1.6 g, 3.72 mmol) was dissolved in 5 mL of trifluoroacetic acid, 5 mL of triethylsilane was slowly added dropwise, and the temperature was raised to 75°C for reaction for 2 hours. Concentrated, the residue was dissolved in dichloromethane, and then a proper amount of silica gel was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to obtain 5C (1.4 g, yield: 90%).

[0336] LCMS m / z = 417.1 [M+1] +

[0337] Third step: synthesis of 5D

[0338] To a solution of 5C (1.2 g, 2.88 mmol) in 30 mL of tetrahydrofuran, LiAlH4(2.5 M in THF, 2.3 mL, 5.76 mmol) was added slowly at ice water bath. After the addition, the mixture was stirred at 0 °C for 1 h. To the reaction mixture, 0.5 mL of water, 0.5 mL of 15% NaOH solution, and 0.5 mL of water were added successively. Then, anhydrous magnesium sulfate was added and stirred for 10 min. The mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to give 5D (440 mg, yield: 41%).

[0339] Fourth Step: Synthesis of 5E

[0340] To a solution of 5D (0.37 g, 0.99 mmol) in 50 mL of dichloromethane, activated manganese dioxide (0.52 g, 5.94 mmol) was added slowly. After the addition, the mixture was stirred at room temperature overnight. The mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to give 5E (260 mg, yield: 71%).

[0341] LCMS m / z = 373.1 [M+1] +

[0342] Fifth Step: Synthesis of 5F

[0343] To a solution of 5E (0.15 g, 0.40 mmol) in 3 mL of ethanol, tert-butyl cyanoacetate (73 mg, 0.52 mmol) and L-proline (18 mg, 0.16 mmol) were added successively. After the addition, the mixture was stirred at room temperature overnight under nitrogen. During the reaction, yellow solid was gradually precipitated. After the reaction, ice water was added to the mixture, stirred for 5 min, and filtered. The filter cake was washed with water and dried to give 5F (190 mg).

[0344] Sixth Step: Synthesis of Compound 5

[0345] To a solution of 5F (190 mg, 0.38 mmol) in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added. After the addition, the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to give Compound 5 (100 mg, yield: 60%).

[0346] LCMS m / z = 440.1 [M+1] +

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (dd, 1H), 8.58 (dd, 1H), 8.53 - 8.45 (m, 1H), 8.11 - 8.02 (m, 2H), 8.00 - 7.94 (m, 1H), 7.71 - 7.60 (m, 1H), 7.21 (dd, 1H), 4.62 (s, 2H).

[0348] Example 6: Preparation of compound 6

[0349] First step: synthesis of 6B

[0350] 6A (5.0 g, 18.72 mmol) was dissolved in 20 mL of DMSO, and ethyl propiolate (2.20 g, 22.46 mmol), pyridazine (1.80 g, 22.46 mmol), potassium carbonate (6.47 g, 46.8 mmol) were added in turn. After nitrogen replacement, the reaction was carried out at room temperature for 2 hours under nitrogen protection. After adding water, a large amount of solid was precipitated. After stirring and filtration, the filter cake was redissolved in ethyl acetate, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to obtain 6B (3.0 g, yield: 44%).

[0351] LCMS m / z = 363.1 [M+1] +

[0352] Second step: synthesis of 6C

[0353] 6B (2.8 g, 7.73 mmol) was dissolved in 5 mL of trifluoroacetic acid, and 5 mL of triethylsilane was slowly added dropwise. The temperature was raised to 75°C and the reaction was carried out for 2 hours. After concentration, the residue was redissolved in dichloromethane, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to obtain 6C (2.0 g, yield: 74%).

[0354] LCMS m / z = 349.1 [M+1] +

[0355] Third step: synthesis of 6D

[0356] To a solution of 6C (1.5 g, 4.31 mmol) in 20 mL of tetrahydrofuran, LiAlH4(2.5 M in THF, 3.5 mL, 8.62 mmol) was added slowly under ice-water bath. After the addition, the mixture was stirred at 0 °C for 1 h. To the ice-cold reaction mixture, 0.5 mL of water, 0.5 mL of 15% NaOH solution, and 0.5 mL of water were added successively dropwise. Then, anhydrous MgSO4was added and stirred for 10 min. The mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to give 6D (1.0 g, yield: 76%).

[0357] LCMS m / z = 307.1 [M+1] +

[0358] Fourth Step: Synthesis of 6E

[0359] To a solution of 6D (1.0 g, 3.26 mmol) in 50 mL of dichloromethane, active manganese dioxide (1.7 g, 19.56 mmol) was added slowly. After the addition, the mixture was stirred at room temperature overnight. The mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-3 / 1) to give 6E (850 mg, yield: 86%).

[0360] Fifth Step: Synthesis of 6F

[0361] To a solution of 6E (0.3 g, 0.99 mmol) in 5 mL of ethanol, tert-butyl cyanoacetate (182 mg, 1.29 mmol) and L-proline (46 mg, 0.4 mmol) were added successively. After the addition, the mixture was stirred at room temperature under nitrogen overnight. During the reaction, yellow solid was gradually precipitated. After the reaction, ice-water was added to the mixture, stirred for 5 min, filtered, and the filter cake was washed with water and dried to give 6F (400 mg).

[0362] Sixth Step: Synthesis of Compound 6

[0363] To a solution of 6F (400 mg, 0.94 mmol) in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added. After the addition, the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to give Compound 6 (250 mg, yield: 72%).

[0364] LCMS m / z = 372.1 [M+1] +

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (dd, 1H), 8.57 (dd, 1H), 8.49 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.63 - 7.50 (m, 3H), 7.20 (dd, 1H), 4.50 (s, 2H).

[0366] Example 7: Preparation of compound 7

[0367] First step: synthesis of 7B

[0368] Dissolve 3-(diethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.0 g, 4.52 mmol) in 10 mL DMF, add 7A (1.58 g, 4.97 mmol), potassium hydroxide (0.3 g, 5.42 mmol) under ice water bath, after addition, protect under nitrogen, react at room temperature for 2 hours. Add 30 mL saturated brine and 30 mL ethyl acetate, stir to separate layers, collect the organic phase, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1), to obtain 7B (0.42 g, yield: 20%).

[0369] LCMS m / z = 458.1 [M+1] +

[0370] Second step: synthesis of 7C

[0371] Dissolve 7B (0.2 g, 0.44 mmol) in 20 mL tetrahydrofuran, add propargyl (1.0 M in THF, 3.5 mL, 3.5 mmol), cuprous iodide (17 mg, 0.088 mmol), dichlorobis(triphenylphosphine)palladium (62 mg, 0.088 mmol), triethylamine (223 mg, 2.2 mmol), after addition, protect under nitrogen, heat to 60°C for 6 hours. Filter the reaction liquid through diatomite, concentrate the filtrate, purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1), to obtain 7C (190 mg, yield: 72%).

