CTLA-4 Low Molecular Weight Degrader and Its Use

Abstract

A CTLA-4 small molecule degrader and use thereof, wherein the CTLA-4 small molecule degrader is a compound having a structure of formula I or a pharma- ceutically acceptable salt, ester, deuterated product, isomer, solvate, prodrug or isotope-labeled product thereof. The CTLA-4 small molecule degrader is a novel small molecule compound having high degrading activity against CTLA-4, and in an in vitro study, the compound shows good degrading activity against CTLA-4 even at the nanomolar (nM) level. [Formula 1] JPEG2024510306000168.jpg46156

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a small molecule degrader that inhibits the interaction between LRBA protein and CTLA-4 protein and causes the degradation of CTLA-4 protein, a method for producing the same, a pharmaceutical composition, and uses in the pharmaceutical field.

Background Art

[0002] PD-1 / PD-L1 inhibitors are currently one of the most important tumor immunotherapy drugs, but the clinical response rate is low (10 - 30%) and ineffective for most tumor patients, so new solutions are needed clinically. The combined administration of PD-1 / PD-L1 inhibitors and other tumor therapeutic agents may be a good approach.

[0003] CTLA-4 (cytotoxic T lymphocyte-associated protein-4) is a type of protein receptor that functions as an immune checkpoint and downregulates the immune response. It is constitutively highly expressed in T cells, especially regulatory T cells, and plays the role of an "off" switch when binding to CD80 or CD86 on the surface of antigen-presenting cells. CTLA-4 inhibitors are used in tumor immunotherapy and can activate the anti-tumor immune response. The CTLA-4 inhibitor ipilimumab (Yervoy, "Y" agent) has already been used in the treatment of various tumors such as melanoma.

[0004] Considering that CTLA-4 and PD-1 / PD-L1 coordinately control the immune response at different stages of the tumor immune response, namely, CTLA-4 at the initial and middle stages of the tumor immune response and PD-1 at the late stage of the tumor immune response, the combined administration of CTLA-4 and PD-1 / PD-L1 inhibitors is promising, and such a combined administration method has already been fully verified clinically. For example, the FDA has approved six clinical indications such as hepatocellular carcinoma and non-small cell lung cancer. For example, the objective response rate (ORR) of the combined administration of ipilimumab (Yervoy, "Y agent") and the PD-1 inhibitor nivolumab (Opdivo, "O agent") is significantly improved compared with that of the "O" agent alone. The dual immunotherapy with the combination of the "Y" agent and the "O" agent is the first and currently the only FDA-approved dual immunotherapy.

Table 1

[0005] However, conventional CTLA-4 inhibitors, such as the "Y" agent, are antibody drugs, and there are several inherent limitations to such antibodies and antibody drugs. 1) The side effects are large, and in clinical practice, severe immune-related adverse events (irAE) of grade 3-4 occur in about 54% of the combined patients, so the clinical use of such drugs is greatly restricted, and the side effects are related to the ADCC activity and immunogenicity of the antibody. 2) It is difficult to diffuse within the tumor. CTLA-4 antibody drugs are macromolecular drugs and it is difficult to infiltrate solid tumors, so the therapeutic effect of single or combined administration is limited. 3) The compliance is poor. The administration methods of CTLA-4 antibody drugs are mainly intravenous, subcutaneous or intramuscular injection, and oral administration is not possible, so the compliance of patients is poor.

[0006] Compared with CTLA-4 monoclonal antibody drugs, CTLA-4 small molecule degrading agents have unique advantages. 1) Significantly reduce toxicity and side effects. CTLA-4 small molecule degrading agents achieve the purpose of eliminating immunosuppression by degrading CTLA-4 protein. They do not affect other activities of T cells themselves, and since small molecules do not have the ADCC activity and immunogenicity of antibodies, side effects are significantly reduced. 2) Easy tumor internal diffusion. Since small molecule drugs are easily infiltrated into solid tumors, the therapeutic effect of single or combined administration is significantly improved. 3) Good compliance. Small molecule drugs can be administered orally. 4) Advantage in price. The manufacturing cost of small molecule drugs is low.

