Small molecule dgraders of ctla-4 and uses thereof

Abstract

The application relates to a CTLA-4 small molecule degrading agent and application thereof, the CTLA-4 small molecule degrading agent has a compound with the structure of formula I or a pharmaceutically acceptable salt, ester, deuteride, isomer, solvate, prodrug or isotope marker thereof, the application firstly reports a kind of small molecule compound with high degradation activity to CTLA-4 in the world, the compound shows good degradation activity to CTLA-4 in the level of nanomole (nM) in vitro research.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, and specifically relates to a class of small molecule degrading agents that cause CTLA-4 protein degradation by inhibiting the interaction between LRBA protein and CTLA-4 protein, their preparation methods, pharmaceutical compositions, and their uses in medicine. Background Technology

[0002] PD-1 / PD-L1 inhibitors are among the most important immuno-oncology drugs currently available, but their clinical response rate is relatively low (10-30%), and they are ineffective for most cancer patients, necessitating new clinical solutions. Combining PD-1 / PD-L1 inhibitors with other cancer treatments may be a better strategy.

[0003] CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) is a protein receptor that acts as an immune checkpoint and downregulates the immune response. It is constitutively highly expressed on T cells, especially regulatory T cells, and acts as a "switch" when it binds to CD80 or CD86 on the surface of antigen-presenting cells. CTLA-4 inhibitors can activate anti-tumor immune responses and are used in cancer immunotherapy. The CTLA-4 inhibitor ipilimumab (Yervoy, "Y drug") has been used to treat various cancers, including melanoma.

[0004] Considering that CTLA-4 and PD-1 / PD-L1 synergistically regulate the immune response at different stages of tumor immune response: CTLA-4 in the early and mid-stages of the tumor immune response, and PD-1 in the late stage, it is feasible to combine CTLA-4 with PD-1 / PD-L1 inhibitors. This combination strategy has been thoroughly validated in clinical practice, as evidenced by FDA approval for six clinical indications, including hepatocellular carcinoma and non-small cell lung cancer. For example, the objective response rate (ORR) of combining ipilimumab (Yervoy, "Y drug") with the PD-1 inhibitor nivolumab (OPDIVO, "O drug") is significantly improved compared to O drug monotherapy. The combination of Yervoy and OPDIVO is the first and currently only FDA-approved dual immunotherapy.

[0005]

[0006] However, current CTLA-4 inhibitors, such as "Y" drugs, are antibody drugs. These antibodies and similar antibody drugs have some inherent limitations: 1) Significant side effects: Clinically, about 54% of patients using combination therapy experience grade 3-4 immunotherapy-related serious adverse events (irAEs), which greatly limits the clinical use of these drugs. Furthermore, these side effects are related to the antibody's ADCC activity and immunogenicity; 2) Difficulty in tumor spread: As large molecule drugs, CTLA-4 antibody drugs are difficult to infiltrate solid tumors, limiting the therapeutic effect of monotherapy or combination therapy; 3) Poor patient compliance: CTLA-4 antibody drugs are mainly administered via intravenous, subcutaneous, or intramuscular injection, and cannot be administered orally, resulting in poor patient compliance.

[0007] Compared to CTLA-4 monoclonal antibody drugs, CTLA-4 small molecule degraders have unique advantages: 1) Significantly reduced toxic side effects: CTLA-4 small molecule degraders relieve immunosuppression by degrading CTLA-4 protein, without affecting other T cell activities. Furthermore, small molecules do not have the ADCC effect or immunogenicity of antibodies, thus greatly reducing side effects; 2) Easy intratumoral spread: Small molecule drugs can more easily infiltrate solid tumors, greatly improving the therapeutic effect of single or combined use; 3) Good compliance: Small molecule drugs can be taken orally; 4) Price advantage: Small molecule drugs have low production costs.

[0008] However, there are currently no reports or developments of small molecule degraders or small molecule inhibitors of CTLA-4 worldwide. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] To address the aforementioned technical problems, this invention provides, for the first time globally, a class of small molecule compounds with high degradation activity and high in vivo activity against CTLA-4.

[0011] Solution for solving the problem

[0012] To address the aforementioned technical problems, the present invention provides the following technical solution: A compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, deuterated derivative, isomer, solvate, prodrug, or isotope label thereof:

[0013] Among them, A, B, C, D, E, F, G, H, I, J, K, L, and M are each independently selected from direct-connecting bonds and CR. 6 CR 6 R 14 , N, NR 7 O, S and C=O; Each R 1 R 2 R 3 R 6 R 7 and R 14 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cyclohexaalkyl, halogen, -OH, unsubstituted or substituted alkoxy, unsubstituted or substituted arylalkyl, unsubstituted or substituted aromatic heteroalkyl, unsubstituted or substituted aryl ether, unsubstituted or substituted aromatic heteroether, -CN, -N(R) 4 R 5 -NO2, -N3, borate group, unsubstituted or substituted borate ester group, carboxyl group, ester group, unsubstituted or substituted aminoformyl group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterogroup, unsubstituted or substituted thioether group, unsubstituted or substituted sulfoxide group, unsubstituted or substituted sulfone group, unsubstituted or substituted sulfonamide group, , Unsubstituted or substituted phosphonate groups, wherein R 4 R 5 R 8 R 9 R 10 and R 11 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C. 1-6 Alkyl, C 3-7 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aromatic heteroyl, and R 4 and R 5 R 8 and R 9 It can form a ring with adjacent nitrogen or carbon atoms; or two adjacent R atoms. 1 and / or two adjacent R 3 It can also be connected into cycloalkyl, cyclohexaalkyl, aryl, or aromatic heteroalkyl groups; m, n, and o are each independently selected from integers from 0 to 4; W is selected from the following: straight-linked group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterolyl group, unsubstituted or substituted cycloalkyl group, unsubstituted or substituted cyclohexaalkyl group, unsubstituted or substituted bridged cycloalkyl group, unsubstituted or substituted bridged cyclohexaalkyl group, unsubstituted or substituted spirocycloalkyl group, unsubstituted or substituted spirocyclohexaalkyl group, unsubstituted or substituted alkyl group, unsubstituted or substituted heteroalkyl group, unsubstituted or substituted alkenyl group, unsubstituted or substituted heteroalkenyl group, unsubstituted or substituted heteroyynyl group, unsubstituted or substituted -N(R) group. 12 R 13 ), unsubstituted or substituted aminoalkyl, unsubstituted or substituted aminoalkylamino, unsubstituted or substituted Unreplaced or replaced , where R 12 and R 13 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-7 Cycloalkyl, unsubstituted or substituted alkylamino, unsubstituted or substituted aryl, substituted or unsubstituted aromatic heteroyl, or R 12 and R 13 They can be connected to form a ring; Q represents -H, -NH2, -OH, -alkyl-NHC(=O)H, cycloalkyl, unsubstituted or substituted alkylacyl, unsubstituted or substituted alkylhydroxy, unsubstituted or substituted alkenylhydroxy, unsubstituted or substituted alkynylhydroxy, unsubstituted or substituted alkylamine, unsubstituted or substituted sulfonamide, unsubstituted or substituted alkylsulfonamide, amino acid residue. , sulfonamide group, sulfonylhydrazine group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterogroup, unsubstituted or substituted Unreplaced or replaced Substituted or unsubstituted -(CH2) n 1 -(M) n 2 -(CH2) n 3 -(M) n 4 -(CH2) n 5 -(M) n 6 Each M is independently selected from O, OH, S, SO, SO2 and unsubstituted or substituted amino groups, and each n1, n2, n3, n4, n5 and n6 is independently selected from integers from 0 to 6; Alternatively, W and Q can be linked or fused to form substituted or unsubstituted cycloalkyl, cyclohexaalkyl, aryl, or aromatic heteroalkyl groups.

[0014] Preferably, at least one of C, G, and I is an N atom.

[0015] Preferably, at least one of J, K, and M is an N atom.

[0016] Preferably, I, J, and K are all N atoms, or I, M, and K are all N atoms.

[0017] Preferably, each R 1 R 2 R 3 R 6 R 7 and R 14 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C. 1-6 Alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6Alkyne group, unsubstituted or substituted C 3-7 Cycloalkyl, unsubstituted or substituted 3-7 membered heteroalkyl, halogen, -OH, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 6-10 arylethyl, unsubstituted or substituted 5-10 arylethyl, unsubstituted or substituted C 6-10 Aryl ether group, unsubstituted or substituted 5-10 membered aromatic hetero ether group, -CN, -NH2, -NO2, -N3, borate group, unsubstituted or substituted borate ester group, carboxyl group, ester group, unsubstituted or substituted aminoformyl group, unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 aryl groups, unsubstituted or substituted thioether groups, unsubstituted or substituted sulfoxide groups, unsubstituted or substituted sulfone groups, unsubstituted or substituted sulfonamide groups, , Unsubstituted or substituted phosphonate groups, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, N3, borate groups, carboxyl groups, ester groups, formamide groups, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0018] Preferably, W is selected from straight-linked, substituted or unsubstituted aryl, aromatic heteroyl, cycloalkyl, cyclohexaalkyl, bridged alkyl, bridged cyclohexaalkyl, spirocycloalkyl, spirocyclohexaalkyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, ynyl, heteroynyl, -N(R) 12 R 13 ), aminoalkyl, aminoalkylamino, unsubstituted or substituted Unreplaced or replaced The substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0019] Preferably, W is selected from substituted or unsubstituted 5-7 membered cyclohexaalkyl groups, substituted or unsubstituted -amino-C groups. 1-6 Alkyl groups, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0020] Preferably, the atom in W that is connected to the ring containing J and K is N.

[0021] Preferably, W is selected from substituted or unsubstituted 5-7 membered heterocyclic alkyl groups, wherein the 5-7 membered heterocyclic alkyl group contains at least one nitrogen atom; more preferably, the 5-7 membered heterocyclic alkyl group is piperidinyl or piperazineyl.

[0022] Preferably, Q is -H, -NH2, -OH, or -C. 1-6 Alkyl-HNC(=O)H, unsubstituted or substituted C 1-6 Alkyl hydroxyl, unsubstituted or substituted C 2-6 alkenyl hydroxyl, unsubstituted or substituted C 2-6 The alkynyl hydroxyl group, unsubstituted or substituted alkylamine group, sulfonamide group, and sulfonylhydrazine group, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0023] Preferably, W and Q can be connected or fused into a ring, wherein the ring is a substituted or unsubstituted 5-7 membered cycloalkyl, a substituted or unsubstituted 5-7 membered heteroalkyl, or a substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted 5-10 aryl heteroalkyl groups.

[0024] More preferably, the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0025] Preferably, the compound with the structure of Formula I is: , Among them, C, G, I, J, and K are each independently selected from CR. 6 And N, and at least one of C, G, and I is N, and at least one of J and K is N; R 1 R 2 R 3 R 6 The definitions of , o, m, n, W, and Q are the same as those above.

[0026] Preferably, the compound with the structure of Formula I is: , Among them, C, G, I, K, and M are each independently selected from CR. 6 And N, and at least one of C, G, I is N, and at least one of K and M is N; R 1 R 2 R 3 R 6 The definitions of , o, m, n, W, and Q are the same as those above.

[0027] The effects of the invention 1. This invention is the first in the world to report a class of small molecule compounds with strong degradation activity against CTLA-4; 2. In in vitro studies, the compounds described in this invention have shown good activity against CTLA-4 at the nanomolar (nM) level; 3. The compounds described in this invention, such as compound 18, have shown excellent tumor-suppressing effects in in vivo xenograft models, such as the commonly used MC-38 model for tumor immunity. Detailed Implementation

[0028] To more clearly describe the content of this invention, all terms involved are defined as follows: As used herein, the term "direct bond" refers to two atoms or groups directly connected by a chemical bond, preferably including single and double bonds.

[0029] Unless otherwise defined, the term "substitution" as used herein refers to a group substituted with one of the following substituents: alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, borate, borate, phosphonate, ester, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylanoylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylanoylamino, thio, alkylthio, arylthiothio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonylamino, e.g., -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl, e.g., -CONH2, substituted carbamoyl, e.g., -CONHalkyl, -CONH Aryl, -CONH arylalkyl or having two substituents selected from alkyl, aryl or arylalkyl on nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic groups such as indolyl, imidazolyl, furanyl, thiophene, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc., and substituted heterocyclic groups.

[0030] As used herein, the terms "alkyl" or "alkylene" are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0031] The term "heteroalkyl" or "alkane-heteroyl" refers to an alkyl group in which 1-4 carbon atoms are replaced by heteroatoms; preferably, 1-3 carbon atoms are replaced by heteroatoms; more preferably, 1-2 carbon atoms are replaced by heteroatoms; preferably, the alkyl group before heteroatom substitution has a carbon atom density of C10. 2-10 Alkyl, more preferably, the alkyl group before heteroatom substitution is C10. 2-6 Alkyl group; the heteroatom can be substituted at the terminal position of the alkyl group or at the middle position of the alkyl group, and the heteroatoms are independently selected from N, O, S, P, etc.

[0032] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C 2-6 "Alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, hexenyl, etc.

[0033] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C 2-6 The "alkynyl" group contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, pentynyl, and hexynyl.

[0034] The term "heterenyl" means that one or more carbon atoms in an "alkenyl" as defined above are replaced by heteroatoms selected from N, O, and S, or are replaced by a heteroatom group containing heteroatoms selected from N, O, and S.

[0035] The term "heterynyl" means that one or more carbon atoms in the "ynyl" group defined above are replaced by heteroatoms selected from N, O, and S, or are replaced by a heteroatom group containing heteroatoms selected from N, O, and S.

[0036] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C" 1-10 Alkoxy (or alkyloxy) is intended to include C1-C 10 Alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy, and alkoxy groups may contain multiple oxygen atoms, such as 1-10 oxygen atoms. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above that has a specified number of carbon atoms and is linked by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0037] The terms "carbonyl" and "acyl" refer to organic functional groups (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0038] The term "ester group" includes carboxylic acid ester group, phosphate ester group, phosphite ester group, silicate ester group, borate ester group, etc., such as -COOR, B(OR)2, where R is an alkyl group.

[0039] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. A monocyclic cyclic alkyl group refers to a C14-C14 cycloalkyl group. 3-8 Cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel, are included in the definition of "cycloalkyl". Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cycloalkyl groups include cycloalkyl groups with bridged rings, spiro rings, or fused rings.

[0040] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. A monocyclic cyclic alkenyl group refers to a C10-C10 group. 3-8 Cyclic alkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cycloalkenyl groups include cycloalkenyl groups of bridged rings, spiro rings, or fused rings.

[0041] "Halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0042] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above, which has a specified number of carbon atoms and is connected by an oxygen bridge. For example, "C 1-6 "Haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a sulfur-bridged haloalkyl group as defined above having a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0043] The term "aryl" / "arylene," alone or as part of a larger group such as "aralkyl," "ararylalkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 6 to 10 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. A fused aryl group may be attached to another group at a suitable position on a cycloalkyl or aromatic ring. For example, an arrow drawn from a ring system indicates that the bond may be attached to any suitable ring atom.