[0372] LCMS m / z = 418.1 [M+1] +

[0373] Third step: synthesis of 7D

[0374] Dissolve 7C (190 mg, 0.46 mmol) in 3 mL of tetrahydrofuran, add 3 mL of 4N H2SO4 solution, after adding, warm to 60°C and stir for 2 hours. Cool, add saturated sodium bicarbonate solution to alkaline, add 20 mL of ethyl acetate, stir and separate the organic phase, collect the organic phase, wash with saturated brine once, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 7D (150 mg).

[0375] Fourth step: synthesis of 7E

[0376] Dissolve 7D (0.15 g, 0.44 mmol) in 2 mL of ethanol, add tert-butyl cyanoacetate (80 mg, 0.57 mmol) and L-proline (20 mg, 0.18 mmol) in turn, after adding, stir at room temperature under nitrogen protection overnight. After the reaction is completed, add saturated brine and ethyl acetate to it, stir and separate the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 7E (60 mg, yield: 29%).

[0377] LCMS m / z = 467.2 [M+1] +

[0378] Fifth step: synthesis of compound 7

[0379] Dissolve 7E (60 mg, 0.13 mmol) obtained in the above step in 1 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. Concentrate in vacuum, purify the residue by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and freeze-dry the preparative liquid to obtain compound 7 (30 mg, yield: 57%).

[0380] LCMS m / z = 411.0 [M+1] +

[0381] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.71 (m, 2H), 8.60 (s, 1H), 7.81-7.74 (m, 1H), 7.68-7.57 (m, 2H), 7.53-7.45 (m, 1H), 5.93 (s, 2H), 2.04 (s, 3H).

[0382] Example 8: preparation of compound 8

[0383] Compound 4 (100 mg, 0.27 mmol) was dissolved in 5 mL of dichloromethane, ethylene glycol (83.79 mg, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (62.11 mg, 0.32 mmol), 4-dimethylaminopyridine (6.6 mg, 0.054 mmol) were added successively, protected by nitrogen, stirred at room temperature for 1 hour. 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, stirred and separated, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum, the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the preparative liquid was freeze-dried to obtain compound 8 (20 mg, yield: 18%).

[0384] LCMS m / z = 416.1 [M+1] +

[0385] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.19 (d, 1H), 8.01 (d, 1H), 7.93-7.82 (m, 1H), 7.75-7.64 (m, 2H), 7.63-7.52 (m, 2H), 7.47-7.31 (m, 1H), 5.96 (s, 2H), 4.97 (t, 1H), 4.42-4.25 (m, 2H), 3.82-3.62 (m, 2H).

[0386] Example 9: Preparation of compound 9

[0387] First step: synthesis of 9C

[0388] 9B (100 mg, 0.85 mmol) was dissolved in 3 mL of DMF, 9A (CAS: 954123-46-7, 324 mg, 1.02 mmol), potassium hydroxide (57 mg, 1.02 mmol) were added under ice water bath, after addition, protected by nitrogen, reacted at room temperature for 2 hours. 20 mL of saturated brine and 20 mL of ethyl acetate were added, stirred and separated, the organic phase was collected, washed with saturated brine twice, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 9C (0.26 g, yield: 86%).

[0389] LCMS m / z = 355.0 [M+1] +

[0390] Second Step: Synthesis of 9D

[0391] 9C (0.4 g, 1.13 mmol) was dissolved in 20 mL of tetrahydrofuran, propargyl (1.0 M in THF, 4.5 mL, 4.5 mmol), cuprous iodide (42 mg, 0.23 mmol), bis(triphenylphosphine)palladium dichloride (159 mg, 0.23 mmol), triethylamine (572 mg, 5.65 mmol) were added, and the reaction was heated to 60 °C under nitrogen protection for 6 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 9D (320 mg, yield: 90%).

[0392] LCMS m / z = 315.1 [M+1] +

[0393] Third Step: Synthesis of 9E

[0394] Phosphorus oxychloride (146 mg, 0.95 mmol) was added dropwise to 2 mL of DMF under an ice water bath, and the reaction was stirred at 0 °C for 10 min under nitrogen protection. 9D (300 mg, 0.95 mmol) dissolved in 2 mL of DMF was slowly added to the reaction solution, and the reaction was stirred at room temperature overnight under nitrogen protection. 10 mL of water and 20 mL of dichloromethane were added, and the organic phase was collected, washed twice with saturated brine, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 9E (300 mg, yield: 92%).

[0395] LCMS m / z = 343.1 [M+1] +

[0396] Fourth Step: Synthesis of 9F

[0397] 9E (300 mg, 0.88 mmol) was dissolved in 4 mL of ethanol, and tert-butyl cyanoacetate (162 mg, 1.14 mmol) and L-proline (41 mg, 0.35 mmol) were sequentially added. The reaction was stirred at room temperature overnight under nitrogen protection. A large amount of solid was precipitated during the reaction. After the reaction was completed, ice water was added, and the mixture was stirred and filtered. The filter cake was redissolved in dichloromethane, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 9F (350 mg, yield: 86%).

[0398] Fifth Step: Synthesis of Compound 9

[0399] Compound 9 (150 mg, yield: 85%) was obtained by the following procedures. Compound 9F (200 mg, 0.43 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to obtain Compound 9 (150 mg, yield: 85%).

[0400] LCMS m / z = 410.1 [M+1] +

[0401] Example 10: Preparation of Compound 10

[0402] First Step: Synthesis of 10A

[0403] Compound 9C (0.4 g, 1.13 mmol) was dissolved in 20 mL of tetrahydrofuran, and trimethylsilylethynyl (444 mg, 4.52 mmol), cuprous iodide (42 mg, 0.23 mmol), dichlorobis(triphenylphosphine)palladium (159 mg, 0.23 mmol), and triethylamine (572 mg, 5.65 mmol) were added. After the addition was completed, the mixture was heated to 60°C under nitrogen protection for 6 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to obtain 10A (320 mg, yield: 77%).

[0404] Second Step: Synthesis of 10B

[0405] Compound 10A (320 mg, 0.7 mmol) was dissolved in 10 mL of methanol, and potassium carbonate (190 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated to obtain 10B (200 mg).

[0406] LCMS m / z = 301.1 [M+1] +

[0407] Third Step: Synthesis of 10C

[0408] Phosphorus oxychloride (103 mg, 0.67 mmol) was added dropwise to 2 mL of DMF under ice water bath, protected by nitrogen, stirred at 0 °C for 10 min. 10B (200 mg, 0.67 mmol) dissolved in 2 mL of DMF was slowly added to the reaction solution, protected by nitrogen, stirred at room temperature overnight, 10 mL of water and 20 mL of dichloromethane were added, extracted, the organic phase was collected, washed with saturated brine twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to give 10C (70 mg, yield: 32%).

[0409] LCMS m / z = 329.1 [M+1] +

[0410] Fourth step: synthesis of 10D

[0411] 10C (70 mg, 0.21 mmol) was dissolved in 2 mL of ethanol, and tert-butyl cyanoacetate (39 mg, 0.27 mmol) and L-proline (10 mg, 0.084 mmol) were added successively. After addition, it was stirred at room temperature overnight under nitrogen protection. During the reaction, a large amount of solid was precipitated. After the reaction was completed, ice water was added, stirred, filtered, and the filter cake was redissolved in dichloromethane and then a proper amount of silica gel was added and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to give 10D (90 mg, yield: 94%).