[0007] However, currently, worldwide, there has been no development or report on CTLA-4 small molecule degrading agents or small molecule inhibitors.

Summary of the Invention

Problems to be Solved by the Invention

[0008] In order to solve the above technical problems, the present invention provides, for the first time in the world, a novel small molecule compound having high degrading activity and high in vivo activity against CTLA-4.

Means for Solving the Problems

[0009] In order to solve the above technical problems, the present invention provides the following technical solutions. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, deuteride, isomer, solvate, prodrug or isotope-labeled compound thereof,

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

[0010] Preferably, at least one of C, G, and I is an N atom.

[0011] Preferably, at least one of J, K, and M is an N atom.

[0012] Preferably, all of I, J, and K are N atoms, or all of I, M, and K are N atoms.

[0013] Preferably, each R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently hydrogen, deuterium, unsubstituted or substituted C 1~6 alkyl group, unsubstituted or substituted C 2~6 alkenyl group, unsubstituted or substituted C 2~6 alkynyl group, unsubstituted or substituted C 3~7 cycloalkyl group, unsubstituted or substituted 3- to 7-membered cycloheteroalkyl group, halogen, -OH, unsubstituted or substituted C 1~6 alkoxy group, unsubstituted or substituted C 6~10 arylethyl group, unsubstituted or substituted 5- to 10-membered arylheteroethyl group, unsubstituted or substituted C 6~10An aryl ether group, an unsubstituted or substituted 5- to 10-membered aryl heteroether group, -CN, -NH2, -NO2, -N3, a boronic acid group, an unsubstituted or substituted boronic acid ester group, a carboxy group, an ester group, an unsubstituted or substituted carbamoyl group, an unsubstituted or substituted C 6~10 An aryl group, an unsubstituted or substituted 5- to 10-membered aryl hetero group, an unsubstituted or substituted thioether group, an unsubstituted or substituted sulfoxide group, an unsubstituted or substituted sulfone group, an unsubstituted or substituted sulfonamide group, [Chemical formula] , selected from an unsubstituted or substituted phosphonate group, wherein the substitution is hydrogen, deuterium, halogen, C 1~6 An alkyl group, C 2~6 An alkenyl group, C 2~6 An alkynyl group, C 1~6 A haloalkyl group, C 1~6 A haloalkenyl group, C 1~6 A haloalkynyl group, C 3~7 A cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, halogen, -OH, C 1~6 An alkoxy group, C1 ~6 A haloalkoxy group, -CN, -NH2, -NO2, N3, a boronic acid group, a carboxy group, an ester group, a formamide group, C 1~6 An alkylamide group, C 6~10 An aryl group, a 5- to 10-membered aryl hetero group, or an alkylamino group, and is substituted by a substituent selected therefrom.

[0014] Preferably, the said W is a direct bond, a substituted or unsubstituted aryl group, an aryl hetero group, a cycloalkyl group, a cycloheteroalkyl group, a bridged alkyl group, a bridged cycloheterocycloalkyl group, a spirocycloalkyl group, a spirocycloheteroalkyl group, an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, -N(R 12 R 13 ), an aminoalkyl group, an aminoalkylamino group, an unsubstituted or substituted [Chemical formula] selected from, and the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, -N3, boronic acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, alkylamino group, and is substituted by a substituent selected therefrom.

[0015] Preferably, the W is a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, a substituted or unsubstituted -amino-C 1~6 alkyl group, and the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, -N3, boronic acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, alkylamino group, and is substituted by a substituent selected therefrom.

[0016] Preferably, in the W, the atom connected to the ring containing J and K is N.

[0017] Preferably, W is selected from a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, and the 5- to 7-membered hetero cycloalkyl group contains at least one nitrogen atom. More preferably, the 5- to 7-membered hetero cycloalkyl group is a piperidinyl group or a piperazinyl group.