[0044] The terms “heteroaryl” / “hybridaryl”, “heterocyclic”, “hemeoaryl”, “aromatic”, “heterocyclic”, or “heterocyclic group” refer to stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocycles that are fully unsaturated or partially unsaturated and contain a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S; and include any of the following polycyclic groups, wherein any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1.Examples of aromatic heterocyclic compounds include, but are not limited to, acridine, azacyclic butyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, pseudoindazole. Indolenyl, dihydroindolenyl, indazinyl, indolenyl, 3H-indolenyl, isatinoyl, isobenzofuranyl, isochoryl, isoindazoleyl, isodihydroindolenyl, isoindolenyl, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl Oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, oxazolylalkyl, naphthalene-intercalated diazoxide, hydroxyindolyl, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazineyl, piperidinyl, piperidoneyl, 4- Piperidinone, piperidine, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylylene, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridinium-imidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolylylene, pyrrololinyl, 2-pyrrolidone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, quininecycloyl Tetraazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazinyl, 1,2,4-thiadiazinyl, 1,2,5-thiadiazinyl, 1,3,4-thiadiazinyl, thiaanthryl, thiazolyl, thiophene, thiazopyridyl, thiophenothiazolyl, thiophenooxazolyl, thiopheneimidazolyl, thiophene, triazinyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indoleyl, isoindoleyl, dihydroindoleyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydro-benzofuranyl, chromyl, 1,2,3,4-tetrahydroquinoxalinyl and 1,2,3,4-tetrahydroquinazolinyl. The present invention also includes fused-ring and spirocyclic compounds containing, for example, the heterocycles described above.

[0045] As used herein, the terms "heterocyclic alkyl" and "cycloheteroalkyl" refer to a monocyclic heterocyclic alkyl system or a bicyclic heterocyclic alkyl system. A monocyclic heterocyclic alkyl system refers to a 3-12 quinone (preferably 3-8 quinone, more preferably 5-7 quinone) cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic cyclic alkyl group selected from O, N, S, and P. A bicyclic heteroalkyl system refers to a heterocyclic alkyl group fused to a phenyl group, a cycloalkyl group, a cycloalkenyl group, a cycloheteroalkyl group, or a heteroaryl group. The heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, 1,4-diazylalkyl, etc.

[0046] As used herein, the term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0047] As used herein, the terms "bridged heterocyclic alkyl," "heterobridged cycloalkyl," and "bridged heteroalkyl" refer to polycyclic compounds sharing two or more carbon atoms or heteroatoms, wherein each "bridged heterocyclic alkyl," "heterobridged cycloalkyl," and "bridged heteroalkyl" contains at least one heteroatom selected from O, N, S, P, etc. They can be classified into bicyclic heterobridged cycloalkyl and polycyclic heterobridged cycloalkyl; the former consists of two alicyclic rings sharing two or more carbon atoms or heteroatoms; the latter consists of heterobridged cycloalkyl compounds composed of three or more rings.

[0048] The terms “spirocyclic hydrocarbon” and “spirocyclic alkyl” used in this article refer to polycyclic hydrocarbons and polycyclic alkyl groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings.

[0049] As used herein, the term "spirocyclic heteroalkyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group.

[0050] The term "isomer" as used herein includes "tautomer," "stereoisomer," etc. A "tautomer" refers to a structural isomer with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. A "stereoisomer" refers to a compound having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, transisomers, etc. Unless otherwise stated, all tautomers and stereoisomers of the compounds of this invention are within the scope of this invention.

[0051] As used herein, the term “substitution” means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0052] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (N → O) derivatives.

[0053] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent is shown to have 0-3 R groups, the substituent may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0054] When the bond to a substituent is shown to be an intersecting bond with two atoms in the linking ring, the substituent may be bonded to any atom in that ring. When a substituent is listed but the atoms of that substituent bonded to the remainder of a compound having a given formula are not specified, the substituent may be bonded via any atom in that substituent. Combinations of substituents and / or variables are permitted only if such combinations produce a stable compound.

[0055] The term "amino" or "amine group" alone or in combination represents a primary amine group (-NH2), a secondary amine group (-NH-), or a tertiary amine group (-NH-). , , etc.

[0056] Term "C" 1-6 "alkylamine" refers alone or in combination to an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C1-6 alkyl group, where "alkyl" is as defined above, and correspondingly, "C" is... 1-6 "Alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, etc. The special "C" 1-6 "alkylamino" includes methylamino, ethylamino, isopropylamino, tert-butylamino, etc.

[0057] The term "(C)" 1-6 "alkyl)2amino" alone or in combination represents an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by two C1-6 alkyl groups, where "alkyl" means as defined above, and correspondingly, "(C 1-6 "alkyl)2amino" includes dimethylamino, diethylamino, methylethylamino, etc.

[0058] The term "amino acid residue" as used in this article refers to an amino acid unit in which the carboxyl or amino group at the carbon terminus participates in bond formation and loses one molecule of water.

[0059] The term "[Cu]" as used in this article refers to monovalent copper (Cu). + ) or divalent copper (Cu) 2+ Reagents, such as CuI, CuBr, CuCl, CuI2, CuBr2, CuCl2, etc.

[0060] The term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers (including cis-trans isomers). Therefore, any single stereochemical isomer of the compound designed in this invention, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), is within the scope of this invention.

[0061] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds of this invention, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups (such as amines); and alkali metal or organic salts of acidic groups (such as carboxylic acids). Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, the aforementioned conventional non-toxic salts include those derived from, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts prepared from, for example, organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethanesulfonic acid, etc.

[0062] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, the salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, 25 Allen, LV Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

[0063] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both a solution phase and a separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0064] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more commonly polyesters.

[0065] The term "isotope derivative" refers to isotope derivatives obtained by replacing hydrogen atoms in general formula (I) with 1-6 deuterium atoms (D) and isotope derivatives obtained by replacing carbon atoms in general formula (I) with 1-3 carbon-14 atoms (14C).

[0066] The term “treatment” as used in this article includes any effect that results in improvement of a condition, disease, disorder, etc., such as reducing, decreasing, regulating, improving or eliminating, or improving its symptoms.

[0067] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, making the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic purposes. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, etc. For therapeutic purposes, the salts of the compounds of the present invention are intended to be pharmaceutically acceptable. However, salts of non-pharmaceutical acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0068] Specific pharmaceutical and medical terminology The term "cancer," as used in this article, refers to an uncontrolled abnormal growth of cells that, under certain conditions, can metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestines, brain, chest, uterus, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or hematologic malignancies (such as non-leukemic leukemia).

[0069] Drug composition and dosage The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I) formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the present invention can be administered in any suitable manner for any of the above-described uses, such as orally, in tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; sublingually; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to a nasal membrane, such as by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They can be administered alone, but are generally administered using a pharmaceutical carrier chosen based on the selected route of administration and standard pharmaceutical practice.

[0070] Pharmaceutical carriers are formulated based on a number of factors known to those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media as well as various solid and semi-solid dosage forms.

[0071] The aforementioned carriers may include a variety of different components and additives besides the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing agents, binders, etc. Descriptions of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0072] Of course, the dosage regimen of the compounds of the present invention varies depending on known factors, such as the pharmacodynamic properties of the specific pharmaceutical agent and its administration mode and route; the recipient's species, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. According to general guidelines, when used for a specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 600 mg / day. During constant-rate infusion, the most preferred intravenous dose should be from about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention can be administered as a single daily dose, or as a total daily dose administered in two, three, or four separate doses daily.

[0073] The compound is typically administered in the form of a mixture with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier) appropriately selected according to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with routine pharmaceutical practice.

[0074] Suitable dosage forms (pharmaceutical compositions) may contain from about 0.1 mg to about 2000 mg of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

[0075] A typical injectable formulation can be prepared as follows: at least one compound of the present invention (250 mg) is aseptically placed in a vial, aseptically lyophilized, and sealed. For use, the vial contents are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0076] The scope of this invention includes (alone or in combination with a drug carrier) pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient. Optionally, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0077] Regardless of the chosen route of administration, the compounds of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0078] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be altered to obtain an amount of active ingredient that is effective and non-toxic to patients in achieving the desired therapeutic response, composition, and administration mode for a particular patient.

[0079] The selected dose level will depend on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide; route of administration; time of administration; excretion rate of the specific compound; absorption rate and extent; duration of treatment; other drugs, compounds and / or substances used in combination with the specific compound; and medically known factors such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0080] Physicians or veterinarians with ordinary skills in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve the desired therapeutic effect, a physician or veterinarian may begin with a dose of the compound of the invention used in the pharmaceutical composition at a level below the desired level and gradually increase the dose until the desired effect is achieved. Typically, the appropriate daily dose of the compound of the invention will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose typically depends on the factors described above. Typically, the range of oral, intravenous, intramuscular, intraventricular, and subcutaneous doses of the compound of the invention for a patient is from about 0.01 to about 1000 mg / kg body weight / day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six, or more sub-dose at appropriate intervals throughout the day, optionally in unit dosage form. In some aspects of the invention, the medication is administered once daily.

[0081] Although the compounds of the present invention can be administered alone, they are preferably administered in the form of pharmaceutical formulations (compositions).

[0082] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0083] First, this invention provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, deuterated derivative, isomer, solvate, prodrug, or isotope label thereof:

[0084] in, A, B, C, D, E, F, G, H, I, J, K, L, and M are each independently selected from direct-connection keys, CR 6 CR 6 R 14 , N, NR 7 O, S and C=O; Each R 1 R 2 R 3 R 6 R 7 and R 14 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cyclohexaalkyl, halogen, -OH, unsubstituted or substituted alkoxy, unsubstituted or substituted arylalkyl, unsubstituted or substituted aromatic heteroalkyl, unsubstituted or substituted aryl ether, unsubstituted or substituted aromatic heteroether, -CN, -N(R) 4 R 5 -NO2, -N3, borate group, unsubstituted or substituted borate ester group, carboxyl group, ester group, unsubstituted or substituted aminoformyl group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterogroup, unsubstituted or substituted thioether group, unsubstituted or substituted sulfoxide group, unsubstituted or substituted sulfone group, unsubstituted or substituted sulfonamide group, , Unsubstituted or substituted phosphonate groups, wherein R 4 R 5 R 8 R 9 R 10 and R 11 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C. 1-6 Alkyl, C 3-7 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aromatic heteroyl, and R4 and R 5 R 8 and R 9 It can connect with adjacent nitrogen or carbon atoms to form a ring; Or two adjacent R 1 and / or two adjacent R 3 It can also be connected into cycloalkyl, cyclohexaalkyl, aryl, or aromatic heteroalkyl groups; m, n, and o are each independently selected from integers from 0 to 4; W is selected from the following: straight-linked group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterolyl group, unsubstituted or substituted cycloalkyl group, unsubstituted or substituted cyclohexaalkyl group, unsubstituted or substituted bridged cycloalkyl group, unsubstituted or substituted bridged cyclohexaalkyl group, unsubstituted or substituted spirocycloalkyl group, unsubstituted or substituted spirocyclohexaalkyl group, unsubstituted or substituted alkyl group, unsubstituted or substituted heteroalkyl group, unsubstituted or substituted alkenyl group, unsubstituted or substituted heteroalkenyl group, unsubstituted or substituted heteroyynyl group, unsubstituted or substituted -N(R) group. 12 R 13 ), unsubstituted or substituted aminoalkyl, unsubstituted or substituted aminoalkylamino, unsubstituted or substituted Unreplaced or replaced , where R 12 and R 13 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-7 Cycloalkyl, unsubstituted or substituted alkylamino, unsubstituted or substituted aryl, substituted or unsubstituted aromatic heteroyl, or R 12 and R 13 They can be connected to form a ring; Q represents -H, -NH2, -OH, -alkyl-NHC(=O)H, cycloalkyl, unsubstituted or substituted alkylacyl, unsubstituted or substituted alkylhydroxy, unsubstituted or substituted alkenylhydroxy, unsubstituted or substituted alkynylhydroxy, unsubstituted or substituted alkylamine, unsubstituted or substituted sulfonamide, unsubstituted or substituted alkylsulfonamide, amino acid residue. , sulfonamide group, sulfonylhydrazine group, unsubstituted or substituted aryl group, unsubstituted or substituted aromatic heterogroup, unsubstituted or substituted Unreplaced or replaced Substituted or unsubstituted -(CH2) n 1 -(M) n 2 -(CH2) n 3 -(M) n 4 -(CH2) n 5 -(M) n 6Each M is independently selected from O, OH, S, SO, SO2 and unsubstituted or substituted amino groups, and each n1, n2, n3, n4, n5 and n6 is independently selected from integers from 0 to 6; Alternatively, W and Q can be linked or fused to form substituted or unsubstituted cycloalkyl, cyclohexaalkyl, aryl, or aromatic heteroalkyl groups.

[0085] Preferably, at least one of C, G, and I is an N atom. For example, any one of C, G, and I is an N atom, or any two of C, G, and I are N atoms (i.e., C and G are N atoms, or C and I are N atoms, or G and I are N atoms), or C, G, and I are all N atoms.

[0086] Preferably, at least one of J, K, and M is an N atom. For example, J is an N atom or K is an N atom, or both J and K are N atoms.

[0087] Preferably, I, J, and K are all N atoms, or I, M, and K are all N atoms.

[0088] Preferably, each R 1 R 2 R 3 R 6 R 7 and R 14 Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C. 1-6 Alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6 Alkyne group, unsubstituted or substituted C 3-7 Cycloalkyl, unsubstituted or substituted 3-7 membered heteroalkyl, halogen, -OH, unsubstituted or substituted C 1-6 Alkoxy, unsubstituted or substituted C 6-10 arylethyl, unsubstituted or substituted 5-10 arylethyl, unsubstituted or substituted C 6-10 Aryl ether group, unsubstituted or substituted 5-10 membered aromatic hetero ether group, -CN, -NH2, -NO2, -N3, borate group, unsubstituted or substituted borate ester group, carboxyl group, ester group, unsubstituted or substituted aminoformyl group, unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 aryl groups, unsubstituted or substituted thioether groups, unsubstituted or substituted sulfoxide groups, unsubstituted or substituted sulfone groups, unsubstituted or substituted sulfonamide groups, , Unsubstituted or substituted phosphonate groups, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0089] Preferably, W is selected from straight-linked, substituted or unsubstituted aryl, aromatic heteroyl, cycloalkyl, cyclohexaalkyl, bridged cycloalkyl, bridged cyclohexaalkyl, spirocycloalkyl, spirocyclohexaalkyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, ynyl, heteroynyl, -N(R) 12 R 13 ), aminoalkyl, aminoalkylamino, unsubstituted or substituted Unreplaced or replaced The substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0090] Preferably, W is selected from substituted or unsubstituted 5-7 membered cyclohexaalkyl groups, substituted or unsubstituted -amino-C groups. 1-6 Alkyl groups, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0091] Preferably, the atom in W that is connected to the ring containing J and K is N.

[0092] Preferably, W is selected from substituted or unsubstituted 5-7 membered heterocyclic alkyl groups, wherein the 5-7 membered heterocyclic alkyl group contains at least one nitrogen atom; more preferably, the 5-7 membered heterocyclic alkyl group is piperidinyl or piperazineyl.

[0093] Preferably, Q is -H, -NH2, -OH, or -C. 1-6 Alkyl-HNC(=O)H, unsubstituted or substituted C 1-6 Alkyl hydroxyl, unsubstituted or substituted C 2-6 alkenyl hydroxyl, unsubstituted or substituted C 2-6 The alkynyl hydroxyl group, unsubstituted or substituted alkylamine group, sulfonamide group, and sulfonylhydrazine group, wherein the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, -NH2, -NO2, -N3, borate group, carboxyl group, ester group, formamide group, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0094] Preferably, W and Q can be connected or fused into a ring, wherein the ring is a substituted or unsubstituted 5-7 membered cycloalkyl, a substituted or unsubstituted 5-7 membered heteroalkyl, or a substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted 5-10 aryl heteroalkyl groups.

[0095] More preferably, the substitution is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Haloalkenyl, C 1-6 Halogenated alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, -OH, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, -CN, -NH2, -NO2, N3, borate groups, carboxyl groups, ester groups, formamide groups, C 1-6 Alkylamide group, C 6-10 Substituents include aryl, 5-10 aryl heteroyl, and alkylamine groups.