[0412] LCMS m / z = 452.2 [M+1] +

[0413] Fifth step: synthesis of compound 10

[0414] 10D (90 mg, 0.20 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and stirred at room temperature for 1 hour. Vacuum concentration, the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparation liquid was freeze-dried to give compound 10 (50 mg, yield: 63%).

[0415] LCMS m / z = 396.1 [M+1] +

[0416] Example 11: preparation of compound 11

[0417] Compound 9 (80 mg, 0.20 mmol) was dissolved in 10 mL of dichloromethane, ethylene glycol (62 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.24 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added successively, protected by nitrogen, stirred at room temperature for 1 hour. 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, stirred and separated, the organic phase was collected, dried by adding anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum, the residue was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the preparative liquid was freeze-dried to obtain compound 11 (40 mg, yield: 45%).

[0418] LCMS m / z = 454.3 [M+1] +

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.60 (s, 1H), 8.58-8.51 (m, 1H), 8.51-8.40 (m, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.48-7.30 (m, 1H), 5.76 (s, 2H), 5.02-4.91 (m, 1H), 4.38-4.19 (m, 2H), 3.79-3.62 (m, 2H), 2.03 (s, 3H).

[0420] Example 12: Preparation of compound 12

[0421] Compound 1 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 2-methyl-1,2-propanediol (103.64 mg, 1.15 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (52.91 mg 0.28 mmol), 4-dimethylaminopyridine (5.62 mg, 0.046 mmol) were added successively, protected by nitrogen, stirred at room temperature for 1 hour. 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, stirred and separated, the organic phase was collected, dried by adding anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-2 / 1) to obtain compound 12 (48 mg, yield: 41%).

[0422] LCMS m / z = 513.1 [M+1] +

[0423] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.72 (m, 2H), 8.70 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.54-7.49 (m, 1H), 6.08 (s, 2H), 4.76 (s, 1H), 4.10 (s, 2H), 1.21 (s, 6H).

[0424] Example 13: Preparation of compound 13

[0425] Compound 1 (50 mg, 0.11 mmol) was dissolved in 3 mL of dichloromethane, ethylene glycol (34.14 mg, 0.55 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (25.30 mg, 0.13 mmol), 4-dimethylaminopyridine (2.69 mg, 0.022 mmol) were added successively, protected by nitrogen, stirred at room temperature for 1 hour. 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, stirred and separated, the organic phase was collected, dried by adding anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-2 / 1) to obtain compound 13 (20 mg, yield: 36%).

[0426] LCMS m / z = 485.0 [M+1] +

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.70 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.54-7.49 (m, 1H), 6.08 (s, 2H), 4.76 (s, 1H), 4.10 (s, 2H), 1.21 (s, 6H).

[0428] Example 14: Preparation of compound 14

[0429] Compound 1 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, diethylene glycol (122.04 mg, 1.15 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (52.91 mg, 0.28 mmol), 4-dimethylaminopyridine (5.62 mg, 0.046 mmol) were added successively, protected by nitrogen, stirred at room temperature for 1 hour. 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, stirred and separated, the organic phase was collected, dried by adding anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-2 / 1) to obtain compound 14 (18 mg, yield: 15%).

[0430] LCMS m / z = 529.1 [M+1] +

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.69 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.54-7.49 (m, 1H), 6.08 (s, 2H), 4.61 (s, 1H), 4.47-4.39 (m, 2H), 3.79-3.72 (m, 2H), 3.52 (s, 4H).

[0432] Example 15: Preparation of compound 15

[0433] Compound 1 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 1,3-propanediol (53 mg, 0.70 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 15 (40 mg, yield: 35%).

[0434] LCMS m / z = 499.1 [M+1] +

[0435] 1H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.67 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.54-7.48 (m, 1H), 6.08 (s, 2H), 4.59 (t, 1H), 4.41-4.34 (m, 2H), 3.60-3.53 (m, 2H), 1.92-1.82 (m, 2H).

[0436] Example 16: Preparation of compound 16

[0437] Compound 1 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, and neopentyl glycol (72 mg, 0.69 mmol), l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, and stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 16 (35 mg, yield: 29%).

[0438] LCMS m / z = 527.2 [M+1] +

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.67 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.54-7.48 (m, 1H), 6.08 (s, 2H), 4.59 (t, 1H), 4.41-4.34 (m, 2H), 3.60-3.53 (m, 2H), 1.92-1.82 (m, 2H).

[0440] Example 17: Preparation of compound 17

[0441] Compound 1 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, and 1,5-pentanediol (72 mg, 0.69 mmol), l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, and stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 17 (40 mg, yield: 33%).

[0442] LCMS m / z = 527.2 [M+1]+

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.66 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.53-7.48 (m, 1H), 6.07 (s, 2H), 4.38 (t, 1H), 4.31 (t, 2H), 3.46-3.39 (m, 2H), 1.78-1.67 (m, 2H), 1.54-1.38 (m, 4H).

[0444] Example 18: Preparation of compound 18

[0445] Compound 3 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 1,3- propanediol (53 mg, 0.70 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 18 (40 mg, yield: 35%).

[0446] LCMS m / z = 498.1 [M+1] +

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m, 2H), 8.66 (s, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 7.53-7.48 (m, 1H), 6.07 (s, 2H), 4.38 (t, 1H), 4.31 (t, 2H), 3.46-3.39 (m, 2H), 1.78-1.67 (m, 2H), 1.54-1.38 (m, 4H).

[0448] Example 19: Preparation of compound 19

[0449] Compound 3 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 1,5-pentanediol (72 mg, 0.69 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 20 (35 mg, yield: 29%).

[0450] LCMS m / z = 526.0 [M+1] +

[0451] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.23-8.16 (m, 3H), 8.11-8.06 (m, 2H), 7.62-7.57 (m, 1H), 7.44-7.38 (m, 1H), 6.05 (s, 2H), 4.70 (t, 1H), 4.07 (s, 2H), 3.28 (d, 2H), 0.93 (s, 6H).

[0452] Example 20: Preparation of compound 20

[0453] Compound 3 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 1,5-pentanediol (72 mg, 0.69 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 20 (35 mg, yield: 29%).

[0454] LCMS m / z = 526.1 [M+1] +

[0455] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.25-8.16 (m, 3H), 8.11-8.06 (m, 2H), 7.63-7.56 (m, 1H), 7.44-7.37 (m, 1H), 6.05 (s, 2H), 4.38 (t, 1H), 4.31 (t, 2H), 3.47-3.40 (m, 2H), 1.79-1.68 (m, 2H), 1.54-1.39 (m, 4H).

[0456] Example 21: Preparation of compound 21

[0457] Compound 4 (30 mg, 0.081 mmol) was dissolved in 3 mL of dichloromethane, 1,3- propanediol (18 mg, 0.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (18 mg, 0.094 mmol), 4-dimethylaminopyridine (4.0 mg, 0.033 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 21 (12 mg, yield: 34%).