[0018] Preferably, the Q is -H, -NH2, -OH, -C 1~6 alkyl-HNC(=O)H, unsubstituted or substituted C 1~6 alkyl hydroxy group, unsubstituted or substituted C 2~6 alkenyl hydroxy group, unsubstituted or substituted C 2~6 alkynyl hydroxy group, unsubstituted or substituted alkylamino group, sulfonamide group and sulfonyl hydrazide group, and the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered hetero cycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, -N3, boric acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, alkylamino group selected from substituents by which it is substituted.

[0019] Preferably, W and Q may be connected or condensed to form a ring, and the ring is a substituted or unsubstituted 5- to 7-membered cycloalkyl group, a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, a substituted or unsubstituted C 6~10 aryl group, a substituted or unsubstituted 5- to 10-membered aryl hetero group.

[0020] More preferably, the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6An alkenyl group, C 2~6 An alkynyl group, C 1~6 A haloalkyl group, C 1~6 A haloalkenyl group, C 1~6 A haloalkynyl group, C 3~7 A cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, a halogen, -OH, C 1~6 An alkoxy group, C 1~6 A haloalkoxy group, -CN, -NH2, -NO2, -N3, a boronic acid group, a carboxy group, an ester group, a formamide group, C 1~6 An alkylamide group, C 6~10 It is substituted by a substituent selected from an aryl group, a 5- to 10-membered aryl hetero group, and an alkylamino group.

[0021] Preferably, the compound having the structure of Formula I is

Chemical formula

[0022] Preferably, the compound having the structure of Formula I is

Chemical formula

Advantages of the Invention

[0023] 1. The present invention reports, for the first time in the world, a novel small molecule compound having high degrading activity against CTLA-4. 2. The compounds described in the present invention exhibit good activity against CTLA-4 even at the nanomolar (nM) level in in vitro studies. 3. The compounds described in the present invention, such as compound 18, etc., have excellent antitumor effects in studies in in vivo transplanted tumor models, such as the MC-38 model often used in tumor immunity.

Mode for Carrying Out the Invention

[0024] For a clearer description of the content of the present invention, all related terms are defined as follows. As used herein, the term "direct bond" refers to two atoms or groups connected to a direct bond being connected via a direct chemical bond, and preferably, the chemical bond includes a single bond and a double bond.

[0025] Unless otherwise defined, the term "substituted" as used herein is intended to be substituted by the following substituents: alkyl group, cycloalkyl group, aryl group, heterocyclyl group, halogen, hydroxy group, alkoxy group, boric acid group, borate ester, phosphonate, ester group, oxo, alkanoyl group, aryloxy group, alkanoyloxy group, amino group, alkylamino group, arylamino group, arylalkylamino group, disubstituted amino group (the substituents of the two amino groups are selected from alkyl group, aryl group or arylalkyl group), alkanoylamino group, aroylamino group, aralkanoylamino group, substituted alkanoylamino group, substituted arylamino group, substituted aralkanoylamino group, thio group, alkylthio group, arylthio group, arylalkylthio group, arylthiocarbonyl group, arylalkylthiocarbonyl group, alkylsulfonyl group, arylsulfonyl group, arylalkylsulfonyl group, sulfonylamino group (e.g., -SO2NH2), substituted sulfonylamino group, nitro group, cyano group, carboxy group, carbamoyl group (e.g., -CONH2), substituted carbamoyl group (e.g., -CONH alkyl group, -CONH aryl group, -CONH arylalkyl group or having two substituents selected from alkyl group, aryl group or arylalkyl group on nitrogen), alkoxycarbonyl group, aryl group, substituted aryl group, guanidyl group, heterocyclyl group (e.g., indolyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrrolidinyl group, pyridinyl group, pyrimidinyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, homopiperazinyl group, etc.) and substituted heterocyclyl group.