[0096] Preferably, the compound with the structure of Formula I is: , Among them, C, G, I, J, and K are each independently selected from CR. 6 And N, and at least one of C, G, and I is N, and at least one of J and K is N; R 1 R 2 R 3 R 6 The definitions of , o, m, n, W, and Q are the same as those above.

[0097] Preferably, the compound with the structure of Formula I is: , Among them, C, G, I, K, and M are each independently selected from CR. 6 And N, and at least one of C, G, I is N, and at least one of K and M is N; R 1 R 2 R 3 R 6 The definitions of , o, m, n, W, and Q are the same as those above.

[0098] In a preferred embodiment, the present invention also provides compounds or pharmaceutically acceptable salts, esters, deuterated derivatives, isomers, solvates, prodrugs, or isotopic labels thereof, said compounds being selected from: , , , , .

[0099] The present invention also provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt, ester, deuterated derivative, isomer, solvate, prodrug, or isotope label thereof, and a pharmaceutically acceptable excipient.

[0100] In a preferred embodiment, the pharmaceutical composition is in the form of any one of an aqueous dispersant, liquid, gel, syrup, slurry, ointment, suspension, aerosol, controlled-release agent, instant solvent, effervescent agent, lyophilized agent, tablet, powder, pill, sugar-coated tablet, capsule, delayed-release agent, extended-release agent, pulsatile controlled-release agent, multi-microparticle agent, or immediate-release agent.

[0101] The present invention also provides the use of any of the compounds described above or their pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels, or any of the pharmaceutical compositions described above, in the preparation of a medicament for treating CTLA-4 related diseases.

[0102] In a preferred embodiment, the CTLA-4-related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, and organ transplant rejection.

[0103] In a more preferred embodiment, the cancer is selected from skin cancer, bladder cancer, breast cancer, pancreatic cancer, bone cancer, brain cancer, neurocytoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, choriocarcinoma, pancreatic cancer, urinary tract cancer, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or Plasma cell tumors, papillomas, budding gliomas, sarcomas (including but not limited to chondrosarcoma, histiosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma), melanomas, hemangiomas, keloids, squamous cell carcinomas, astrocytomas, lymphomas (including but not limited to non-Hodgkin's lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphomas), respiratory tract cancers (including but not limited to lung cancer, such as small cell and non-small cell lung cancer, as well as bronchial adenoma and pleural pulmonary blastoma), head and neck cancers (including but not limited to head cancer, neck cancer, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer and / or oropharyngeal cancer, as well as lip and oral cavity cancers), bladder cancer, breast cancers (including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), and gastrointestinal cancers (including but not limited to anal cancer, ...). Colorectal cancer, colorectal cancer, esophageal cancer, gallbladder cancer, rectal cancer, stomach cancer, small bowel cancer, and salivary gland cancer), thyroid cancer, parathyroid cancer and its distant metastases, pancreatic cancer, liver cancer (including but not limited to hepatocellular carcinoma, hepatocellular carcinoma with or without fibrolamellar structure, cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma), leukemia (including but not limited to acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and chorionic villus leukemia), brain cancer (including but not limited to brainstem and pituitary gliomas, thyroid cancer, and hysteroblastic leukemia), and other types of cancer. Related cancers include: neurocyte tumors, cerebellar and cerebral astrocytomas, tympanic membrane tumors, neuroectodermal tumors, and pineal adenomas; reproductive organ cancers (including but not limited to prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and uterine sarcoma); urethral cancer; eye cancers (including but not limited to intraocular melanoma and retinoblastoma); skin cancers (including but not limited to Kaposi's sarcoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer); renal parenchymal carcinoma; and kidney cancer (also known as renal cell carcinoma and renal adenocarcinoma).

[0104] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0105] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0106] The units in the weight-volume percentages of this invention are well known to those skilled in the art, for example, referring to the weight of the solute in 100 ml of solution.

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0108] These embodiments are for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0109] 1 H-NMR spectroscopy was performed using a Bruker-400 or OXFORD-AS500 NMR spectrometer. Chemical shifts were expressed in parts per million (ppm), with tetramethylsilane as the internal standard. The coupling constant (J) was approximately 0.1 Hz. The abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; brs, broad peak. Mass spectrometry was performed using a Quattro Micro™ API triple quadrupole mass spectrometer.

[0110] Example 1 Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 1)

[0111] 3-(2-Chloroprene-4-yl)quinoline

[0112] Quinoline-3-ylboronic acid (5.0 g, 33.58 mmol) and 2,4-dichloropyrimidine (5.8 g, 33.58 mmol) were added to acetonitrile (100 mL), followed by 2M sodium carbonate aqueous solution (50 mL), and finally Pd(dppf)Cl2 (492 mg, 0.67 mmol). After the addition was complete, the mixture was purged with nitrogen three times, and the temperature was raised to 80 °C. After the reaction was confirmed to be complete by TLC, the reaction system was filtered through diatomaceous earth, and the filtrate was concentrated. Ethyl acetate was added, and the mixture was separated. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography with an elution system of petroleum ether / ethyl acetate = 2 / 1. 6.2 g of the target product was obtained, with a yield of 77%.

[0113] 1 H NMR (400 MHz, CDCl3) δ 9.51 (d, J = 4.0 Hz, 1H), 8.95 (d, J = 4.0Hz, 1H), 8.73 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0Hz, 1H), 7.86 – 7.79 (m, 2H), 7.68 – 7.60 (m, 1H).

[0114] Compound 1

[0115] 3-(2-chloropyrimidin-4-yl)quinoline (1.1 g, 4.56 mmol) and piperidin-4-ylmethylamine (0.52 g, 4.56 mmol) were added to DMSO (10 mL), followed by DIPEA (1.2 g, 9.12 mmol). After the addition was complete, the mixture was heated to 80 °C. After 2 h, TLC confirmed the reaction was complete. The mixture was then added to water (30 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine. After washing with water, the mixture was concentrated, and the residue was separated by rapid column chromatography with an elution system of dichloromethane / methanol = 10 / 1. 600 mg of the target product was obtained, with a yield of 40%.

[0116] 1H NMR (400 MHz, DMSO-d6) δ 9.59 (d, J = 4.0 Hz, 1H), 9.07 (d, J =4.0 Hz, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.08 (d, J =8.0 Hz, 1H), 7.87 –7.81 (m, 1H), 7.74 – 7.65 (m, 1H), 7.38 (d, J = 4.0 Hz, 1H), 4.86 (d, J = 12.0 Hz, 2H), 3.16 (s, 2H), 3.02 – 2.88 (m, 2H), 1.87 –1.76 (m, 2H), 1.68 –1.52 (m, 1H), 1.19 – 1.02 (m, 2H).

[0117] MS-ESI: 320.5 [M+H] + .

[0118] Example 2 Preparation of N-((1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)formamide (compound 2)

[0119] Except that the reaction time was changed from 2 hours to 24 hours, the preparation of compound 2 was the same as that of compound 1. The yield was 26%.

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 4.0 Hz, 1H), 9.06 (d, J =2.0 Hz, 1H), 8.49 (d, J = 4.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.06 (dd, J= 12.0, 8.0 Hz, 3H), 7.87 – 7.79 (m, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.37 (d,J = 8.0 Hz, 1H), 4.83 (d, J = 12.0 Hz, 2H), 3.06 – 3.00 (m, 2H), 2.94 (t, J =12.0 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.20 – 1.07 (m, 2H).

[0121] MS-ESI: 348.6 [M+H] + .

[0122] Example 3 Preparation of (1-(4-(quinolin-6-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 3)

[0123] 6-(2-Chloroprene-4-yl)quinoline

[0124] Except that quinoline-3-boronic acid was replaced with quinoline-6-boronic acid in Example 1, the synthesis of compound 6-(2-chloropyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 81%.

[0125] 1 H NMR (400 MHz, CDCl3) δ 9.01 (dd, J = 4.0, 2.0 Hz, 1H), 8.72 (d, J =8.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.36 (dd, J = 8.0, 4.0 Hz, 1H), 8.32(d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.50(dd, J = 8.0, 4.0 Hz, 1H).

[0126] MS-ESI: 242.4 [M+H] + .

[0127] Compound 3

[0128] Except for replacing 3-(2-chloropyrimidin-4-yl)quinoline with 6-(2-chloropyrimidin-4-yl)quinoline, the synthesis of compound 3 is the same as that of compound 1. The yield is 46%.

[0129] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 4.0, 2.0 Hz, 1H), 8.77 (d,J = 4.0 Hz, 1H), 8.55 – 8.44 (m, 3H), 8.12 (d, J = 8.0 Hz, 1H), 7.59 (dd, J 1.89 – 1.76 (m, 2H),1.70 – 1.57 (m, 1H), 1.20 – 1.06 (m, 2H).

[0130] MS-ESI: 320.5 [M+H] + .

[0131] Example 4 Preparation of N-((1-(4-(quinolin-6-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)formamide (compound 4)

[0132] Except that 3-(2-chloropyrimidin-4-yl)quinoline was replaced with 6-(2-chloropyrimidin-4-yl)quinoline, compound 4 was synthesized the same as compound 2 in Example 2. The yield was 56%.

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 4.0, 2.0 Hz, 1H), 8.76 (d,J = 4.0 Hz, 1H), 8.54 – 8.44 (m, 3H), 8.11 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.59 (dd, J = 8.0, 4.0 Hz, 1H), 7.32 (d, J = 4.0 Hz, 1H), 4.83 (d, J = 12.0Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 2.93 (t, J = 12.0 Hz, 2H), 178 – 1.70 (m,3H), 1.20 – 1.05 (m, 2H).

[0134] MS-ESI: 348.6 [M+H] +.

[0135] Example 5 Preparation of (1-(4-(quinolin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 5)

[0136] 1-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)acet-1-one

[0137] Except for replacing 3-(2-chloropyrimidin-4-yl)ethyl-1-one in Example 1, the synthesis of 1-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)ethyl-1-one was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 98%.

[0138] MS-ESI: 235.4 [M+H] + .

[0139] (1-(4-(quinolin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine

[0140] o-Aminobenzaldehyde (197 mg, 1.63 mmol) and 1-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)ethyl-1-one (380 mg, 1.63 mmol) were dissolved in EtOH (10 mL), followed by the addition of potassium hydroxide (182 mg, 3.25 mmol). After the addition was complete, the reaction was carried out overnight at 80 °C. The reaction was confirmed to be complete by TLC the next day. The solvent was removed by vacuum distillation, and ethyl acetate and water were added to the residue. The mixture was separated, and the organic phase was washed with water. The solvent was removed by vacuum distillation, and the residue was separated by rapid column chromatography to give 450 mg of the product, with a yield of 86%.

[0141] 1H NMR (400 MHz, CDCl3) δ 8.50 (t, J = 6.8 Hz, 2H), 8.25 (d, J = 8.6Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.2Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 4.97 (d, J = 13.2 Hz, 2H), 3.01 - 2.94 (m,2H), 2.67 (d, J = 6.6 Hz, 2H), 2.32 (brs, 2H), 1.89 (d, J = 13.2 Hz, 2H),1.75 -1.65 (m, 1H), 1.32 - 1.19 (m, 2H).

[0142] MS-ESI: 320.5 [M+H] + .

[0143] Example 6 Preparation of (1-(4-(quinoxalo-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 6)

[0144] 2-(2-Chloroprene-4-yl)quinoxaline

[0145] Except for replacing quinoline-3-ylboronic acid in Example 1 with 2-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)quinoxaline, the synthesis of compound 2-(2-chloropyrimidin-4-yl)quinoxaline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 57%.

[0146] MS-ESI: 243.2 [M+H] + .

[0147] Compound 6

[0148] Except that 2-(2-chloropyrimidin-4-yl)quinoxaline was used instead of 3-(2-chloropyrimidin-4-yl)quinoxaline in Example 1, compound 6 was synthesized in the same manner as compound 1 in Example 1. The yield was 63%.

[0149] MS-ESI: 321.2 [M+H] + .

[0150] Example 7 Preparation of (1-(4-(6-fluoroquinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 7)

[0151] 3-(2-Chloroprene-4-yl)-6-fluoroquinoline

[0152] Except for replacing quinoline-3-ylboronic acid in Example 1 with 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)quinoline, the synthesis of compound 3-(2-chloropyrimidin-4-yl)-6-fluoroquinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 56%.

[0153] 1 H NMR (400 MHz, CD3OD) δ 9.54 (d, J = 4.0 Hz, 1H), 9.13 (d, J = 4.0Hz, 1H), 8.80 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.16 – 8.12 (m,1H), 7.79 (dd, J = 8.0, 4.0 Hz, 1H), 7.73 – 7.66 (m, 1H).

[0154] MS-ESI: 260.3 [M+H] + .

[0155] Compound 7

[0156] Except that 3-(2-chloropyrimidin-4-yl)-6-fluoroquinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, compound 7 was synthesized in the same manner as compound 1 in Example 1. The yield was 73%.

[0157] 1H NMR (400 MHz, CD3OD) δ 9.51 (d, J = 4.0 Hz, 1H), 8.97 (d, J = 4.0Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.15 – 8.10 (m, 1H), 7.76 (dd, J = 12.0,4.0Hz, 1H), 7.66 (td, J = 8.0, 4.0 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 4.96(d, J = 12.0 Hz, 2H), 3.00 (td, J = 12.0, 4.0 Hz, 2H), 2.66 (d, J =8.0 Hz,2H), 1.89 (d, J = 12.0 Hz, 2H), 1.86 – 1.72 (m, 1H), 1.30 – 1.18 (m, 2H).

[0158] MS-ESI: 338.4 [M+H] + .

[0159] Example 8 (1-(3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinoline-2-yl)piperidin-4-yl)methylamine (Compound 8)

[0160] 3-(2-chloropyrimidin-4-yl)-2-fluoroquinoline

[0161] Except for replacing quinoline-3-ylboronic acid in Example 1 with (2-fluoroquinoline-3-yl)boronic acid, the synthesis of compound 3-(2-chloropyrimidin-4-yl)-6-fluoroquinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 42%.

[0162] 1 H NMR (400 MHz, CD3OD) δ 9.28 (d, J = 8.0 Hz, 1H), 8.82 (d, J = 8.0Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.0, 4.0 Hz, 1H), 7.97 –7.85 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H).

[0163] MS-ESI: 260.3 [M+H] + .

[0164] Compound 8

[0165] Except that 3-(2-chloropyrimidin-4-yl)-2-fluoroquinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, compound 8 was synthesized in the same manner as compound 1 in Example 1. The yield was 73%.

[0166] 1 H NMR (400 MHz, CD3OD ) δ 8.40 – 8.32 (m, 2H), 7.81 (dd, J = 8.0, 4.0Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0Hz, 1H), 4.96 (d, J = 16.0 Hz, 2H), 3.79 (d, J = 16.0 Hz, 2H), 3.01 (t, J =12.0 Hz, 2H), 2.93 – 2.85 (m, 6H), 2.08 – 1.96 (m, 1H), 1.94 – 1.74 (m, 5H),1.46 – 1.26 (m, 4H).

[0167] MS-ESI: 432.5 [M+H] + .

[0168] Example 9 Preparation of (1-(4-(2-methoxyquinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 9)

[0169] 3-(2-Chloroprene-4-yl)-2-methoxyquinoline

[0170] Except that the compound (2-methoxyquinoline-3-yl)boronic acid was used instead of quinoline-3-ylboronic acid in Example 1, the synthesis of compound 3-(2-chloropyrimidin-4-yl)-2-methoxyquinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 52%.

[0171] 1H NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.67 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.94 -7.85 (m, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 4.0 Hz, 1H), 4.21 (s, 3H).

[0172] MS-ESI: 272.3 [M+H] + .

[0173] Compound 9

[0174] Except that 3-(2-chloropyrimidin-4-yl)-2-methoxyquinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, compound 9 was synthesized the same as compound 1 in Example 1. The yield was 76%.