[0458] LCMS m / z = 430.2 [M+1] +

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.19 (d, 1H), 8.01 (d, 1H), 7.88 (s, 1H), 7.71-7.65 (m, 2H), 7.61-7.53 (m, 2H), 7.42-7.36 (m, 1H), 5.95 (s, 2H), 4.60 (t, 1H), 4.37 (t, 2H), 3.60-3.53 (m, 2H), 1.92-1.82 (m, 2H).

[0460] Example 22: Preparation of compound 22

[0461] Compound 4 (30 mg, 0.081 mmol) was dissolved in 5 mL of dichloromethane, neopentyl glycol (25 mg, 0.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.099 mmol), 4-dimethylaminopyridine (4.0 mg, 0.033 mmol) were added successively, protected by nitrogen, stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 22 (10 mg, yield: 27%).

[0462] LCMS m / z = 458.2 [M+1] +

[0463] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.87 (s, 1H), 7.71-7.64 (m, 2H), 7.61-7.53 (m, 2H), 7.43-7.35 (m, 1H), 5.96 (s, 2H), 4.71 (t, 1H), 4.07 (s, 2H), 3.28 (d, 2H), 0.93 (s, 6H).

[0464] Example 23: Preparation of compound 23

[0465] Compound 4 (30 mg, 0.081 mmol) was dissolved in 5 mL of dichloromethane, 1,5-pentanediol (25 mg, 0.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.099 mmol), 4-dimethylaminopyridine (4.0 mg, 0.033 mmol) were added successively, and the mixture was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain compound 23 (12 mg, yield: 32%).

[0466] LCMS m / z = 458.2 [M+1] +

[0467] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.19 (d, 1H), 8.01 (d, 1H), 7.88 (s, 1H), 7.71-7.65 (m, 2H), 7.61-7.53 (m, 2H), 7.42–7.36 (m, 1H), 5.95 (s, 2H), 4.39 (t, 1H), 4.30 (t, 2H), 3.46-3.39 (m, 2H), 1.78–1.67 (m, 2H), 1.54–1.38 (m, 4H).

[0468] The following examples were synthesized according to the synthetic method of Example 12:

[0469] Control compound 1:

[0470] Biological test example:

[0471] 1. Lactic acid content generation assay

[0472] MCF-10A human mammary epithelial cells were purchased from ATCC, and the complete medium was MEBM (Lonza / Clonetics, CC-3150) or MEGM (Nanjing Kebai, CBP60419M) + 100 ng / ml cholera toxin (Sigma, C8052), and the cells were cultured in a 37℃, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration to plate 6-well plates, so that the cells were 2000000 cells / well (or 3.3x10 4 6 cells / well in 12-well plates), and the next day, different concentrations of compounds were added, and the cells were incubated in a CO2 incubator for 24-30 hours. After the culture ended, according to the operation instruction of L-Lactate Assay kit (Colorimetric Fluorometric, item number ab65330), 50 μL sample was taken from each treatment well, the lactic acid content was determined, and it was normalized to the cell number and the experimental maintenance time to obtain the lactic acid production rate Lac (nmol lactic acid / million cells / hour). The following formula was used to calculate the lactic acid production rate (Growth) caused by the detected compound: Growth (%) = (Lac 化合物 – Lac 空白对照 ) / (Lac 溶媒对照 – Lac 空白对照 )*100%, the lactic acid production rate of different concentrations of compounds was calculated in Excel, and then the GraphPad Prism software was used to make a curve and calculate the related parameters, including the minimum production rate, the maximum production rate and EC 50 .

[0473] Conclusion: The compound of the present application, for example, the compound of the example, has a good effect of promoting lactic acid production in MCF-10A human mammary epithelial cells.

[0474] 2. MCF-10A cell oxygen consumption rate inhibition test

[0475] MCF-10A cells were cultured in Culture Medium to 80-90% confluence, washed once with PBS, and then harvested by digestion. The cells were counted and suspended in Culture Medium. The cells were seeded into 96-well plates (Seahorse XFe96) at a density of 20,000 cells / well and incubated overnight in a 5% CO2, 37°C incubator. The next day, the Culture Medium was replaced with Seahorse Assay medium, and the test compound was added. The cell plates were equilibrated in a Seahorse XF96 Extracellular Flux Analyzer for 1 hour. The FCCP (1 mM)-induced oxygen consumption rate (OCR) of the cells was then measured in real time using the Seahorse XF96 Extracellular Flux Analyzer. Each measurement lasted 30-40 minutes (about 12 cycles) to ensure that the sample was fully taken up by the cells and affected mitochondrial function. OCR measurements were performed in 5-8 replicates. After the experiment, the Kinetic rate curve was exported using the Wave analysis software provided with the instrument, and the maximal respiration (maximum OCR value) was obtained. The % Inhibition of Respiration (relative to DMSO) was calculated in Excel according to Formula 2-1, and the OCR signal value at the time point at which the DMSO group reached a stable state was selected for comparison:

[0476] Formula 2-1: % Inhibition of Respiration = (1- Test Group Sample / DMSO Group Sample) * 100%

[0477] Test Group Sample: the maximum OCR value of the drug-treated well; DMSO Group Sample: the maximum OCR value of the DMSO well;

[0478] Cell experiment condition information:

[0479] Table 2: Inhibition of MCF-10A cell oxygen consumption rate by test compounds

[0480] Note: 30% ≤ C < 40%; 40% ≤ B < 50%; 50% ≤ A;

[0481] Conclusion: The compounds of the present application, such as the compounds of the examples, have good inhibitory effects on the oxygen consumption rate of MCF-10A cells.

[0482] 3. Compound transformation test in mouse skin homogenate

[0483] Objective: To verify whether certain prodrug compounds are converted into corresponding carboxylic acid products by esterase in mouse skin homogenate and to quantify the conversion efficiency by LC-MS.

[0484] Test method:

[0485] 1. Preparation of mouse skin homogenate: The dorsal skin of SPF ICR mice (6-8 weeks old, male or female) was taken, subcutaneous fat was removed, and the skin was cut into small pieces and added to PBS at a ratio of 1:10 (w / v). The mixture was homogenized in an ice bath using a tissue homogenizer (3000 rpm for 30 seconds, with 1 minute intervals, for a total of 3 times), and then centrifuged at 12000 x g for 10 minutes at 4°C. The supernatant was collected, and the protein concentration was determined by the BCA method. The supernatant was diluted with PBS to a concentration of 0.5 mg / mL, and the solution was prepared immediately before use.

[0486] 2. Solution preparation

[0487] Compound stock solution: Each test compound was weighed and dissolved in DMSO to prepare a stock solution with a concentration of 10 mM.

[0488] Compound working solution: The stock solution was diluted with PBS to a concentration of 10 μM (the final concentration of DMSO was ≤1% to avoid affecting enzyme activity), and the solution was prepared immediately before use. Blank control: DMSO (the concentration was consistent with the DMSO in the working solution, i.e., 0.1%).