[0026] As used herein, the term "alkyl group" or "alkylene group" is each intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a predetermined number of carbon atoms. For example, "C" 1~6The term "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl group (Me), ethyl group (Et), propyl group (e.g., n-propyl group and isopropyl group), butyl group (e.g., n-butyl group, isobutyl group, tert-butyl group), pentyl group (e.g., n-pentyl group, isopentyl group, neopentyl group).

[0027] The term "heteroalkyl group" or "alkyl hetero group" refers to a group in which 1 to 4 carbon atoms in the alkyl group are substituted by heteroatoms, preferably 1 to 3 carbon atoms in the alkyl group are substituted by heteroatoms, more preferably 1 or 2 carbon atoms in the alkyl group are substituted by heteroatoms. Preferably, the alkyl group before being substituted by heteroatoms is a C 2~10 alkyl group, and more preferably, the alkyl group before being substituted by heteroatoms is a C 2~6 alkyl group, and the substitution position of the heteroatom may be at the terminal position of the alkyl group or at the middle position of the alkyl group. Each of the heteroatoms is independently selected from N, O, S, P, etc.

[0028] The term "alkenyl group" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, "C 2~6 alkenyl group" contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl group, propenyl group, butenyl group, 1-methyl-2-buten-1-yl, hexenyl group, etc.

[0029] The term "alkynyl group" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, "C 2~6The "alkynyl group" contains 2 to 6 carbon atoms. Representative alkynyl groups include, for example, ethynyl group, 1-propynyl group, 1-butynyl group, pentynyl group, hexynyl group, etc., but are not limited thereto.

[0030] The term "heteroalkenyl group" means that one or more carbon atoms of the "alkenyl group" defined above are replaced by a heteroatom selected from N, O, S, or are substituted by a group containing a heteroatom selected from N, O, S.

[0031] The term "heteroalkynyl group" means that one or more carbon atoms of the "alkynyl group" defined above are replaced by a heteroatom selected from N, O, S, or are substituted by a group containing a heteroatom selected from N, O, S.

[0032] The term "alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. "C 1~10 alkoxy group (or alkyloxy group)" is intended to include alkoxy groups of C1 to C 10 . Examples of alkoxy groups include methoxy group, ethoxy group, propoxy groups (e.g., n-propoxy group and isopropoxy group), tert-butoxy group, but are not limited thereto, and a plurality of oxygen atoms (e.g., 1 to 10 oxygen atoms) may be included in the alkoxy group. Similarly, the "alkylthio group" or "thioalkoxy group" refers to a group in which a predetermined number of carbon atoms in the alkyl group defined above are connected by a sulfur bridge, e.g., methyl-S-, ethyl-S-.

[0033] The terms "carbonyl group" and "acyl group" refer to an organic functional group (C=O) formed by connecting two kinds of atoms, carbon and oxygen, by a double bond.

[0034] The term "ester group" includes carboxylic acid ester groups, phosphate ester groups, phosphite ester groups, silicate ester groups, borate ester groups, etc., e.g., -COOR, B(OR)2, where R is an alkyl group.

[0035] The term "cycloalkyl group" refers to a monocyclic or bicyclic cyclic alkyl group. A monocyclic cyclic alkyl group refers to a cyclic alkyl group of C 3~8 and includes, but is not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, norbornyl group, etc. Branched cycloalkyl groups such as 1-methylcyclopropyl group and 2-methylcyclopropyl group are included in the definition of "cycloalkyl group". Bicyclic cyclic alkyl groups include bridged-ring, spiro-ring or fused-ring cycloalkyl groups.

[0036] The term "cycloalkenyl group" refers to a monocyclic or bicyclic cyclic alkenyl group. A monocyclic cyclic alkenyl group refers to a cyclic alkenyl group of C 3~8 and includes, but is not limited to, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, norbornenyl group . Branched cycloalkenyl groups such as 1-methylcyclopropenyl group and 2-methylcyclopropenyl group are included in the definition of "cycloalkenyl group". Bicyclic cyclic alkenyl groups include bridged-ring, spiro-ring or fused-ring cyclic alkenyl groups.