[0175] 1 H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.37 (d, J = 4.0 Hz, 1H), 7.85 (t, J = 7.0 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H),7.27 (s, 1H), 4.93 (d, J = 16.0 Hz, 2H), 4.15 (s, 3H), 3.71 (q, J = 7.0 Hz,2H), 2.94 (t, J = 12.8 Hz, 2H), 2.65 (d, J = 4.0 Hz, 2H), 1.86 (d, J = 16.0Hz, 2H), 1.78 -1.60 (m, 1H), 1.31 -1.17 (m, 2H).

[0176] MS-ESI: 350.4 [M+H] + .

[0177] Example 10 Preparation of 3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinoline-2-ol (compound 10)

[0178] Compound 9 (300 mg, 0.86 mmol) and DCM (6 mL) were added to a sealed tube, followed by boron tribromide (539 mg, 2.16 mmol), and the reaction was heated to 50 °C. After the reaction was complete as monitored by TLC, water was added to separate the organic phase, which was then washed successively with saturated sodium bicarbonate and water. The solvent was removed by vacuum distillation, and the residue was separated by rapid column chromatography. Compound 10 was obtained in a yield of 155 mg, with a yield of 54%.

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.39 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.60 – 7.54(m, 1H), 7.36(d, J = 8.0 Hz, 1H), 7.25 – 7.9 (m, 1H), 4.78 (d, J = 12.0 Hz, 2H), 3.47 –3.42 (m, 2H), 2.97 – 2.76 (m, 4H), 1.75 (d, J = 16.0 Hz, 2H),1.70–1.60(m,1H).

[0180] MS-ESI: 336.4 [M+H] + .

[0181] Example 11 Preparation of (1-(4-(quinolin-3-yl-2-d)pyrimidin-2-yl)piperidin-4-yl)methylamine (compound 11)

[0182] 3-(2-chloropyrimidin-4-yl)quinoline-2-d

[0183] Except for replacing quinoline-3-ylboronic acid in Example 1 with (quinoline-3-yl-2-d)boronic acid, the synthesis of 3-(2-chloropyrimidin-4-yl)quinoline-2-d is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 32%.

[0184] 1H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.09 (d, J = 4.0 Hz, 2H), 7.90 – 7.78 (m, 1H), 7.73 – 7.64 (m, 1H), 7.27 (d, J =4.0 Hz, 1H).

[0185] MS-ESI: 243.2 [M+H] + .

[0186] Compound 11

[0187] Except that 3-(2-chloropyrimidin-4-yl)quinoline-2-d was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of compound 11 was the same as that of compound 1 in Example 1. The yield was 67%.

[0188] 1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.13– 8.03 (m, 2H), 7.89 – 7.81 (m, 1H), 7.72 – 7.63 (m, 1H), 7.27 (d, J = 4.0Hz, 1H), 4.96 (d, J = 16.0 Hz, 2H), 2.99 (td, J = 12.0, 4.0 Hz, 2H), 2.59 (d,J = 8.0 Hz, 2H), 1.94 – 1.84 (m, 2H), 1.80 – 1.66 (m, 1H), 1.27 – 1.19 (m,2H).

[0189] MS-ESI: 321.3 [M+H] + .

[0190] Example 12 Preparation of (1-(4-(quinolin-3-yl)pyridin-2-yl)piperidin-4-yl)methylamine (compound 12)

[0191] 3-(2-chloropyridin-4-yl)quinoline

[0192] Except that quinoline-3-ylboronic acid in Example 1 was replaced with compound 3-bromoquinoline, and 2,4-dichloropyrimidine in Example 1 was replaced with (2-chloropyridin-4-yl)boronic acid, the synthesis of compound 12 was the same as that of 3-(2-chloropyrimidine-4-yl)quinoline in Example 1. The yield was 65%.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 4.0 Hz, 1H), 8.94 (d, J =4.0 Hz, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.13 (s, 1H), 8.10 (d, J = 12.0 Hz,2H), 8.00 (dd, J = 8.0, 4.0 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.71 (t, J = 8.0Hz, 1H).

[0194] MS-ESI: 241.2 [M+H] + .

[0195] Compound 12

[0196] Except that 3-(2-chloropyridin-4-yl)quinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of compound 12 was the same as that of compound 1 in Example 1. The yield was 64%.

[0197] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 4.0 Hz, 1H), 8.77 (d, J =4.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 12.0 Hz, 2H), 7.80 (t, J= 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.10 (d, J = 4.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 2H), 2.84 (t, J = 12.0 Hz, 2H), 2.63 (d, J = 4.0Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H), 1.75 –1.65 (m, 1H), 1.26 – 1.14 (m, 2H).

[0198] MS-ESI: 319.3 [M+H] + .

[0199] Example 13 Preparation of 2-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)-4-hydro-benzopyran-4-one (compound 13)

[0200] 2-(4-((tert-Butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidin-4-carboxylic acid methyl ester

[0201] Except that methyl 2-chloropyrimidin-4-carboxylate was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of methyl 2-(4-((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidin-4-carboxylate was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 88%.

[0202] MS-ESI: 351.2 [M+H] + .

[0203] ((1-(4-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)methyl)tert-butyl carbamate)

[0204] Methyl 2-(4-((tert-Butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidin-4-carboxylic acid (1.56 g, 4.5 mmol) was dissolved in DCM (30 mL) and stirred. DIBAL-H (4.5 mL, 6.7 mmol) was slowly added at -70 °C. The next day, TLC monitoring showed residual starting material; DIBAL-H (3 mL) was added, and the reaction was completed after 3 hours. MeOH (5 mL) was added to quench the reaction. Saturated NaHCO3 was added, and the mixture was separated by vacuum distillation. The residue was separated by rapid column chromatography. 760 mg of the target product was obtained, with a yield of 55%.

[0205] 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 8.0, 0.6 Hz, 1H), 6.35 (d, J= 4.0 Hz, 1H), 4.79 (d, J = 16.0 Hz, 2H), 4.65 (s, 1H), 4.54 (d, J = 4.0 Hz,2H), 3.73-3.71 (m, 1H), 3.05-3.02 (m, 2H), 2.86 (t, J =12.0, 7.6 Hz, 2H), 1.79-1.75 (m, 2H), 1.45 (s, 9H), 1.18 (dd, J = 12.2, 3.8 Hz, 2H).

[0206] MS-ESI: 323.4 [M+H] + .

[0207] ((1-(4-formylpyrimidin-2-yl)piperidin-4-yl)methyl)tert-butyl carbamate

[0208] 760 mg (0.24 mmol) of tert-butyl (1-(4-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate was dissolved in 30 mL of DCM. Then, 1.5 g (7.0 mmol) of PCC and 1.5 g of silica gel were mixed thoroughly and added to the reaction system. After 3 hours, the reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was separated. The organic phase was washed with brine, and the solvent was removed by vacuum distillation. The residue was separated by rapid column chromatography. 360 mg of the target product was obtained, with a yield of 46%.

[0209] 1 H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 8.50 (d, J = 4.0 Hz, 1H), 6.92 (d, J = 4.0 Hz, 1H), 4.87 (d, J = 12.0 Hz, 2H), 3.07-3.04 (m, 2H), 2.86 (t, J =12.0, 7.6 Hz, 2H), 1.87 - 1.74 (m, 3H), 1.45 (s, 9H), 1.29 -1.11 (m, 2H).

[0210] MS-ESI: 321.6 [M+H] + .

[0211] ((1-(4-(1-hydroxy-3-(2-hydroxyphenyl)-3-oxopropyl)pyrimidin-2-yl)piperidin-4-yl)methyl)tert-butyl carbamate)

[0212] (360 mg, 0.1 mmol) of tert-butyl carbamate ((1-(4-formylpyrimidin-2-yl)piperidin-4-yl)methyl)carbamate (184 mg, 0.1 mmol)) and 1-(2-hydroxyphenyl)ethane-1-one (184 mg, 0.1 mmol) were dissolved in MeOH (20 mL), followed by the addition of KOH (126 mg, 0.2 mmol). The reaction was allowed to proceed to completion by TLC after 3 hours. The pH was adjusted to 6-7 with 2M HCl solution. The solvent was removed by vacuum evaporation, and the residue was dried under high vacuum to obtain the crude product. No purification was performed, and the reaction proceeded directly to the next step.

[0213] MS-ESI: 457.5 [M+H] + .

[0214] ((1-(4-(4-oxo-4H-chromen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)tert-butyl carbamate)

[0215] (1-(4-(1-hydroxy-3-(2-hydroxyphenyl)-3-oxopropyl)pyrimidin-2-yl)piperidin-4-yl)methyl)tert-butyl carbamate was dissolved in DMSO (6 mL), and I2 (5 mg) was added. After the addition was complete, the system temperature was raised to 100 °C. The next day, TLC monitoring showed that the reaction was almost complete. Water was added, and the mixture was extracted with DCM. The organic phase was washed with saturated sodium bicarbonate, and the solvent was removed by vacuum distillation. The residue was separated by rapid column chromatography. 40 mg of the target product was obtained, with a yield of 38%.

[0216] 1 H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 4.0 Hz, 1H), 7.82-7.79 (m,1H), 7.71-7.67 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.29 -7.27 (m, 1H), 7.24 -7.21 (m, 1H), 6.77-6.72 (m, 1H), 4.89-4.79 (m, 2H), 3.78 - 3.66 (m, 1H), 3.08-3.02 (m, 2H), 2.92-2.86 (m, 2H), 1.80 (d, J = 12.0 Hz, 2H), 1.44 (s,9H), 1.33-1.15 (m, 2H).

[0217] MS-ESI: 437.4 [M+H] + .

[0218] Compound 13

[0219] 40 mg (0.09 mmol) of tert-butyl carbamate (1-(4-(4-oxo-4H-chromen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate was dissolved in HCl-Dioxane (6 mL). The reaction was monitored by TLC after 1 h to indicate completion. The solvent was evaporated under reduced pressure, and the pH was adjusted to 6-7 with the addition of saturated sodium bicarbonate. The residue was separated by rapid column chromatography. Compound 13 was obtained in a dose of 20 mg, with a yield of 65%.

[0220] 1 H NMR (400 MHz, CD3OD): δ 8.44 (d, J = 4.0 Hz, 1H), 7.81 (t, J =7.4Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 16.0, 6.4 Hz, 2H), 6.61(s, 1H), 4.59 (s, 2H), 2.95 (t, J = 12.0, 7.4 Hz, 2H), 2.87 (d, J = 8.0 Hz, 2H), 2.0-1.90 (m, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.35- 1.22 (m, 2H).

[0221] MS-ESI: 337.3 [M+H] + .

[0222] Example 14 Preparation of (1-(6-(quinolin-3-yl)pyridin-2-yl)piperidin-4-yl)methylamine (compound 14)

[0223] (1-(6-bromopyridin-2-yl)piperidin-4-yl)methylamine

[0224] 2,6-Dibromopyridine (1.7 g, 7.17 mmol) and piperidin-4-ylmethylamine (0.9 g, 7.88 mmol) were dissolved in 1,4-dioxane (15 mL), and potassium phosphate (1.52 g, 7.17 mmol) was added. The mixture was then purged with nitrogen three times and heated to 105 °C. After 8 h, the reaction was essentially complete. The system was concentrated, and ethyl acetate and water were added. The mixture was separated by liquid-liquid chromatography, and the organic phase was separated by rapid column chromatography after removing the solvent residue under reduced pressure. 1.36 g of the product was obtained, with a yield of 70%.

[0225] 1 H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.33 (m, 1H), 6.77 (d, J = 12.0Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.21 (d, J = 16.0 Hz, 2H), 2.76 (td, J =12.0, 4.0 Hz, 2H), 2.42 (d, J = 8.0 Hz, 2H), 1.73 (d, J = 12.0 Hz, 2H), 1.55– 1.40 (m, 1H), 1.03 (qd, J = 12.0, 4.0 Hz, 2H).

[0226] Compound 14

[0227] Except that compound 14 was synthesized identically to compound 1 in Example 1, except that compound 1-(6-bromopyridin-2-yl)piperidin-4-yl)methylamine was used instead of 2,4-dichloropyrimidine in Example 1. The yield was 42%.

[0228] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 4.0 Hz, 1H), 8.93 (d, J =4.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.82 – 7.74(m, 1H), 7.73 – 7.60 (m, 2H), 7.42 (d, J = 4.0 Hz, 1H), 6.92 (d, J = 8.0 Hz,1H), 4.50 (d, J = 12.0 Hz, 2H), 2.88 (t, J = 12.0 Hz, 3H), 2.69 (d, J = 4.0Hz, 3H), 1.95 – 1.85 (d, J = 11.3 Hz, 3H), 1.33 – 1.14 (m, 2H).

[0229] MS-ESI: 319.3 [M+H] + .

[0230] Example 15 Preparation of (1-(3-(quinolin-3-yl)phenyl)piperidin-4-yl)methylamine (compound 15)

[0231] 3-(3-bromophenyl)quinoline

[0232] Except that compound 15 was synthesized in the same manner as 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, except that compound 1-bromo-3-iodobenzene was used instead of 2,4-dichloropyrimidine in Example 1. The yield was 82%.

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 4.0 Hz, 1H), 8.71 (d, J =4.0 Hz, 1H), 8.11 (t, J = 4.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.91 (d, J =8.0 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.69 – 7.63 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H).

[0234] Compound 15

[0235] Compound 3-(3-bromophenyl)quinoline (630 mg, 2.22 mmol / L), piperidin-4-ylmethylamine (380 mg, 3.33 mmol / L), and XPos (21 mg, 0.044 mmol / L) were added to THF (10 mL). Then, 2.0 M NaHMDS (1.42 g, 7.77 mmol / L) was slowly added to the system. Finally, Pd(dba)3 (41 mg, 0.044 mmol / L) was added to replace nitrogen three times. The reaction was carried out at 70 °C for 7 h, and TLC monitoring showed that the reaction was essentially complete. Hydrochloric acid was added to adjust the pH to neutral. The reaction system was concentrated, and DCM and water were added. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 150 mg of product was obtained, with a yield of 21%.

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 4.0 Hz, 1H), 8.64 (d, J =4.0 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 – 7.61(m, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.10 (d, J =12.0 Hz, 1H), 7.06 – 6.98 (m, 1H), 3.87 (d, J = 12.0 Hz, 2H), 2.80 – 2.64 (m,4H), 1.90 – 1.80 (m , 3H),1.38 – 1.26 (m , 2H).

[0237] Example 16 Preparation of 3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinoline-2-amine (compound 16)

[0238] 3-(2-Chloropyrimidin-4-yl)quinoline-2-amine

[0239] Except that compound 3-(2-chloropyrimidin-4-yl)quinoline-2-amine was used instead of quinoline-3-ylboronic acid in Example 1, the synthesis of compound 3-(2-chloropyrimidin-4-yl)quinoline-2-amine was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 64%.

[0240] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 8.0 Hz, 1H), 8.51 (d, J =4.0Hz, 1H), 8.14 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H).

[0241] MS-ESI: 257.3 [M+H] + .

[0242] Compound 16

[0243] Except that 3-(2-chloropyrimidin-4-yl)quinoline-2-amine was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, compound 16 was synthesized in the same manner as compound 1 in Example 1. The yield was 82%.

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.12 (s, 1H), 7.85 (d, J =8.0 Hz, 2H), 7.79 – 7.68 (m, 1H), 7.66 – 7.58 (m, 1H),7.54 – 7.46 (m , 1H), 4.73 (d, J = 12.0 Hz, 2H), 3.11 (t, J = 12.0 Hz, 2H), 2.90 (d, J = 8.0 Hz, 2H), 2.09 – 1.99 (m, 1H), 1.92 (d, J = 16.0 Hz, 2H), 1.38 (dd, J = 12.0, 4.0Hz, 2H).