[0489] 3. Incubation reaction

[0490] Total system 1 mL: 890 μL PBS + 100 μL skin homogenate + 10 μL test compound solution (final concentration 10 μM, DMSO as a solvent, final concentration ≤1%). After pre-incubation at 37°C for 5 minutes, the reaction was started, and the incubation was carried out at a constant temperature for 1 hour.

[0491] 4. Reaction termination and processing

[0492] After incubation, the reaction was immediately quenched. Before analysis and detection, all samples were stored at -60°C. The samples were quantitatively analyzed by LC-MS / MS.

[0493] 5. Detection and analysis

[0494] The remaining amount of compound and the amount of corresponding carboxylic acid product generated in the supernatant were detected by LC-MS, and the conversion rate (product generation amount / initial compound addition amount x 100%) was calculated to evaluate the esterase conversion ability.

[0495] Conclusion: The compounds of the present application, such as the compounds of the examples, have good conversion rates in mouse skin homogenate.

[0496] 4. hERG potassium ion channel effect test

[0497] Experimental platform: electrophysiological manual patch clamp system

[0498] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[0499] Experimental method: hERG potassium channel currents were recorded using whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel. Glass microelectrodes were pulled from glass electrode capillary (BF150-86-10, Sutter) using a micropipette puller, and the tip resistance was about 2-5 MΩ after filling the electrode with internal solution. The glass microelectrode was inserted into the amplifier probe and connected to the patch-clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the step voltage to induce hERG potassium current (I hERG ) was given from -80 mV to a 2s depolarization voltage to +20 mV, and then repolarized to -50 mV for 1s, and then returned to -80 mV. This voltage stimulation was given every 10s, and after the hERG potassium current was determined to be stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0500] Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different concentrations of compounds was calculated using the following formula: Inhibition% = [1–(I / Io)]x100%

[0501] where Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively.

[0502] Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0503] where X is the Log value of the test concentration of the test product, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0504] and Top are the minimum and maximum inhibition percentages, respectively.

[0505] Conclusion: The compounds of the present application, such as the example compounds, have no significant inhibition effect on hERG potassium ion channel.

[0506] 5. Mouse microsomal stability test

[0507] After 1 μM of the test compound is incubated with mouse liver microsomes (0.5 mg / mL) supplemented with NADPH regenerating system at 37 °C for 5, 10, 20, 30 and 60 minutes, the concentration of the test compound in the generated sample is detected by using LC-MS / MS method. By calculating the residual percentage of the compound at the corresponding time points, the half-life (T 1 / 2 ) and intrinsic clearance (CL int(mic) ) of the compound in mouse liver microsomal solution are obtained.

[0508] Conclusion: The compounds of the present application, such as the example compounds, have suitable mouse liver microsomal stability.

[0509] 6. Rat microsomal stability test

[0510] After 1 μM of the test compound is incubated with rat liver microsomes (0.5 mg / mL) supplemented with NADPH regenerating system at 37 °C for 5, 10, 20, 30 and 60 minutes, the concentration of the test compound in the generated sample is detected by using LC-MS / MS method. By calculating the residual percentage of the compound at the corresponding time points, the half-life (T 1 / 2 ) and intrinsic clearance (CL int(mic) ) of the compound in rat liver microsomal solution are obtained.

[0511] Conclusion: The compounds of the present application, such as the example compounds, have suitable rat liver microsomal stability.

[0512] 7. Monkey microsomal stability test

[0513] After 1 μM of the test compound is incubated with monkey liver microsomes (0.5 mg / mL) supplemented with NADPH regenerating system at 37 °C for 5, 10, 20, 30 and 60 minutes, the concentration of the test compound in the generated sample is detected by using LC-MS / MS method. By calculating the residual percentage of the compound at the corresponding time points, the half-life (T 1 / 2 ) and intrinsic clearance (CL int(mic) ) of the compound in monkey liver microsomal solution are obtained.

[0514] Conclusion: The compounds of the present application, such as the example compounds, have suitable monkey liver microsomal stability.

[0515] 8. Dog microsomal stability test

[0516] The concentration of the test compound in the resulting sample was detected by LC-MS / MS method after 1 μM test compound was incubated with dog liver microsomes (0.5 mg / mL) supplemented with NADPH regenerating system at 37 °C for 5, 10, 20, 30 and 60 minutes. The half-life (T 1 / 2 ) and intrinsic clearance (CL int(mic) ) of the compound in dog liver microsomal solution were obtained by calculating the percentage of the compound remaining at the corresponding time points.

[0517] Conclusion: The compounds of the present application, for example the example compounds, have suitable dog liver microsomal stability.

[0518] 9. Human microsomal stability test

[0519] The concentration of the test compound in the resulting sample was detected by LC-MS / MS method after 1 μM test compound was incubated with human liver microsomes (0.5 mg / mL) supplemented with NADPH regenerating system at 37 °C for 5, 10, 20, 30 and 60 minutes. The half-life (T 1 / 2 ) and intrinsic clearance (CL int(mic) ) of the compound in human liver microsomal solution were obtained by calculating the percentage of the compound remaining at the corresponding time points.

[0520] Conclusion: The compounds of the present application, for example the example compounds, have suitable human liver microsomal stability.

[0521] 10. Caco2 permeability test

[0522] The test used single layer Caco-2 cells incubated in triplicate in 96-well Transwell plates. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the present application (5 μM) was added to the donor wells on the apical or basolateral side. DMSO-containing transport buffer solution was added to the corresponding receiver wells. After incubation at 37 ± 1 °C for 2 hours, the cell plates were removed and an aliquot of sample was taken from both the apical and basolateral sides into fresh 96-well plates. Acetonitrile containing internal standard was then added to precipitate the proteins. The samples were analyzed by LC MS / MS and the concentration of the compound of the present application and control compound was determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side, and from the basolateral side to the apical side of the monolayer, and thus the efflux ratio. The integrity of the monolayer after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0523] Conclusion: The compounds of the present application, for example the example compounds, have good Caco2 permeability.

[0524] 11. CYP3A4 induction activity test (PXR activation)

[0525] Objective: The objective of this study is to evaluate the potential of test compounds to induce the activity of drug metabolizing enzymes by activating PXR in vitro.

[0526] 1. Cell Seeding

[0527] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[0528] 2) DPX2 cells were cultured in T-75 flasks at 37°C, 5% CO2, 95% relative humidity in an incubator and the cells were harvested when they were 80-90% confluent.

[0529] 3) The cell layer was washed with 10 mL PBS and the PBS was aspirated. 3-5 mL trypsin was added and the cells were incubated at 37°C for 5 minutes or until the cells were detached and in suspension. The trypsinization was stopped by adding an excess of culture medium containing fetal bovine serum.