[0037] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl group" is intended to include branched-chain and straight-chain saturated aliphatic hydrocarbon groups having a predetermined number of carbon atoms and substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, pentafluoroethyl group, pentachloroethyl group, 2,2,2-trifluoroethyl group, heptafluoropropyl group, heptachloropropyl group. Examples of haloalkyl groups further include "fluoroalkyl groups" intended to include branched-chain and straight-chain saturated aliphatic hydrocarbon groups containing a predetermined number of carbon atoms and substituted by one or more fluorine atoms.

[0038] The "haloalkoxy group" or "haloalkyloxy group" represents a group in which a predetermined number of carbon atoms in the haloalkyl group defined above are connected by an oxygen bridge. For example, "C 1~6 haloalkoxy group" is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group. Similarly, the "haloalkylthio group" or "thiohaloalkoxy group" represents a group in which a predetermined number of carbon atoms in the haloalkyl group defined above are connected by a sulfur bridge, for example, trifluoromethyl-S-, pentafluoroethyl-S-.

[0039] The term "aryl group" / "arylene group" refers to a monocyclic, bicyclic or tricyclic ring system having a total of 6 to 10 ring atoms, either by itself or, for example, as part of an "aralkyl group", "aralkoxy group" or "aryloxyalkyl group", where at least one ring in said system is aromatic and each ring in said system contains 3 to 7 ring atoms. In some embodiments of the present invention, the "aryl group" refers to an aromatic ring system, including, but not limited to, phenyl group, indanyl group, 1-naphthyl group, 2-naphthyl group, tetrahydronaphthyl group. The fused aryl group may be connected to another group at an appropriate position of the cycloalkyl ring or aromatic ring. For example, the arrow drawn from the ring system represents that the bond may be connected to any appropriate ring atom.

[0040] The terms "heteroaryl group" / "heteroarylene group", "heteroaromatic ring", "arylene hetero group", "aryl hetero group", "heteroaromatic ring group" or "heteroaromatic ring group" refer to stable 3-, 4-, 5- or 7-membered aromatic monocyclic or aromatic bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic polycyclic heterocyclic rings, which are fully unsaturated or partially unsaturated and contain carbon atoms and one, two, three or four heteroatoms independently selected from N, O and S, and include any of the following polycyclic groups in which any of the heterocyclic rings defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom may or may not be substituted (i.e., N or NR, where R is H or, when defined, another substituent). The heterocyclic ring may be connected to its pendant group at any heteroatom or carbon atom capable of having a stable structure. When the resulting compound is stable, the heterocyclyl groups described herein may be substituted at carbon or nitrogen atoms. The nitrogen in the heterocyclic ring may be optionally quaternized. When the total number of S and O atoms in the heterocyclic ring exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocyclic ring is 1 or less. Examples of aromatic heterocyclic rings are acridinyl group, azetidinyl group, azocinyl group, benzimidazolyl group, benzofuryl group, benzothiofuryl group, benzothienyl group, benzoxazolyl group, Benzoxazolinyl group, benzothiazolyl group, benzotriazolyl group, benzotetrazolyl group, benzoisoxazolyl group, benzoisothiazolyl group, benzimidazolinyl group, carbazolyl group, 4aH-carbazolyl group, carbolinyl group, chromanyl group, chromenyl group, cinnolinyl group, decahydroquinolinyl group, 2H,6H-1,5,2-dithiazinyl group, dihydrofuro[2,3-b]tetrahydrofuryl group, furyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, imidazolyl group, 1H-indazolyl group, imidazopyridinyl group, indolenyl group, dihydroindolyl group, indolizinyl group, indolyl group, 3H-indolyl group, isatinoyl group, isobenzofuryl group, isochromanyl group, isoindazolyl group, isodihydroindolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridinyl group, isoxazolyl group, isoxazolopyridinyl group, methylenedioxyphenyl group, morpholinyl group, diazanaphthyl group, octahydroisoquinolinyl group, oxadiazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridinyl group, oxazolidinyl group, perimidinyl group, hydroxyindolyl group, pyrimidinyl group, phenanthridinyl group, phenanthrolinyl group, phenazinyl group, phenothiazinyl group, phenoxathiinyl group, phenoxazinyl group, phthalazinyl group, piperazinyl group, piperidinyl group, piperidonyl group, 4-piperidonyl group, piperonyl group, pteridinyl group, purinyl group, pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridinyl group, pyrazolyl group, pyridazinyl group, pyridooxazolyl group, pyridoimidazolyl group, pyridothiazolyl group, pyridinyl group, pyrimidinyl group, pyrrolidinyl group, pyrrolinyl group, 2-pyrrolidonyl group, 2H-pyrrolyl group, pyrrolyl group, quinazolinyl group, quinolinyl group, 4H-quinolizidinyl group, quinoxalinyl group, quinuclidinyl group, tetrazolyl group, tetrahydrofuryl group, tetrahydroisoquinolinyl group, tetrahydroquinolinyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3-thiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridinyl group, thieno[2,3-d]thiazolyl group, thieno[2,3-d]oxazolyl group, thieno[2,3-d]imidazolyl group, thienyl group, triazinyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,2,5-triazolyl group, 1,3,4-triazolyl group, and xanthenyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, quinazolinyl group, indolyl group, isoindolyl group, dihydroindolyl group, 1H-indazolyl group, benzimidazolyl group, 1,2,3,4-tetrahydroquinolinyl group, 1,2,3,4-tetrahydroisoquinolinyl group, 5,6,7,8-tetrahydroquinolinyl group, 2,3-dihydrobenzofuryl group, chromanyl group, 1,2,3,4-tetrahydroquinoxalinyl group, 1,2,3,4-tetrahydroquinazolinyl group, including but not limited to these. The present invention further includes, for example, condensed ring compounds and spiro ring compounds containing the above heterocycles.,