[0245] MS-ESI: 335.4 [M+H] + .

[0246] Example 17 Preparation of 1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-amine (compound 17)

[0247] Except that piperidine-4-amine was used instead of piperidine-4-ylmethylamine in Example 1, the synthesis of compound 17 was the same as that of compound 1 in Example 1. The yield was 65%.

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (d, J = 4.0 Hz, 1H), 9.11 (d, J =4.0 Hz, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.11 (d, J =8.0 Hz, 1H), 7.91 – 7.84 (m, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 4.0Hz, 1H), 4.75 (d, J = 8.0 Hz, 2H), 3.11 (t, J = 12.0 Hz, 2H), 3.04 – 2.94 (m,1H), 1.89 (d, J = 8.0 Hz, 2H), 1.40 – 1.20 (m, 2H).

[0249] MS-ESI: 306.3 [M+H] + .

[0250] Example 18 Preparation of 3-(2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 18)

[0251] 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0252] Except that piperazine-1-carboxylic acid tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, the synthesis of 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 95%.

[0253] MS-ESI: 392.2 [M+H] + .

[0254] Compound 18

[0255] To 6.1 g of tert-butyl piperazine-1-carboxylate (15.56 mmol), 50 mL of 4 M hydrochloric acid / 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC until complete. The reaction system was concentrated, and the product was released by adding a methanol solution of sodium methoxide. The solvent was removed under reduced pressure, and the residue was separated by rapid column chromatography to give 4.55 g of the product, with a yield of 98%.

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 4.0 Hz, 1H), 9.15 (d, J =4.0Hz, 1H), 8.60 (d, J =8.0Hz, 1H), 8.17 – 8.12 (m, 1H), 8.09 (d, J = 8.0 Hz,1H), 7.86 (t, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz,1H), 4.15 – 4.08 (m, 4H), 3.25 – 3.12 (m, 4H).

[0257] MS-ESI: 292.2 [M+H] + .

[0258] Example 19 Preparation of 2-(1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)ethylamine (compound 19)

[0259] Except that piperidine-4-methylamine was used instead of piperidine-4-methylamine in Example 1, the synthesis of compound 19 was the same as that of compound 1 in Example 1. The yield was 36%.

[0260] 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 4.0 Hz, 1H), 9.09 (d, J =4.0 Hz, 1H), 8.51 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.09 (d, J =8.0 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 4.86 (d, J = 12.0Hz, 2H), 2.98 – 2.92 (m, 2H), 2.90 – 2.83 (m, 2H), 2.54 (s, 2H), 1.79 (d, J =8.0 Hz, 2H), 1.54 –1.48 (m, 1H), 1.20 – 1.12 (m, 2H).

[0261] MS-ESI: 334.2 [M+H] + .

[0262] Example 20 Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanol (compound 20)

[0263] Except that piperidine-4-ylmethanol was used instead of piperidine-4-ylmethylamine in Example 1, compound 20 was synthesized in the same manner as compound 1 in Example 1. The yield was 83%.

[0264] 1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 4.0 Hz, 1H), 9.07 (d, J =4.0 Hz, 1H), 8.49 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.07 (d, J =8.0 Hz, 1H), 7.88 – 7.79 (m, 1H), 7.73 – 7.63 (m, 1H), 7.36 (d, J = 4.0 Hz, 1H), 4.85 (d, J = 12.0 Hz, 2H), 4.51 (t, J = 8.0 Hz, 1H), 3.31 – 3.24 (m,2H), 2.98 – 2.86 (m, 2H), 1.76 (d, J = 12.0 Hz, 2H), 1.72 – 1.63 (m, 1H), 1.11 (qd, J = 12.0, 4.0 Hz, 2H).

[0265] MS-ESI: 321.2 [M+H] + .

[0266] Example 21 Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)ethanol (compound 21)

[0267] Except that piperidine-4-ylethanol was used instead of piperidine-4-ylmethylamine in Example 1, compound 21 was synthesized the same as compound 1 in Example 1. The yield was 49%.

[0268] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 4.0 Hz, 1H), 9.05 (d, J =1.9 Hz, 1H), 8.48 (d, J = 4.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.07 (d, J =8.0 Hz, 1H), 7.88 – 7.77 (m, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 4.81 (d, J = 12.0 Hz, 2H), 4.40 (s, 1H), 3.47 (d, J = 4.0 Hz, 1H),2.91 (t, J = 12.0 Hz, 1H), 1.82 – 1.63 (m, 3H), 1.38 (q, J = 8.0 Hz, 2H), 1.17 – 0.99 (m, 2H).

[0269] MS-ESI: 335.3 [M+H] + .

[0270] Example 22 Preparation of 3-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)quinoline (compound 22)

[0271] Except that (2S,6R)-2,6-dimethylpiperazine was used instead of piperidine-4-ylmethylamine in Example 1, the synthesis of compound 22 was the same as that of compound 1 in Example 1. The yield was 83%.

[0272] 1H NMR (400 MHz, DMSO-d6): δ 9.61 (d, J = 2.2 Hz, 1H), 9.08 (d, J =2.2 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.09 (d, J =8.4 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 5.2Hz, 1H), 4.72 (d, J = 12.4 Hz, 2H), 2.81 - 2.74 (m, 2H), 2.45 (t, J = 12.0Hz, 2H), 1.09 (s, 3H), 1.07 (s, 3H).

[0273] MS-ESI: 320.2 [M+H] + .

[0274] Example 23 Preparation of 3-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)quinoline (compound 23)

[0275] Except that 1-methylpiperazine was used instead of piperidine-4-ylmethylamine in Example 1, compound 23 was synthesized in the same manner as compound 1 in Example 1. The yield was 78%.

[0276] 1 H NMR (400 MHz, CD3OD): δ 9.56 (d, J = 4.0 Hz, 1H), 9.05 (d, J = 2.4Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.39 (d, J = 8.0Hz, 1H), 3.86-3.79 (m, 4H), 2.41 -2.34 (m, 4H), 2.20 (s, 3H).

[0277] MS-ESI: 306.4 [M+H] + .

[0278] Example 24 Preparation of 3-(2-(1,4-diaza-1-yl)pyrimidin-4-yl)quinoline (compound 24)

[0279] 4-(4-(quinolin-3-yl)pyrimidin-2-yl)-1,4-diazane-1-carboxylic acid tert-butyl ester

[0280] Except that tert-butyl 1,4-diazane-1-carboxylate was used instead of piperidin-4-ylmethylamine in Example 1, the synthesis of 4-(4-(quinolin-3-yl)pyrimidin-2-yl)-1,4-diazane-1-carboxylate tert-butyl ester was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 71%.

[0281] MS-ESI: 406.3 [M+H] + .

[0282] Compound 24

[0283] Except that tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)-1,4-diazane-1-carboxylate was used instead of tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18, compound 24 was synthesized in the same manner as compound 18 in Example 18. The yield was 84%.

[0284] 1 H NMR (400 MHz, CDCl3) δ 9.59 (d, J = 4.0 Hz, 1H), 8.75 (d, J = 4.0Hz, 1H), 8.45 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.82 – 7.74 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz,1H), 4.12 – 3.84 (m, 4H), 3.13 (s, 2H), 3.03 – 2.86 (m, 2H), 2.38 –2.20 (m,1H), 2.00 (s, 2H).

[0285] MS-ESI: 306.2 [M+H] + .

[0286] Example 25 Preparation of 3-(2-(3,8-diazabicyclo[3.2.1]octane-3-yl)pyrimidin-4-yl)quinoline (compound 25)

[0287] 8-(4-(quinolin-3-yl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0288] Except for replacing piperidine-4-ylmethylamine in Example 1 with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the synthesis of 8-(4-(quinolin-3-yl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 41%.

[0289] MS-ESI: 418.2 [M+H] + .

[0290] Compound 25

[0291] Except that tert-butyl 8-(4-(quinolin-3-yl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid was substituted for tert-butyl 8-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid in Example 18, the synthesis of compound 25 was the same as that of compound 18 in Example 18. The yield was 63%.

[0292] 1 H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 4.0 Hz, 1H), 8.76 (d, J = 4.0Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0Hz, 1H), 3.22 (d, J = 12.0 Hz, 2H), 2.84 (d, J = 12.0 Hz, 2H), 2.20 – 1.99(m, 6H).

[0293] MS-ESI: 318.2 [M+H] + .

[0294] Example 26 Preparation of N-(4-(quinolin-3-yl)pyrimidin-2-yl)ethane-1,2-diamine (compound 26)

[0295] (2-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)ethyl)tert-butyl carbamate)

[0296] Except that piperidine-4-ylmethylamine was replaced with (2-aminoethyl)carbamate tert-butyl ester in Example 1, the synthesis of (2-((4-(quinoline-3-yl)pyrimidin-2-yl)amino)ethyl)carbamate tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 64%.

[0297] MS-ESI: 366.2 [M+H] + .

[0298] Compound 26

[0299] Except that tert-butyl 2-(2-((4-(quinoline-3-yl)pyrimidin-2-yl)amino)ethyl)carbamate was used instead of tert-butyl 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid in Example 18, the synthesis of compound 26 was the same as that of compound 18 in Example 18. The yield was 79%.

[0300] 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.78 (s, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.15 (d, J =12.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.68 – 3.56 (m,2H), 3.02 (t, J =8.0 Hz, 2H).

[0301] MS-ESI: 266.2 [M+H] + .

[0302] Example 27 Preparation of N-(4-(quinolin-3-yl)pyrimidin-2-yl)propane-1,3-diamine (compound 27)

[0303] (3-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)propyl)tert-butyl carbamate)

[0304] Except that (2-aminopropyl)carbamate tert-butyl ester was used instead of piperidine-4-ylmethylamine in Example 1, the synthesis of (2-((4-(quinoline-3-yl)pyrimidin-2-yl)amino)propyl)carbamate tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 50%.

[0305] MS-ESI: 380.2 [M+H] + .

[0306] Compound 27

[0307] Except that tert-butyl carbamate (2-((4-(quinoline-3-yl)pyrimidin-2-yl)amino)propyl)carbamate was used instead of tert-butyl piperazine-1-carboxylate in Example 18, compound 27 was synthesized in the same manner as compound 18 in Example 18. The yield was 98%.

[0308] 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81– 7.75 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 5.68 (s,1H), 3.67 – 3.62 (m, 2H), 2.88 (t, J = 8.0 Hz, 2H), 1.82 (p, J =8.0 Hz, 2H),1.41 (s, 2H).

[0309] MS-ESI: 280.3 [M+H] + .

[0310] Example 28 Preparation of 7-(2-(piperazin-1-yl)pyrimidin-4-yl)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridine (compound 28)

[0311] 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0312] Compound 2,4-dichloropyrimidine (3.72 g, 21.5 mmol) and 4-methylpiperazine-1-carboxylic acid tert-butyl ester (4.3 g, 21.5 mmol) were dissolved in toluene (50 mL) and refluxed overnight. The reaction was confirmed to be complete by TLC the following day. The solvent was removed under reduced pressure, and n-propanol / water (55 mL / 83 mL) was added to the residue. The mixture was heated to 90 °C until the system was completely dissolved. The mixture was cooled to room temperature to precipitate a solid, which was filtered, washed with n-propanol / water (1 v / 1.5 v, 30 mL × 3), and dried under high vacuum. 4.0 g of product was obtained, with a yield of 62%.

[0313] 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 5.2 Hz, 1H), 6.52 (d, J = 5.2Hz, 1H), 3.85 - 3.72 (m, 4H), 3.52 - 3.41 (m, 4H), 1.48 (s, 9H).

[0314] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxoborane-2-yl)2,3-dihydro-[1,4]dioxin[2,3b]pyridine

[0315] Compound 7-bromo-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (180 mg, 0.84 mmol), pinacol boronic acid ester (318 mg, 1.26 mmol), potassium acetate (329 mg, 3.36 mmol), and Pd(dppf)Cl2 (61 mg, 0.084 mmol) were added to 1,4-dioxane (5 mL), and the reaction was carried out overnight at 90 °C under nitrogen protection. The reaction was detected by TLC the next day. The reaction mixture was filtered through diatomaceous earth, and the solvent was removed by evaporation under reduced pressure. Ethyl acetate was added to the residue. The mixture was separated, and the solvent was removed by evaporation under reduced pressure. The residue was separated by rapid column chromatography. 186 mg of the target product was obtained, with a yield of 84%.

[0316] 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6Hz, 1H), 7.26 (s, 1H), 4.48 - 4.41 (m, 2H), 4.27 - 4.20 (m, 2H), 1.33 (s,12H).

[0317] MS-ESI: 264.4 [M+H] + .

[0318] 4-(4-(2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0319] Except for the substitution of quinoline-3-ylboronic acid with 7-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)2,3-dihydro-[1,4]dioxin[2,3b]pyridine, and the substitution of 2,4-dichloropyrimidine with 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, the synthesis of 4-(4-(2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 46%.

[0320] 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 5.2Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 5.2 Hz, 1H), 4.54 - 4.44 (m,2H), 4.37 - 4.26 (m, 2H), 3.94 - 3.84 (m, 4H), 3.56 - 3.46 (m, 4H), 1.49 (s,9H).

[0321] MS-ESI: 400.5 [M+H] + .

[0322] Compound 28

[0323] Except that 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 28 was synthesized in the same manner as compound 18 in Example 18. The yield was 92%.

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 5.2Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 4.52 - 4.42 (m,2H), 4.33 - 4.27 (m, 2H), 3.77 - 3.69 (m, 4H), 2.83 - 2.72 (m, 4H).

[0325] Example 29 Preparation of 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperazin-1-yl)pyrimidine (compound 29)

[0326] 4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0327] Except for replacing quinoline-3-boronic acid in Example 1 with (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid, the synthesis of compound 4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 57%.

[0328] 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 2.2Hz, 1H), 7.55 (dd, J = 8.4, 2.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.88 (d, J= 5.2 Hz, 1H), 4.36 - 4.20 (m, 4H), 3.89 (t, J = 5.2 Hz, 4H), 3.52 (t, J =5.2 Hz, 4H), 1.50 (s, 9H).

[0329] MS-ESI: 399.5 [M+H] + .

[0330] Compound 29

[0331] Except for replacing 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 29 was synthesized identically to compound 18 in Example 18. The yield was 53%.

[0332] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 2.2Hz, 1H), 7.54 (dd, J = 8.4, 2.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 5.2 Hz, 1H), 4.36 - 4.26 (m, 4H), 3.95 - 3.88 (m, 4H), 3.00 - 2.98 (m, 4H).

[0333] MS-ESI: 299.5 [M+H] + .

[0334] Example 30 Preparation of 4-(5,6-dimethoxy-pyridin-3-yl)-2-piperazin-1-yl-pyrimidine (compound 30)

[0335] 2,3-Dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxoborane-2-yl)-pyridine

[0336] Except for replacing 7-bromo-2,3-dimethoxypyridine with 5-bromo-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine, the synthesis of 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxon-2-yl)-pyridine was the same as that of 7-(4,4,5,5-tetramethyl-1,3,2-dioxon-2-yl)2,3-dihydro-[1,4]dioxin[2,3-b]pyridine in Example 28. The yield was 93%.

[0337] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.34 (s, 1H), 4.04 (s, 3H), 3.89 (s, 3H), 1.34 (s, 12H).

[0338] MS-ESI: 266.4 [M+H] + .

[0339] 4-[4-(5,6-dimethoxy-pyridin-3-yl)pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester

[0340] Except for replacing 7-(4,4,5,5-tetramethyl-[1,3,2]dioxon-2-yl)-pyridine, the synthesis of 4-[4-(5,6-dimethoxy-pyridin-3-yl)-pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was carried out in the same manner as that of 4-(4-(2,3-dihydro-[1,4]dioxon-[2,3-b]pyridin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 28. The yield was 54%.