[0530] 4) The cell suspension was transferred to a conical centrifuge tube and centrifuged at 150g for 5 minutes at room temperature. The supernatant was carefully aspirated and the cells were resuspended in assay medium and adjusted to a concentration of 3.2 x 105 cells / mL (incubation time of 24 hours, seeding density of 4.0 x 105 cells / mL). Twenty-five μL of the cell suspension was added to each well of a 384-well cell culture plate. The cell plate was incubated in an incubator at 95% humidity, 37°C and 5% CO2 for 24 hours.

[0531] 2. Compound Preparation

[0532] 1) Stock solutions of test compounds, positive control (rifampicin) and negative control (propranolol) were prepared in DMSO at 1000x. The final concentrations of the positive control (rifampicin) were 1 μM and 10 μM and the final concentration of the negative control (propranolol) was 10 μM. The final concentrations of the test compounds were 10, 1, 0.1 uM or EC50 (30, 10, 3, 1, 0.3, 0.1 uM). The final concentration of DMSO was 0.1%.

[0533] 2) The cell plate was removed from the incubator and 25 nL of the positive, negative control or test compound stock solution was added directly to the wells using the Echo, with three replicates for each concentration. The cell plate was returned to the incubator for an additional 48 hours (24 hours) of incubation.

[0534] 3) The cell morphology and monolayer integrity were checked prior to the start of the assay with substrate to ensure that the monolayer was of acceptable quality for the study.

[0535] 3. Quantitative PXR Activation Assay

[0536] 1) After 48 hours (24 hours) of drug treatment, the cultures can be assayed for PXR activation.

[0537] 2) The CellTiter-Fluor TM Cell Viability Assay Kit and One-Glo Luciferase Reagent were equilibrated to room temperature. GF-AFC substrate (10 μL) was added to Assay Buffer (10 ml) to make a 2X reagent, which was then diluted with 10 ml PBS to make a IX reagent. ONE-Glo Luciferase substrate was added to ONE-Glo Luciferase Assay Buffer.

[0538] 3) The culture plates were removed from the incubator and the media was discarded. IX CellTiter-Fluor TM reagent was poured into the wells and 25 μL of reagent was added to each well using the pipetting station. The plates were returned to the incubator for 30 minutes.

[0539] 4) The cell culture plates were removed from the incubator and allowed to cool slightly to room temperature. The fluorescence values were determined using a full-automated plate reader with excitation at 400 nm and emission at 505 nm.

[0540] 5) The ONE-Glo reagent was poured into the wells and 25 μL was added to each well. The plates were gently mixed and incubated at room temperature for 5 minutes. The luminescence values were determined.

[0541] 4. Data Analysis

[0542] All data were calculated using Microsoft Excel.

[0543] 1) Luciferase activity was expressed as RFU / RLU, where RLU is the average luminescence intensity value for three replicates for each compound at each concentration and RFU is the average fluorescence intensity value for three replicates for each compound at each concentration.

[0544] Fold activation of mRNA was calculated using the following formula: Fold activation = (RLU test / RFU test) / (RLU vehicle / RFU vehicle)

[0545] 2) The percent cell viability for each compound was calculated using the following formula: Cell Viability % = (RFU test / RFU vehicle) x 100

[0546] 3) The percent of positive control was calculated according to the following formula: Percent of positive control (%) = (Fold activation test / Fold activation Positive control) x 100

[0547] Conclusion: The compounds of the present application, such as the example compounds, do not have a significant induction effect on CYP3A4.

[0548] 12. CYP3A4 induction activity test (enzyme activity and mRNA)

[0549] The objective of this study project was to evaluate the effects of test substances on the enzyme activity and gene expression levels of cytochrome P450 isozymes CYP1A2, CYP2B6 and CYP3A4 by in vitro hepatocyte induction experiments.

[0550] Three donor-derived cryopreserved human hepatocytes were incubated with different concentrations (≥ 5 concentration points) of test substances at 37°C for 48 hours, and the culture medium was replaced with freshly prepared culture medium every 24 hours. The lactate dehydrogenase release in the culture medium after 24 and 48 hours of cell incubation was measured to evaluate the possible cytotoxic effects of the test substances. The concentration of the test substances in the culture medium after the second dose was measured at 0, 5 and 24 hours of incubation to evaluate the concentration of the prototype drug in the human hepatocytes. After 48 hours of incubation of the cryopreserved human hepatocytes from three donors with the test substances, the cell culture medium was removed, and the cells were washed with Hank's balanced salt solution (HBSS) preheated to 37°C, and then enzyme-specific substrates were added for incubation at 37°C for 30 minutes. The amount of metabolites of each substrate was quantitatively analyzed by liquid chromatography-tandem mass spectrometry. The expression levels of genes in cells were evaluated by fluorescence real-time quantitative PCR.

[0551] Conclusion: The compounds of the present application, such as the example compounds, do not have a significant induction effect on CYP3A4.

[0552] 13. P-gp transporter inhibition test

[0553] This project used the MDR1-MDCK II monolayer cell model to evaluate the inhibitory effect of test substances on the activity of P-glycoprotein transporter.

[0554] MDR1-MDCK II cells were seeded in 96-well cell plates and cultured for 7 days before the transport experiment. Digoxin, a known P-gp substrate, was given bi-directionally with and without test articles at different concentrations (0-30 mM) and incubated for 150 minutes. The samples were collected and the digoxin content was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The efflux ratio (ER) of digoxin with and without test articles was calculated to obtain the P-gp transport activity percentage of MDR1-MDCK II cells under the effect of different concentrations of test articles (% VC (Vehicle Control, solvent control), the P-gp transport activity percentage with and without test articles), and the half-inhibitory concentration (IC 50 ) was calculated.

[0555] Conclusion: The compounds of the present application, such as the example compounds, have no obvious inhibitory effect on P-gp transporters.

[0556] 14. BCRP transporter inhibition

[0557] The purpose of this study is to evaluate the inhibitory effect of test articles on breast cancer resistance protein transporter activity using a Caco-2 monolayer cell model.

[0558] Caco-2 cells were seeded in 96-well cell plates and cultured for 22 days before the transport experiment. 5.00 mM estrone 3-sulfate, a substrate of BCRP, was given bi-directionally with and without test articles at different concentrations (0-30 mM) and incubated for 120 minutes. The samples were collected and the estrone 3-sulfate content was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The efflux ratio (ER) of estrone 3-sulfate with and without test articles was calculated to obtain the BCRP transport activity percentage of Caco-2 cells under the effect of different concentrations of test articles (% VC (Vehicle Control, solvent control), the BCRP transport activity percentage with and without test articles), and the half-inhibitory concentration (IC 50 ) was calculated.

[0559] Conclusion: The compounds of the present application, such as the example compounds, have no obvious inhibitory effect on BCRP transporters.

[0560] 15. SLC transporter inhibition

[0561] The purpose of the present study is to evaluate the inhibitory effect of the test substance on the activity of transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K.

[0562] The HEK293-OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K cells are incubated with and without the test substance (0-30 μM) for a corresponding time, and then the samples are collected and the content of the substrate in the samples is detected by using the liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. The transport activity of the transporters with and without the test substance is calculated to obtain the transport activity percentage of the transporter cells under the action of the test substance at different dosing concentrations (% VC (Vehicle Control, solvent control), the percentage of the transport activity of the transporters with and without the test substance), and the half-inhibitory concentration (IC 50 ) is calculated therefrom.

[0563] Conclusion: The compound of the present application, for example, the compound of the examples, has no obvious inhibitory effect on the SLC transporter.

Claims

A compound or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, the compound being selected from the group consisting of compounds of general formula (I) or (II), Ring AA is selected from its lower side is connected to Y, and ring AA is not connected to Y by heteroatom-heteroatom; represents an aromatic or non-aromatic ring; A1, A2, A3, A4 are each independently selected from the group consisting of a bond, C(=0), O, S, N, NR a3 , CR a1 or CR a1 R a2 , at most one of A1, A2, A3, A4 is selected from a bond; Ring W is selected from C 4-6 carbocyclyl or 4- to 6-membered heterocyclyl; Y is selected from O, S, NR Y3 or CR Y1 R Y2 ; R 1 selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, said R 1 optionally substituted with 1 to 4 R k substituents; R 5 , R a1 , R a2 each independently is selected from the group consisting of H, deuterium, halogen, CN, OH, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 R k ; R 2 selected from H, deuterium, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 7-membered heterocyclyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy; R Y1 , R Y2 each independently is selected from H, deuterium, halogen, C 1-6 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; R Y3 , R a3 each independently is selected from H, deuterium, C 1-6 alkyl, said alkyl being optionally substituted with one to four R k substituents; R Y1 , R Y2 and the carbon atom to which they are attached collectively form a C 3-6 carbocyclyl group, which carbocyclyl group is optionally substituted with 1 to 4 R k groups; Ring A is selected from Z is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and C 4-6 carbocyclyl; Q is selected from -C(R q1 R q2 ) p -; p is selected from 1 or 2; R q1 , R q2 are each independently selected from H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, or 4- to 7-membered heterocyclyl, said alkyl, cycloalkyl, or heterocyclyl optionally substituted with 1 to 4 R k ; As an option, any R q1 With R q2 Direct connection forms C 3-6 Cycloalkyl or 4- to 7-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 3 Selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 Alkylene-OH, wherein the alkylene group, alkyl group, heterocyclic group, or cycloalkyl group is optionally selected from one to four groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 Substituents of alkyl groups; R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, and is optionally coated with 1 to 4 R. k One of the following groups is substituted: C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, SF5, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 alkylene-3 to 7-membered heterocyclic groups, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 2-4 Ethyne-C 3-6 Carbocyclic group, -C 2-4 Ethyne-3 to 7-membered heterocyclic groups; As an option, any R q1 With R b Direct connection forms C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 4 , R a each independently is selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 1-4 alkyl, OC 1-6 1-4 alkyl, SC 1-6 1-4 alkyl, C 2-6 2-4 alkenyl, C 2-6 2-4 alkynyl, NHC 1-6 1-4 alkyl, N(C 1-6 1-4 alkyl)2, -O-C 3-6 arbocyclic, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 arbocyclic, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 arbocyclic, -C 0-4 alkylene-3 to 7 membered heterocyclyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclyl group being optionally substituted with 1 to 4 R k groups; m is 0, 1, 2, 3 or 4; R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 carbocyclyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl, which alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy; n are each independently selected from 0, 1, 2, 3, 4; with the proviso that the ring AA of general formula (II) is not selected from with the proviso that the general formula (I): 1) when ring A is selected from Ring R q1 with R q2 not directly linked to form a ring or R q1 with R b not directly linked to form a ring, Z is selected from C 6-10 aryl, n is selected from 1, 2, 3 or 4, and at least one R b is R b1 , R b1 is selected from deuterium, NH2, SF5, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl or alkoxy being substituted with 1 to 4 substituents selected from deuterium, Cl, Br, I, CN, OH, NH2, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 7 membered heterocyclyl, or R b1 is selected from one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3 to 7 membered heterocyclyl; 2) Ring A is selected from Q is selected from CH2, and Z is selected from pyridyl, n is selected from 1, 2, 3 or 4; 3) when ring A is selected from Z is selected from C 6-10 n is selected from 1, 2, 3 or 4, and at least one R b is R b2 , R b2 is selected from deuterium, NH2, SF5 or one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, vinyl, ethynyl, 3- to 7-membered heterocyclyl, -ethynyl-C 3-6 carbocyclyl, -ethynyl-3- to 7-membered heterocyclyl; 4) when ring A is selected from Ring R q1 With R q2 Not directly connected to form a loop or R q1 With R b Z is selected from benzo[C] and does not directly form a ring. 4-6 When R is a carbocyclic group or a benzo[4] to 6-membered heterocyclic group, 3 Selected from R 3a R 3a Selected from -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 alkylene-OH, wherein the alkylene group is optionally surrounded by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 Alkyl groups are substituted. The compound according to claim 1, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein Ring W is selected from non-aromatic C 4-6 carbocyclyl or non-aromatic 4- to 6-membered heterocyclyl; R 1 selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, said R 1 optionally substituted with 1 to 4 R k substituents; R 5 , R a1 , R a2 each independently is selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 R k ; R 2 selected from H, deuterium, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 7-membered heterocyclyl, -C 1-5 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy; R Y3 , R a3 each independently is selected from H, deuterium, C 1-4 alkyl, said alkyl being optionally substituted with one to four R k substituents; R Y1 , R Y2 each independently is selected from H, deuterium, halogen, C 1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R k substituents; R Y1 and the carbon atom to which they are attached join to form a C Y2 ring; or R 3-6 and the carbon atom to which they are attached join to form a C k cycloalkyl group, optionally substituted with 1 to 4 R R k each independently selected from the group consisting of deuterium, =0, halogen, CN, OH, COOH, NH2, SF5, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -O-C 3-6 carbocyclyl, -O-4- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4- to 7-membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4- to 7-membered heterocyclyl, C 3-6 carbocyclyl, 4- to 7-membered heterocyclyl group, which alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl group is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy; Z is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and C 4-6 carbocyclyl; R q1 R q2 Each is independently selected from H, deuterium, or arbitrarily selected from 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, pyrrolidinyl, piperidinyl, morpholinyl; as an alternative, any R q1 is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl; q2 is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl; k is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxet R 3 selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-4- to 7-membered heterocyclyl, -C 1-5 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkylene-OH, said alkylene, alkyl, heterocyclyl, cycloalkyl being optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy; R b Each element is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, CONH2, or optionally coated by 1 to 4 R. k One of the following groups is substituted: C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, SF5, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, -CH2-C 3-6 Carbocyclic groups, -CH2-3 to 7-membered heterocyclic groups, -C 2-3 Ethyne-C 3-6 Carbocyclic group, -C 2-3 Ethyne-3 to 7-membered heterocyclic groups; As an option, any R q1 With R b Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the carbocyclic or heterocyclic group is optionally replaced by 1 to 4 R groups. k replace; R 4 R a Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, and 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 Carbocyclic groups, -O-3 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-3 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 3- to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-3 to 7-membered heterocyclic group, wherein the alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace. The compound according to claim 2, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein, At most two of