[0341] 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 5.2Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.93 – 3.85 (m, 4H), 3.59 – 3.49 (m, 4H), 1.50 (s, 9H).

[0342] MS-ESI: 402.5 [M+H] + .

[0343] Compound 30

[0344] Except that 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[4-(5,6-dimethoxy-pyridin-3-yl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 30 was synthesized the same as compound 18 in Example 18. The yield was 40%.

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.8 Hz, 1H), 8.41 (d, J =5.2 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 3.93 (s,3H), 3.87 (s, 3H), 3.82 – 3.76 (m, 4H), 2.90 – 2.80 (m, 4H).

[0346] MS-ESI: 302.4 [M+H] + .

[0347] Example 31 Preparation of 4-(3,4-dimethoxy-phenyl)-2-piperazin-1-yl-pyrimidine (compound 31)

[0348] 4-[4-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester

[0349] Except for replacing 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxoborane-2-yl)-pyridine with 2-(3,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxoborane-2-yl)-pyridine, the synthesis of 4-[4-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was carried out in the same manner as in Example 30. The yield was 60%.

[0350] 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 5.2 Hz, 1H), 7.67 – 7.60 (m,2H), 6.94 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.92 – 3.86 (m, 4H), 3.57 – 3.50 (m, 4H), 1.49 (s, 9H).

[0351] MS-ESI: 401.5 [M+H] + .

[0352] Compound 31

[0353] Except that 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[4-(3,4-dimethoxy-phenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 31 was synthesized the same as compound 18 in Example 18. The yield was 51%.

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.2 Hz, 1H), 7.72 (dd, J =8.4, 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.06(d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 – 3.72 (m, 4H), 2.83 –2.76 (m, 4H).

[0355] MS-ESI: 301.5 [M+H]+ .

[0356] Example 32 Preparation of 3-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indole (compound 32)

[0357] 3-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid tert-butyl ester

[0358] Except for replacing quinoline-3-boronic acid in Example 1 with 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester, the synthesis of compound 3-(2-chloropyrimidin-4-yl)quinoline in Example 1 was the same. The yield was 69%.

[0359] 1H NMR (400 MHz, CDCl3): δ 8.40 – 8.36 (m, 1H), 8.34 (d, J = 8.0Hz, 1H), 8.19 (s, 2H), 7.39-7.5 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 3.93 (t, J =8.0Hz, 4H), 3.57 (t, J = 8.0Hz, 4H), 1.71 (s, 9H), 1.51 (s, 9H).

[0360] MS-ESI: 480.6 [M+H] + .

[0361] 3-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid tert-butyl ester

[0362] 284 mg (0.59 mmol) of compound 3-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in DCM (8 mL), and HCl / 1,4-dioxane (4 M, 5 mL) was added. The reaction was carried out at room temperature for 30 min, and the reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, and water (5 mL) was added to the residue. The pH was adjusted to 14 with NaOH (3 M). The solvent was removed under reduced pressure, and the residue was separated by rapid column chromatography. 210 mg of the target product was obtained, with a yield of 93%.

[0363] 1 H NMR (400 MHz, CDCl3): δ 8.39 – 8.36 (m, 1H), 8.33 (d, J =4.0Hz,1H), 8.19 (d, J = 8.0Hz, 2H), 7.39-7.34 (m, 2H), 6.92 (d, J = 4.0 Hz, 1H), 3.98 (t, J = 12.0 Hz, 4H), 3.05 (t, J = 12.0 Hz, 4H), 1.71 (s, 9H).

[0364] MS-ESI: 380.5 [M+H] + .

[0365] Compound 32

[0366] 210 mg (0.551 mmol) of tert-butyl 3-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indole-1-carboxylic acid was dissolved in a mixture of n-butanol (2.1 mL) and water (1.2 mL). Concentrated hydrochloric acid (0.23 mL) was added, and the mixture was heated overnight. The reaction was confirmed to be complete by TLC. The solvent was removed under reduced pressure. Water (5 mL) was added to the residue, and the pH was adjusted to 14 with NaOH (3 M). The solvent was evaporated under reduced pressure, and the residue was subjected to rapid column chromatography to obtain 124 mg of the target product, with a yield of 80%.

[0367] 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.44 – 8.38 (m, 1H), 8.29 (d,J = 4.0 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.29 (s, 1H), 6.88 (d, J = 5.2 Hz, 1H), 3.96 – 3.90 (m, 4H), 3.03-3.00 (m, 4H).

[0368] MS-ESI: 280.5 [M+H] + .

[0369] Example 33 Preparation of 4-(benzofuran-3-yl)-2-(piperazin-1-yl)pyrimidine (compound 33)

[0370] 4-(4-(benzofuran-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0371] Except for replacing quinoline-3-boronic acid with benzofuran-3-ylboronic acid and replacing 2,4-dichloropyrimidine with 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester, the synthesis of 4-(4-(benzofuran-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 84%.

[0372] 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.1 Hz, 1H), 8.23 ​​(q, J = 4.3,3.4 Hz, 2H), 7.67 – 7.50 (m, 1H), 7.43 – 7.30 (m, 2H), 6.89 (d, J = 5.1 Hz,1H), 4.01 – 3.85 (m, 4H), 3.57 (dd, J = 6.5, 4.0 Hz, 4H), 1.50 (s, 9H).

[0373] MS-ESI: 381.5 [M+H] + .

[0374] Compound 33

[0375] Except that 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was substituted for 4-(4-(benzofuran-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 33 was synthesized the same as compound 18 in Example 18. The yield was 86%.

[0376] 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 5.1 Hz, 1H), 8.24 (d, J = 10.3Hz, 2H), 7.65 – 7.50 (m, 1H), 7.43 – 7.31 (m, 2H), 6.86 (d, J = 5.1 Hz, 1H), 3.98 – 3.89 (m, 4H), 3.01 (dd, J = 6.0, 4.2 Hz, 4H).

[0377] MS-ESI: 281.4 [M+H]+ .

[0378] Example 34 Preparation of 3-methoxy-5-(2-piperazin-1-yl-pyrimidin-4-yl)-pyridin-2-ol (compound 34)

[0379] Compound 34

[0380] Except for extending the Boc removal reaction time of hydrochloric acid to overnight, the synthesis of compound 34 was carried out in the same manner as in Example 30 with 4-(5,6-dimethoxy-pyridin-3-yl)-2-piperazin-1-yl-pyrimidine. The yield was 50%.

[0381] 1 H NMR (400 MHz, DMSO) δ 8.31 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 2.2Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 5.4 Hz, 1H), 3.79 (s, 3H), 3.76 – 3.64 (m, 4H), 2.83 – 2.68 (m, 4H).

[0382] MS-ESI: 288.4 [M+H] + .

[0383] Example 35 Preparation of 3-(4-(piperazin-1-yl)-1,3,5-triazin-2-yl)quinoline (compound 35)

[0384] 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0385] Except for replacing 3-(2-chloropyrimidin-4-yl)quinoline in Example 1 with 2,4-dichloro-1,3,5-triazine, and replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester, the synthesis of 4-(4-chloro-1,3,5-triazine-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperridin-4-yl)methylamine in Example 1. The yield was 46%.

[0386] MS-ESI: 300.3 [M+H] + .

[0387] 4-(4-(quinolin-3-yl)-1,3,5-triazine-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0388] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of quinoline-3-boronic acid in Example 1, the synthesis of compound 4-(4-(quinoline-3-yl)-1,3,5-triazine-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 42%.

[0389] 1 H NMR (400 MHz, CDCl3) δ :9.92 (d, J = 4.0 Hz, 1H), 9.25 (d, J = 4.0Hz, 1H), 8.78 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 4.07 (d, J = 44.0 Hz, 4H), 3.65 (d, J = 8.0 Hz, 4H), 1.58 (s, 9H).

[0390] MS-ESI: 393.4 [M+H] + .

[0391] Compound 35

[0392] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(4-(quinolin-3-yl)-1,3,5-triazine-2-yl)piperazine-1-carboxylate in Example 18, compound 35 was synthesized the same as compound 18 in Example 18. The yield was 72%.

[0393] 1H NMR (400 MHz, DMSO-d6) δ :9.75 (d, J = 4.0 Hz, 1H), 9.30 (s, 1H), 8.74 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.88 (t, J= 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 3.89 (d, J = 28.0 Hz, 4H), 2.81 (d,J = 16.0 Hz, 4H), 1.23 (s, 1H).

[0394] MS-ESI: 293.4 [M+H] + .

[0395] Example 36 Preparation of 2-(piperazin-1-yl)-4-(quinolin-3-yl)quinazoline (compound 36)

[0396] 2-Chloro-4-(quinolin-3-yl)quinazoline

[0397] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,4-dichloroquinazoline and replacing acetonitrile with 1,4-dioxane, the synthesis of 2-chloro-4-(quinolin-3-yl)quinazoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 73%.

[0398] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 4.0 Hz, 1H), 8.67 (d, J = 2.0Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.19 – 8.10 (m, 2H), 8.05 – 7.97 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 2H).

[0399] MS-ESI: 292.4 [M+H] + .

[0400] 4-(4-(quinolin-3-yl)quinazolin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0401] Except that piperazine-1-carboxylic acid tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, the synthesis of 4-(4-(quinoline-3-yl)quinazoline-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 84%.

[0402] 1 H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.91 – 7.80 (m,2H), 7.73 – 7.62 (m, 3H), 7.25 – 7.20 (m, 1H), 4.10 – 3.97 (m, 4H), 3.64 –3.52 (m, 4H), 1.50 (s, 9H).

[0403] MS-ESI: 442.5 [M+H] + .

[0404] Compound 36

[0405] Except that compound 36 was synthesized the same as compound 18 in Example 18, except that compound 4-(4-(quinolin-3-yl)quinazolin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. The yield was 82%.

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 4.0 Hz, 1H), 8.80 (d, J =2.0 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.95 – 7.85 (m, 2H), 7.80 – 7.70 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 3.96 – 3.84 (m, 4H), 2.92– 2.81 (m, 4H).

[0407] MS-ESI: 342.3 [M+H] + .

[0408] Example 37 Preparation of 2-(piperazin-1-yl)-4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazoline (compound 37)

[0409] 2-Chloro-4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazoline

[0410] Except for replacing 2,4-dichloropyrimidine with 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, the synthesis of 2-chloro-4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 92%.

[0411] 1 H NMR (400 MHz, CDCl3) δ :9.09 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.5Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 2.81 (t, J = 8.0Hz, 2H), 2.00-1.87 (m, 2H), 1.82-1.69 (m, 2H).

[0412] MS-ESI: 296.4 [M+H] + .

[0413] 4-(4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0414] Except for replacing piperidin-4-ylmethylamine in Example 1 with piperazine-1-carboxylate tert-butyl ester, and replacing 3-(2-chloropyrimidin-4-yl)quinoline in Example 1 with 2-chloro-4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazoline-2-yl)piperazine-1-carboxylate tert-butyl ester, the yield of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-4-yl)methylamine in Example 1 was 78%.

[0415] 1H NMR (400 MHz, CDCl3) δ :9.14 (d, J = 4.0 Hz, 1H), 8.33 (d, J = 4.0Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0Hz, 1H), 7.59 (t, J =8.0Hz, 1H), 3.88-3.77 (m, 4H), 3.57-3.42 (m, 4H), 2.81(t, J = 8.0 Hz, 2H), 2.70 (t, J = 8.0Hz, 2H), 1.95-1.83 (m, 2H), 1.79-1.67(m, 2H), 1.48 (s, 9H).

[0416] MS-ESI: 446.6 [M+H] + .

[0417] Compound 37

[0418] Except that 4-(4-(quinoline-3-yl)-5,6,7,8-tetrahydroquinazoline-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 37 was synthesized in the same manner as compound 18 in Example 18. The yield was 73%.

[0419] 1 H NMR (400 MHz, DMSO-d6) δ :9.07 (d, J = 4.0 Hz, 1H), 8.58 (d, J =2.4 Hz, 1H), 8.08 (t, J = 8.0 Hz, 2H), 7.83 (t, J = 8.0Hz, 1H), 7.67 (t, J =8.0 Hz, 1H), 3.71-3.63 (m, 4H), 2.80-2.69 (m, 6H), 2.66 (t, J = 8.0 Hz, 2H), 1.86-1.77 (m, 2H), 1.71-1.62 (m, 2H), 1.23 (s, 1H).

[0420] MS-ESI: 346.5 [M+H] + .

[0421] Example 38 Preparation of 3-(5-amino-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 38)

[0422] 3-(2-Chloro-6-methoxypyrimidin-4-yl)quinoline

[0423] Except that 2,4-dichloropyrimidine was substituted for 2,4-dichloropyrimidine in Example 1, the synthesis of 3-(2-chloro-5-aminopyrimidine-4-yl)quinoline was the same as that of 3-(2-chloropyrimidine-4-yl)quinoline in Example 1. The yield was 86%.

[0424] 1 H NMR (400 MHz, CDCl3) δ: 9.19 (d, J = 2.2 Hz, 1H), 8.76 (d, J = 2.2Hz, 1H), 8.29 (s, 1H), 8.14 - 8.05 (m, 2H), 7.90 - 7.80 (m, 1H), 7.69 (t, J =8.0 Hz, 1H), 5.95 (s, 2H).

[0425] MS-ESI: 257.3 [M+H] + .

[0426] 4-(5-amino-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0427] Except for replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester and 3-(2-chloropyrimidin-4-yl)quinoline with 3-(2-chloropyrimidin-4-yl)quinoline, the synthesis of 4-(5-amino-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-4-yl)methylamine in Example 1. The yield was 42%.

[0428] 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (d, J = 2.2 Hz, 1H), 8.85 (d, J =2.2 Hz, 1H), 8.22 (s, 1H), 8.16 - 8.06 (m, 2H), 7.86 - 7.82 (m, 1H), 7.71 -7.66 (m, 1H), 4.88 (s, 2H), 3.68 - 3.61 (m, 4H), 3.48 - 3.42 (m, 4H), 1.45 (s, 9H).

[0429] MS-ESI: 407.4 [M+H] + .

[0430] Compound 38

[0431] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(5-amino-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18, compound 38 was synthesized in the same manner as compound 18 in Example 18. Yield: 63%.

[0432] 1 H NMR (400 MHz, DMSO) δ : 9.32 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.2Hz, 1H), 8.18 (s, 1H), 8.09 - 8.03 (m, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.66(t, J = 7.6 Hz, 1H), 4.80 (s, 2H), 3.59 (t, J = 5.0 Hz, 4H), 2.82 (t, J = 5.0Hz, 4H).

[0433] MS-ESI: 307.4 [M+H] + .

[0434] Example 39 Preparation of 3-(6-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 39)

[0435] 3-(2-Chloro-6-methoxypyrimidin-4-yl)quinoline

[0436] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,4-dichloropyrimidine, the synthesis of 3-(2-chloro-6-methoxypyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 57%.

[0437] 1 H NMR (400 MHz, CDCl3) δ : 9.44 (d, J = 2.4 Hz, 1H), 8.90 (d, J = 2.4Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.81 (t, J = 8.6 Hz,1H), 7.67 - 7.58 (m, 1H), 7.21 (s, 1H), 4.10 (s, 3H).

[0438] MS-ESI: 272.3 [M+H] + .

[0439] 4-(4-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0440] Except that piperidine-4-ylmethylamine was replaced with piperazine-1-carboxylate tert-butyl ester in Example 1, and 3-(2-chloropyrimidin-4-yl)quinoline was replaced with 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of 4-(4-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. Yield: 55%.