A1, A2, A3, A4are selected from O, S, N or NR a3 ; ring W is selected from cyclobutenyl, cyclopentenyl, oxalopentenyl, oxalocyclohexenyl, 1,3-dioxolyl; R 1 selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, said R 1 optionally substituted with 1 to 4 R k substituents; R 3 , R a1 , R a2 each independently is selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl being optionally substituted with 1 to 4 R k ; R Y3 , R a3 each independently is selected from H, deuterium, methyl, ethyl, said alkyl groups being optionally substituted with 1 to 4 R k groups; R Y1 , R Y2 each independently is selected from the group consisting of H, deuterium, F, Cl, Br, methyl, ethyl, said alkyl groups being optionally substituted with 1 to 4 R k groups; As an option, R Y1 R Y2 Together with the carbon atoms attached thereto, they form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally bonded by 1 to 4 R atoms. k replace; Z is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzocyclopentenyl, benzocyclohexenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolo pyridyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazolopyridyl, imidazolopyrimidinyl, imidazolopyrazinyl, imidazolopyridazinyl, R q1 , R q2 are each independently selected from H, deuterium, methyl, CF3, CD3, CH2CF3; as an alternative, any R q1 is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl; q2 is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl; k is directly linked to form an optionally substituted group selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxet R 3 selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2CH2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, said R 3 optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, ethoxy; R b each independently selected from deuterium, F, CI, Br, I, OH, CN, NH2, CONH2, or optionally substituted by one to four R k one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, SF5, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, NHCH3, N(CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azetidinyl, -NH-oxetanyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, As an option, any R q1 With R b Direct connection forms an optional 1 to 4 R k The following groups are substituted: cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, wherein the carbocyclic or heterocyclic group is optionally replaced by 1 to 4 R groups. k replace; R 4 , R a each independently is selected from H, deuterium, halogen, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, NHCH3, N(CH3)2, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, -O-cyclopropyl, -O-cyclobutyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-piperidinyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-azetidinyl, -NH-oxetanyl, -NH-pyrrolidinyl, -NH-piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, said alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, or heterocyclyl optionally substituted with 1 to 4 R k . The compound according to claim 3, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein Ring AA is selected from its lower side is connected to Y, and ring AA is not connected to Y by heteroatom-heteroatom; n are each independently selected from 0, 1, 2; R 2 H, deuterium, methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, -methylene-OH, -ethylene-OH, -propylene-OH, -butylene-OH, -pentylene-OH, -methylene-O-methylene-OH, -ethylene-O-methylene-OH, -ethylene-O-ethylene-OH, -propylene-O-ethylene-OH, -propylene-O-propylene-OH, said methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methylene, ethylene, propylene, butylene, pentylene optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, =O, CN, OH, NH2, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, said methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methylene, ethylene, propylene, butylene, pentylene optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, =O, CN, OH, NH2, C R k each independently is selected from the group consisting of deuterium, =0, F, Cl, Br, I, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one to four substituents selected from the group consisting of deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy. The compound according to claim 4, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein, Y is selected from O, S, NH or CH2; preferably from CH2; R 1 selected from the group consisting of optionally substituted: k substituted with 1 to 3 R R 2 selected from H, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2C(CH3)2CH2OH, -CH2C(CH3)2OH, -C(CH3)2CH2OH, -CH2CH2OCH2CH2OH, -CH2CH2OCH2OH, -CH2OCH2OH, said CH2groups being optionally substituted with one to three substituents selected from deuterium, F, Cl, Br, CN, OH, CF3, CHF2, CH2F, methyl; R 5 each independently selected from deuterium, F, Cl, Br, CN, OH, CD3, CHD2, CH2D, CF3, CHF2, CH2F, methyl; R k each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, SF5, -S-CHF2, -S-CF3, -SCH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The compound according to claim 1 or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, wherein the compound of general formula (I) is selected from general formula (la), (lb), (lc) or (Id), R b1 selected from the group consisting of deuterium, NH2, SF5, C 1-6 alkyl, -OC 1-6 alkyl, said alkyl or alkoxy being substituted with one to four substituents selected from the group consisting of deuterium, Cl, Br, I, CN, OH, NH2, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being substituted with one to four substituents selected from the group consisting of deuterium, Cl, Br, I, CN, OH, NH2, C or R b1 is selected from one of the following groups optionally substituted with 1 to 4 R k SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -O-C 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-C 3-6 carbocyclyl, -C 2-4 alkynylene-3 to 7 membered heterocyclyl; Q 1 selected from C 3-6 cycloalkyl or 4- to 7-membered heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 R k substituents; Ring B is selected from C 4-6 cycloalkyl or 4- to 7-membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being optionally substituted with 1 to 4 R k substituents; Z 1 selected from benzene C 4-6 carbocyclyl, benzene 4- to 6-membered heterocyclyl; R 3a Selected from -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 alkylene-OH, wherein the alkylene group is optionally surrounded by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy or halogen-substituted C 1-6 Substituents of alkyl groups; n1 is selected from 1, 2, 3 or 4; n2 is selected from 0, 1, 2 or 3. The compound according to claim 6, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein R b1 SF5, SCF3, oxetanyl, ethynyl, propynyl, propargyl, said oxetanyl group, ethynyl group, propynyl group, propargyl group, optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl; R b each independently selected from F, CI, Br, I, OH, CN, CF3, CHF2, CH2F, CD3, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, SF5, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, NHCH3, N(CH3)2, -O-cyclopropyl; Q 1 selected from cyclopropyl, cyclobutyl, cyclopentyl, said Q 1 optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =0, CN, OH, NH2, methyl, CF3, methoxy; Q is selected from -CH2-; selected from the group consisting of Preferably R 3a -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-O-CH2-OH, -CH2-O-CH2CH2-OH, -CH2-O-CH2CH2CH2-OH, -CH2CH2-O-CH2-OH, -CH2CH2-O-CH2CH2-OH, -CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2-O-CH2-OH, -CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2-OH, -CH2CH2CH2CH2-O-CH2CH2CH2CH2-OH, said CH2groups being optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, halogen, =0, CN, OH, NH2, methyl, ethyl, isopropyl, CF3, methoxy, ethoxy; Z is selected from Z 1 selected from R k each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, SF5, -S-CHF2, -S-CF3, -SCH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The compound according to claim 1, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown in Table E. A pharmaceutical composition comprising a compound according to any one of claims 1-8, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition comprises 1-1500 mg of a compound according to any one of claims 1-8, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1-8, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, in the manufacture of a medicament for growing hair. A method for treating or alleviating a disease affecting hair growth in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-8, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, preferably 1-1500 mg, of a disease selected from a condition affecting hair growth (preferably alopecia or baldness). A method for treating or alleviating a disease affecting hair growth in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-8, or a racemate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, preferably 1-1500 mg, of a disease selected from a condition affecting hair growth (preferably alopecia or baldness).

Images