[0441] 1 H NMR (400 MHz, DMSO-d6) δ :9.58 (d, J = 2.2 Hz, 1H), 9.07 (d, J =2.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.90 - 7.78(m, 1H), 7.68 (t, J = 7.4 Hz, 1H), 6.93 (s, 1H), 3.94 (s, 3H), 3.91 - 3.81(m, 4H), 3.54 - 3.43 (m, 4H), 1.44 (s, 9H).

[0442] MS-ESI: 422.5 [M+H]+ .

[0443] Compound 39

[0444] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-methoxy-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 39 was synthesized in the same manner as compound 18 in Example 18. The yield was 60%.

[0445] 1 H NMR (400 MHz, DMSO) δ : 9.56 (d, J = 2.2 Hz, 1H), 9.04 (d, J = 2.2Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 8.4Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 6.87 (s, 1H), 3.92 (s, 3H), 3.82 (t, J =5.0 Hz, 4H), 2.81 (t, J = 5.0 Hz, 4H).

[0446] MS-ESI: 322.5 [M+H] + .

[0447] Example 40 Preparation of 3-(2-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)quinoline (compound 40)

[0448] 4-(4-chloro-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0449] Except that piperidine-4-ylmethylamine was replaced with piperazine-1-carboxylate tert-butyl ester in Example 1, and 3-(2-chloropyrimidin-4-yl)quinoline was replaced with 2,4-dichloro-6-(trifluoromethyl)pyrimidine, the synthesis of 4-(4-chloro-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. Yield: 40%.

[0450] 1H NMR (400 MHz, CDCl3): δ 6.79 (s, 1H), 3.86-3.83 (m, 4H), 3.52 -3.50 (m, 4H), 1.49 (s, 9H).

[0451] 4-(4-(quinolin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0452] Except for replacing 2,4-dichloropyrimidine with 4-(4-(quinolin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester and ethanol with 1,4-dioxane, the synthesis of 4-(4-(quinolin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 85%.

[0453] 1 H NMR (400 MHz, CDCl3): δ 9.58 (d, J = 2.0 Hz, 1H), 8.79 (m, d, J =2.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.96-7.95 (m, 1H), 7.84-7.80(m,1H),7.66-7.64(m,1H), 7.37(s,1H), 4.00-3.99(m,4H), 3.60-3.57(m,4H), 1.51(s,9H).

[0454] Compound 40

[0455] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(4-(quinolin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18, compound 40 was synthesized the same as compound 18 in Example 18. The yield was 83%.

[0456] 1H NMR (400 MHz, DMSO-d6): δ 9.67 (d, J = 4.0 Hz, 1H), 9.25 (d, J =2.0 Hz, 1H), 8.17-8.15 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.90 -7.86 (m, 1H),7.82 (s, 1H), 7.73 -7.71 (m, 1H), 3.90-3.84(m, 4H), 2.85-2.83 (m, 4H).

[0457] MS-ESI: 360.3 [M+H] + .

[0458] Example 41 Preparation of 3-(5-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-7-yl)quinoline (compound 41)

[0459] 4-(7-Clonimidozopo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0460] Except for replacing 3-(2-chloropyrimidin-4-yl)quinoline with 5,7-dichloroimidazolo[1,2-c]pyrimidinyl in Example 1, replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester, and replacing DIPEA with TEA, the synthesis of 4-(7-chloroimidazolo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-4-yl)methylamine in Example 1. The yield was 90%.

[0461] 1 H NMR (400 MHz, CDCl3) δ: 7.60 (s, 1H), 7.40 (s, 1H), 7.21 (s, 1H), 3.68 – 3.62 (m, 4H), 3.51 – 3.44 (m, 4H), 1.49 (s, 9H).

[0462] 3-(7-(quinolin-3-yl)imidazo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0463] Except for replacing 2,4-dichloropyrimidine with 4-(7-chloroimidazolo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester and ethanol with 1,4-dioxane, the synthesis of 4-(7-(quinolin-3-yl)imidazolo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 31%.

[0464] 1 H NMR (400 MHz, CDCl3) δ: 9.59 (s, 1H), 8.77 (s, 1H), 8.15 (d, J =8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.75 (t, J = 8.0 Hz,1H), 7.70 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.49 (s, 1H), 3.74 (m, 4H), 3.62– 3.55 (m, 4H), 1.52 (s, 9H).

[0465] Compound 41

[0466] Except that 4-(4-(quinolin-3-yl)imidazo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(7-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, the synthesis of compound 41 was the same as that of compound 18 in Example 18. The yield was 53%.

[0467] 1 H NMR (400 MHz, DMSO) δ: 9.68 (d, J = 2.0 Hz, 1H), 9.07 (d, J = 2.0Hz, 1H), 8.12 – 8.04 (m, 3H), 7.89 (s, 1H), 7.83 – 7.76 (m, 1H), 7.71 – 7.63 (m, 2H), 3.60 – 3.54 (m, 4H), 3.12 – 3.06 (m, 4H).

[0468] MS-ESI: 331.5 [M+H] + .

[0469] Example 42 Preparation of 3-(6-cyano-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 42)

[0470] 4-(4-chloro-6-cyanopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0471] Compound 2,6-dichloropyrimidin-4-onitrile (125 mg, 0.72 mmol / L) and 4-methylpiperazine-1-carboxylic acid tert-butyl ester (144 mg, 0.72 mmol / L) were dissolved in toluene (5 mL), and the mixture was refluxed for 1.5 h. The reaction was confirmed to be complete by TLC. The solvent was removed under reduced pressure, and the residue was separated by rapid column chromatography. 156 mg of the target product was given, with a yield of 67%.

[0472] 1 H NMR (400 MHz, CDCl3) δ 6.79 (s, 1H), 3.93 - 3.72 (m, 4H), 3.58 -3.43 (m, 4H), 1.49 (s, 9H).

[0473] MS-ESI: 224.3 [M-100] + .

[0474] 4-(4-cyano-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0475] Except that 4-(4-cyano-6-cyanopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 2,4-dichloropyrimidine in Example 1, the synthesis of 4-(4-cyano-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 94%.

[0476] 1 H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 1.8Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.86-7.80 (m,1H), 7.64 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H), 4.03 - 3.91 (m, 4H), 3.65 - 3.51(m, 4H), 1.51 (s, 9H).

[0477] MS-ESI: 417.5 [M+H] +.

[0478] Compound 42

[0479] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-cyano-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 42 was synthesized in the same manner as compound 18 in Example 18. The yield was 60%.

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (d, J = 2.0 Hz, 1H), 9.19 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.88 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 3.87-3.75 (m, 4H), 2.88 - 2.76 (m, 4H).

[0481] MS-ESI: 317.4 [M+H] + .

[0482] Example 43 Preparation of 3-(5-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 43)

[0483] 3-(2-chloro-5-methoxypyrimidin-4-yl)quinoline

[0484] Except that 2,4-dichloropyrimidine was substituted for 2,4-dichloropyrimidine in Example 1, the synthesis of 3-(2-chloro-5-methoxypyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 76%.

[0485] 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 2.2 Hz, 1H), 8.95 (d, J = 1.8Hz, 1H), 8.39 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.65 - 7.58 (m, 1H), 4.07 (s, 3H).

[0486] MS-ESI: 272.3 [M+H] + .

[0487] 4-(5-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0488] Except that piperazine-1-carboxylic acid tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, and 3-(2-chloro-5-methoxypyrimidin-4-yl)quinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of 4-(5-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 68%.

[0489] 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.91 (s, 1H), 8.26 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.79-7.73 (m, 1H), 7.62-7.56 (m, 1H), 3.90 (s, 3H), 3.86-3.80 (m, 4H), 3.58-3.51 (m, 4H), 1.50 (s, 9H).

[0490] MS-ESI: 422.5 [M+H] + .

[0491] Compound 43

[0492] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(5-methoxy-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 43 was synthesized in the same manner as compound 18 in Example 18. The yield was 79%.

[0493] 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 2.2 Hz, 1H), 8.96 (d, J = 1.8Hz, 1H), 8.44 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H),7.86 - 7.79 (m, 1H), 7.70 - 7.62 (m, 1H), 3.88 (s, 3H), 3.72 - 3.63 (m, 4H), 2.85 - 2.75 (m, 4H).

[0494] MS-ESI: 322.5 [M+H] + .

[0495] Example 44 Preparation of 3-(6-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 44)

[0496] 3-(6-Chloroprene-4-yl)quinoline

[0497] Except that 4,6-dichloropyrimidine was used instead of 2,4-dichloropyrimidine in Example 1, the synthesis of 3-(6-chloropyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. Yield: 60%.

[0498] 1 H NMR (400 MHz, DMSO-d6) δ: 9.68 (d, J = 4.0 Hz, 1H), 9.27 (d, J =4.0 Hz, 1H), 9.20 (d, J = 4.0 Hz, 1H), 8.58 (d, J =2.0 Hz, 1H), 8.13 (dd, J =20.0, 8.0 Hz, 2H), 7.94 – 7.86 (m, 1H), 7.77 – 7.69 (m, 1H).

[0499] MS-ESI: 242.4 [M+H] +.

[0500] 4-(6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0501] Except for replacing piperidin-4-ylmethylamine in Example 1 with piperazine-1-carboxylate tert-butyl ester, replacing 3-(2-chloropyrimidin-4-yl)quinoline in Example 1 with 3-(6-chloropyrimidin-4-yl)quinoline, and replacing DIPEA with TEA, the synthesis of 4-(6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 95%.

[0502] 1 H NMR (400 MHz, DMSO-d6) δ: 9.64 (d, J = 2.0 Hz, 1H), 9.12 (d, J =2.0 Hz, 1H), 8.68 (s, 1H), 8.10 (t, J = 8.0 Hz, 2H), 7.84 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.60 (s, 1H), 3.82 – 3.75 (m, 4H), 3.50 – 3.44 (m, 4H), 1.44 (s, 9H).

[0503] MS-ESI: 392.4 [M+H] + .

[0504] Compound 44

[0505] Except that 4-(4-(quinoline-3-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 44 was synthesized in the same manner as compound 18 in Example 18. The yield was 85%.

[0506] 1H NMR (400 MHz, DMSO-d6) δ: 9.62 (d, J = 2.0 Hz, 1H), 9.11 (d, J =2.0 Hz, 1H), 8.63 (s, 1H), 8.09 (t, J = 8.0 Hz, 2H), 7.87 – 7.78 (m, 1H), 7.72 – 7.64 (m, 1H), 7.54 (s, 1H), 3.74 – 3.66 (m, 4H), 2.84 – 2.76 (m, 4H).

[0507] MS-ESI: 292.5 [M+H] + .

[0508] Example 45 Preparation of 3-(9-methyl-2-(piperazin-1-yl)-9H-purin-6-yl)quinoline (compound 45)

[0509] 3-(2-chloro-9-methyl-9H-purin-6-yl)quinoline

[0510] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,6-dichloro-9-methyl-9H-purine, the synthesis of 3-(2-chloro-9-methyl-9H-purin-6-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 58%.

[0511] 1 H NMR (400 MH z, DMSO-d6) δ: 10.11 (d, J = 2.2 Hz, 1H), 9.63 (d, J =2.2 Hz, 1H), 8.74 (s, 1H), 8.23 ​​(d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz,1H), 7.91 (t, J = 8.2, Hz, 1H), 7.72 (t, J = 8.2 Hz, 1H), 3.87 (s, 3H).

[0512] MS-ESI: 296.3 [M+H] + .

[0513] 4-(9-methyl-6-(quinolin-3-yl)-9H-purin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0514] Except that piperazine-1-carboxylic acid tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, and 3-(2-chloro-9-methyl-9H-purin-6-yl)quinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of 4-(9-methyl-6-(quinolin-3-yl)-9H-purin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidine-4-yl)methylamine in Example 1. The yield was 84%.

[0515] 1 H NMR (400 MHz, DMSO-d6) δ: 10.14 (d, J = 2.1 Hz, 1H), 9.67 (d, J =2.2 Hz, 1H), 8.29 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz,1H), 7.86 (t, J = 8.6 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 3.96 - 3.89 (m, 4H), 3.73 (s, 3H), 3.55 - 3.47 (m, 4H).

[0516] MS-ESI: 446.5 [M+H] + .

[0517] Compound 45

[0518] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(4-(quinolin-3-yl)-9H-purin-2-yl)piperazine-1-carboxylate in Example 18, compound 45 was synthesized the same as compound 18 in Example 18. The yield was 92%.

[0519] 1H NMR (400 MHz, DMSO-d6) δ : 10.12 (d, J = 2.0 Hz, 1H), 9.64 (d, J =2.0 Hz, 1H), 8.26 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.4 Hz,1H), 7.86 (t, J = 8.2 Hz, 1H), 7.69 (t, J = 8. 2 Hz, 1H), 3.86 (t, J = 5.0Hz, 4H), 3.72 (s, 3H), 2.86 (t, J = 5.0 Hz, 4H).

[0520] MS-ESI: 346.4 [M+H] + .

[0521] Example 46 Preparation of 3-(5-fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 46)

[0522] 3-(2-chloro-5-fluoropyrimidin-4-yl)quinoline

[0523] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,4-dichloropyrimidine, the synthesis of 3-(6-chloropyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. Yield: 84%.

[0524] MS-ESI: 260.7 [M+H] + .

[0525] 4-(5-fluoro-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0526] Except for replacing piperidin-4-ylmethylamine in Example 1 with piperazine-1-carboxylate tert-butyl ester, replacing 3-(2-chloropyrimidin-4-yl)quinoline in Example 1 with 3-(2-chloropyrimidin-4-yl)quinoline, and replacing DIPEA with TEA, the synthesis of 4-(5-fluoro-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-4-yl)methylamine in Example 1. The yield is 95%.

[0527] 1H NMR (400 MHz, DMSO-d6) δ: 9.48 (d, J = 2.0 Hz, 1H), 9.00 (s, 1H), 8.63 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H),7.93 – 7.85 (m, 1H), 7.71 (m, 1H), 3.84 – 3.77 (m, 4H), 3.49 – 3.44 (m, 4H), 1.43 (s, 9H).

[0528] MS-ESI: 410.5 [M+H] + .

[0529] Compound 46

[0530] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(5-fluoro-4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 46 was synthesized in the same manner as compound 18 in Example 18. The yield was 75%.

[0531] 1 H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 8.97 (s, 1H), 8.59 (d, J =4.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.92 – 7.84 (m, 1H), 7.70 (m, 1H), 3.77 – 3.70 (m, 4H), 2.84 – 2.76 (m, 4H).

[0532] MS-ESI: 310.4 [M+H] + .

[0533] Example 47 Preparation of 2-(piperazin-1-yl)-6-(quinolin-3-yl)pyrimidine-4-amine (compound 47)

[0534] 4-(4-((tert-butoxycarbonyl)amino)-6-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 395 mg (1.26 mmol) of 4-(4-amino-6-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (254 mg, 2.52 mmol). Di-tert-butyl dicarbonate (412 mg, 1.89 mmol) was slowly added dropwise under ice bath conditions, and the temperature was gradually raised to room temperature after the addition was complete. After 1 h of reaction, TLC showed that the reaction was essentially unreacted. DMAP (40 mg, 0.33 mmol) was added, and the reaction was continued at room temperature. TLC showed that the reaction was essentially complete. The solvent was removed under reduced pressure, and the residue was separated by rapid column chromatography. 487 mg of the target product was obtained, with a yield of 93%.

[0535] 1 H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 3.76-3.73 (m, 4H), 3.47-3.44(m, 4H), 1.49 (s, 9H), 1.46 (s, 9H).

[0536] 4-(4-((tert-butyloxycarbonyl)amino)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0537] Except for replacing 2,4-dichloropyrimidine with 4-(4-((tert-butoxycarbonyl)amino)-6-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 1, and replacing ethanol with 1,4-dioxane, the synthesis of 4-(4-((tert-butoxycarbonyl)amino)-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 92%.

[0538] 1 H NMR (400 MHz, CDCl3): δ 9.62-9.57 (m, 1H), 8.77-8.75 (m, 1H), 8.17-8.14 (m, 1H), 7.96-7.93 (m, 1H), 7.83 -7.75 (m, 1H), 7.61 -7.58 (m, 1H),7.07- 7.06 (m, 1H), 3.90 -3.87 (m, 4H), 3.54-3.51 (m, 4H), 1.58 (s, 9H), 1.50(s, 9H).

[0539] Compound 47

[0540] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(4-((tert-butyloxycarbonyl)amino)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18, compound 47 was synthesized the same as compound 18 in Example 18. The yield was 43%.

[0541] 1 H NMR (400 MHz, DMSO-d6): δ 9.42 (d, J = 2.0Hz, 1H), 8.86 (d, J = 2.0Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.82-7.79 (m,1H), 7.67-7.64 (m, 1H), 6.61 (s, 2H), 6.46 (s, 1H), 3.78-3.75 (m, 4H), 2.82-2.80 (m, 4H).

[0542] MS-ESI: 307.4 [M+H] + .

[0543] Example 48 Preparation of 6-(piperazin-1-yl)-2-(quinolin-3-yl)pyrimidine-4-amine (compound 48)

[0544] 4-(4-amino-6-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-(6-amino-2-chloropyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0545] Except that piperazine-1-carboxylate tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, and 2,6-dichloropyrimidin-4-amine was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of 4-(6-amino-2-chloropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 13%.

[0546] 1 H NMR (400 MHz, CDCl3): δ 5.41 (s, 1H), 3.56 -3.48 (m, 8H), 1.48 (s, 9H).

[0547] 4-(6-amino-2-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0548] Except for replacing 2,4-dichloropyrimidine with 4-(6-amino-2-chloropyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester in Example 1, and replacing ethanol with 1,4-dioxane, the synthesis of 4-(6-amino-2-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 46%.

[0549] 1H NMR (400 MHz, CDCl3): δ 9.84 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 2.0Hz, 1H), 8.15 (d, J = 12.0Hz, 1H), 7.95 -7.93 (m, 1H), 7.76-7.72 (m, 1H),7.58-7.54 (m, 1H), 5.59 (s, 1H), 4.70 (s, 2H), 3.72-3.69 (m, 4H), 3.59-3.56(m, 4H), 1.50 (s, 9H).

[0550] Compound 48

[0551] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(6-amino-2-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate in Example 18, compound 48 was synthesized the same as compound 18 in Example 18. The yield was 53%.

[0552] MS-ESI: 307.3 [M+H] + .

[0553] Example 49 Preparation of 4-(2-(piperazin-1-yl)-6-(quinolin-3-yl)pyrimidin-4-yl)morpholine (compound 49)

[0554] 4-(4-chloro-6-morpholinidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0555] Except for replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester and 3-(2-chloropyrimidin-4-yl)quinoline with 4-(2,6-dichloropyrimidin-4-yl)morpholine, the synthesis of 4-(4-chloro-6-morpholinopyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinolino-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 89%.

[0556] 1 H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 3.78 - 3.70 (m, 8H), 3.58 -3.51 (m, 4H), 3.49 - 3.42 (m, 4H).

[0557] MS-ESI: 384.4 [M+H] + .

[0558] 4-(4-morpholino-6-(quinolino-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0559] Except for replacing 2,4-dichloropyrimidine in Example 1 with 4-(4-chloro-6-morpholinopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, and replacing ethanol with 1,4-dioxane, the synthesis of 4-(4-morpholino-6-(quinolino-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester is the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 74%.

[0560] 1 H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 1.6Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.79 - 7.71 (m,1H), 7.59 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 3.94 - 3.86 (m, 4H), 3.86 - 3.80(m, 4H), 3.72 - 3.66 (m, 4H), 3.57 - 3.51 (m, 4H), 1.50 (s, 9H).

[0561] MS-ESI: 477.5 [M+H] + .

[0562] Compound 49

[0563] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-morpholino-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 49 was synthesized in the same manner as compound 18 in Example 18. The yield was 81%.

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 2.1 Hz, 1H), 9.03 (d, J = 1.8Hz, 1H), 8.08 (t, J = 9.1 Hz, 2H), 7.86 - 7.76 (m, 1H), 7.66 (t, J = 7.1 Hz,1H), 6.89 (s, 1H), 3.81 - 3.72 (m, 4H), 3.71-3.63 (m, 8H), 2.84 - 2.78 (m,4H).

[0565] MS-ESI: 377.5 [M+H] + .

[0566] Example 50 Preparation of 3-(5-cyclopropyl-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 50)

[0567] 3-(2-chloro-5-cyclopropylpyrimidin-4-yl)quinoline

[0568] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,4-dichloropyrimidine and ethanol with 1,4-dioxane, the synthesis of 3-(2-chloro-5-cyclopropylpyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 67%.

[0569] 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 1.7Hz, 1H), 8.40 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.86 – 7.76 (m, 1H), 7.66 – 7.61 (m, 1H), 2.05 (tt, J = 8.5, 5.5 Hz, 1H), 1.15 – 1.08 (m, 2H), 0.80 (q, J = 5.2 Hz, 2H).

[0570] MS-ESI: 282.4 [M+H] + .

[0571] 4-(5-cyclopropyl-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0572] Except that piperazine-1-carboxylic acid tert-butyl ester was used instead of piperidin-4-ylmethylamine in Example 1, and 3-(2-chloro-5-cyclopropylpyrimidin-4-yl)quinoline was used instead of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, the synthesis of 4-(5-cyclopropyl-4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-4-yl)methylamine in Example 1. The yield was 79%.

[0573] 1 H NMR (400 MHz, CDCl3) δ 9.37 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.8Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.59 (dd, J = 20.7, 13.5 Hz, 1H), 3.90 – 3.80 (m,4H), 3.58 – 3.46 (m, 4H), 1.93 (dq, J = 8.4, 5.4 Hz, 1H), 1.49 (s, 10H), 0.90(s, 2H), 0.57 (d, J = 5.4 Hz, 2H).

[0574] Compound 50

[0575] Except that 4-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(5-cyclopropyl-4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 50 was synthesized in the same manner as compound 18 in Example 18. The yield was 81%.

[0576] 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 2.2 Hz, 1H), 8.79 (d, J =1.9 Hz, 1H), 8.29 (s, 1H), 8.13 – 8.01 (m, 2H), 7.86 – 7.79 (m, 1H), 7.68 (t,J = 7.5 Hz, 1H), 3.79 – 3.66 (m, 4H), 2.84 – 2.70 (m, 4H), 2.06 – 1.94 (m,2H), 0.87 – 0.71 (m, 3H), 0.53 (q, J = 5.9 Hz, 2H).

[0577] MS-ESI: 331.4 [M+H] + .

[0578] Example 51 Preparation of 3-(6-(4-methoxyphenyl)-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 51)

[0579] 3-(2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)quinoline

[0580] Except for replacing 2,4-dichloropyrimidine in Example 1 with 2,4-dichloropyrimidine, the synthesis of 3-(2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 88%.

[0581] 1H NMR (400 MHz, CDCl3) δ :9.57 (d, J = 4.0 Hz, 1H), 8.99 (d, J = 4.0Hz, 1H), 8.26-8.13 (m, 3H), 8.11 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.83 (t,J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 3.92 (s,3H).

[0582] MS-ESI: 348.4 [M+H] + .

[0583] 4-(4-(4-methoxyphenyl)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0584] Except for replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester and 3-(2-chloropyrimidin-4-yl)quinoline with 3-(2-chloropyrimidin-4-yl)quinoline, the synthesis of 4-(4-(4-methoxyphenyl)-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate)methylamine in Example 1. The yield was 70%.

[0585] 1 H NMR (400 MHz, CDCl3) δ :9.61 (d, J = 4.0 Hz, 1H), 8.84 (d, J = 4.0Hz, 1H), 8.19-8.13 (m, 3H), 7.97 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz,1H), 7.62 (t, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.15-3.99 (m, 4H), 3.90 (s, 3H), 3.66-3.55 (m, 4H), 1.52 (s, 9H).

[0586] MS-ESI: 498.4 [M+H] + .

[0587] Compound 51

[0588] Except that tert-butyl piperazine-1-carboxylate was used instead of 4-(4-(4-methoxyphenyl)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18, compound 51 was synthesized the same as compound 18 in Example 18. The yield was 74%.

[0589] 1 H NMR (400 MHz, DMSO-d6) δ :9.73 (d, J = 4.0 Hz, 1H), 9.23 (d, J =4.0Hz, 1H), 8.30 (d, J = 8.0 Hz, 2H), 8.13 (dd, J = 19.3, 8.1 Hz, 2H), 7.95(s, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0Hz, 2H), 3.96-3.87 (m, 4H), 3.86 (s, 3H), 2.89-2.82 (m, 4H), 1.23 (s, 1H).

[0590] MS-ESI: 398.4 [M+H] + .

[0591] Example 52 Preparation of 3-(1-methyl-6-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinoline (compound 52)

[0592] 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinoline

[0593] Except for replacing 2,4-dichloropyrimidine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and acetonitrile with 1,4-dioxane, the synthesis of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The next reaction was carried out directly without purification.

[0594] MS-ESI: 296.2 [M+H] + .

[0595] 4-(1-Methyl-4-(quinolin-3-yl)-1H-pyrazol[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[0596] Except for replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester, the synthesis of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinoline was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 91%.

[0597] MS-ESI: 296.2 [M+H] + .

[0598] Compound 52

[0599] Except that compound 4-(4-(quinolin-3-yl)-1H-pyrazol[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 52 was synthesized in the same manner as compound 18 in Example 18. The yield was 82%.

[0600] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (d, J = 2.0 Hz, 1H), 9.18 (d, J =2.0 Hz, 1H), 8.55 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.92 – 7.84 (m, 1H), 7.74 – 7.69 (m, 1H), 3.93 – 23.89 (m, 4H), 3.88 (s, 3H), 2.90 – 2.79 (m, 4H).

[0601] MS-ESI: 346.4 [M+H] + .

[0602] Example 53 Preparation of 3-(5-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)quinoline (compound 53)

[0603] 3-(6-chloro-5-methylpyrimidin-4-yl)quinoline

[0604] Except for replacing 2,4-dichloropyrimidine with 4,6-dichloro-5-methylpyrimidine, the synthesis of 3-(6-chloro-5-methylpyrimidin-4-yl)quinoline was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 49%.

[0605] 1 H NMR (400 MHz, CDCl3): δ 9.12 (d, J = 4.0Hz, 1H), 8.95 (s, 1H), 8.41 (d, J = 2.0Hz, 1H), 8.19 (dd, J = 16.0,4.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0Hz,1H), 7.85-7.80 (m, 1H), 7.66-7.62 (m, 1H), 2.53 (s, 3H).

[0606] MS-ESI: 256.3 [M+H] + .

[0607] 4-(5-methyl-6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0608] Except for replacing piperidin-4-ylmethylamine with piperazine-1-carboxylate tert-butyl ester, replacing 3-(2-chloropyrimidin-4-yl)quinoline with 3-(6-chloro-5-methylpyrimidin-4-yl)quinoline, and replacing DIPEA with TEA, the synthesis of 4-(5-methyl-6-(quinoline-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester is the same as that of (1-(4-(quinoline-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 89%.

[0609] 1H NMR (400 MHz, CDCl3): δ 9.15 (d, J =8.0Hz, 1H), 8.76 (s, 1H), 8.44-8.43 (m, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.0, 4.0Hz, 1H), 7.81-7.77 (m, 1H), 7.63-7.59 (m, 1H), 3.62-3.59 (m, 4H), 3.48-3.45 (m, 4H), 2.31 (s, 3H), 1.50 (s, 9H).

[0610] Compound 53

[0611] Except that 4-(4-(quinoline-3-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(5-methyl-6-(quinoline-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 18, compound 53 was synthesized in the same manner as compound 18 in Example 18. The yield was 82%.

[0612] 1 H NMR (400 MHz, DMSO-d6): δ 9.17 (d, J = 4.0Hz, 1H), 8.69-8.66(m, 2H), 8.09 (d, J = 8.0Hz, 2H), 7.87-7.83 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 3.42-3.35 (m, 4H), 2.85 (t, J =8.0 Hz, 4H), 2.27 (s, 3H).

[0613] MS-ESI: 306.3 [M+H] + .

[0614] Example 54 Detection of CTLA-4 small molecule degrader activity (protein-protein interaction reporter system detection method, initial screening of CTLA-4 protein expression level) HEK293 cells were seeded in 96-well plates. After 24 hours, LRBA and a CTLA-4 reporter system were co-transfected into the HEK293 cells. After another 24 hours, different compounds were added at final concentrations of 0.01, 0.033, 0.10, 0.33, 1.00, 3.33, 10.00, 33.33, and 100.00 µM. After 24 hours, the cell culture medium was removed, and the cells were washed with cold PBS. The activity of the compounds was then detected using a dual-luciferase assay kit, and the IC50 was calculated based on the results. 50 .

[0615] For highly reactive compounds (IC) 50 The degradation effect on CTLA-4 protein was further detected by Western blotting (< 200 nM).

[0616] IC 50 The concentration of compounds that inhibit 50% of the reporter system activity. IC 50 Size is divided into four levels: ++++, IC 50 < 200nM; +++, IC 50 For 200-1000nM; ++, IC50 1000-2000nM; +, IC 50 > 2000nM.

[0617] Compound IC of the present invention 50 As shown in Table 1 below.

[0618] Table 1. Effects of compounds on CTLA-4 protein expression levels (protein-protein interaction reporter system) , , , , .

[0619] Example 55 In vivo activity study of xenograft model (MC-38) 1. Cell Culture: Mouse colon cancer MC-38 cells were cultured in vitro in adherent medium at 37°C in a 5% CO2 incubator. The culture conditions were RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. The cells were passaged two to three times per week using standard methods. When the cell saturation reached 80%-90% and the desired number was achieved, the cells were harvested, counted, and the cell concentration was adjusted before use for experimental seeding.

[0620] 2. Animals: C57BL / 6 mice, female, 7 weeks old, weighing 18-20 grams, 8 mice per group.

[0621] 3. Tumor inoculation: 0.02 mL (0.2 × 10⁻⁶) 6 MC-38 cells were subcutaneously injected into the right posterior back of each mouse. On day 7 post-inoculation, tumor volume was measured, and the animals were then randomized into groups based on tumor size and drug administration began.

[0622] 4. Experimental Indicators: The experimental indicators are used to examine whether tumor growth is inhibited, delayed, or cured. The tumor diameter is measured two to three times per week using calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The tumor-suppressing efficacy of the compound is expressed as TGI (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0623] 5. Animal experiment grouping, dosing regimen, and experimental results:

[0624] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: ； 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of any one of an aqueous dispersant, gel, aerosol, controlled-release agent, instant solvent, lyophilized agent, tablet, powder, pill, capsule or multi-particle formulation.

4. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 2-3, in the preparation of a medicament for treating CTLA-4 related diseases.

5. The application according to claim 4, characterized in that, The CTLA-4-related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, and organ transplant rejection.

6. The application according to claim 5, characterized in that, The cancers mentioned are selected from skin cancer, breast cancer, pancreatic cancer, neurocytoma, adenocarcinoma, urinary tract cancer, brain tumor, teratoma, plasmacytoma, papilloma, budding glioma, sarcoma, hemangioma, squamous cell carcinoma, lymphoma, respiratory tract cancer, head and neck cancer, digestive tract cancer, leukemia, reproductive organ cancer, and eye cancer.

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