[0041] As used herein, the terms "heterocycloalkyl group" and "cycloheteroalkyl group" refer to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system. The monocyclic heterocycloalkyl group has 3 to 12 members (preferably 3 to 8 members, more preferably 5 to 7 members) and refers to a saturated or unsaturated non-aromatic cyclic alkyl system containing at least one selected from O, N, S, and P. The bicyclic heteroalkyl system refers to a system in which one heterocycloalkyl group is condensed with one phenyl group, one cycloalkyl group, one cycloalkenyl group, one cycloheteroalkyl group, or one heteroaryl group. The heterocycloalkyl group includes, but is not limited to, an aziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, a tetrahydropyranyl group, a 1,1-dioxothiomorpholinyl group, a 1,4-diazinyl group, etc.,

[0042] As used herein, the term "bridged cycloalkyl group" refers to a fully carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0043] As used herein, the terms "bridged heterocycloalkyl group", "hetero-bridged cycloalkyl group" and "bridged cycloheteroalkyl group" refer to polycyclic compounds that share two or more carbon atoms or heteroatoms, and the "bridged heterocycloalkyl group", "hetero-bridged cycloalkyl group" and "bridged cycloheteroalkyl group" contain at least one heteroatom selected from O, N, S, P, etc. It can be divided into bicyclic hetero-bridged cycloalkyl groups and polycyclic hetero-bridged cycloalkyl groups. The former is composed of two alicyclic rings sharing two or more carbon atoms or heteroatoms, and the latter is a hetero-bridged cycloalkyl group composed of three or more rings.

[0044] As used herein, the terms "spirocyclic hydrocarbon" and "spirocycloalkyl group" refer to polycyclic hydrocarbons and polycyclic alkyl groups in which single rings share one carbon atom (referred to as a spiro atom).

[0045] As used herein, the term "spirocycloheteroalkyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which two monocycles share one atom (referred to as a spiro atom), and one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may be optionally oxidized (i.e., form a sulfoxide or a sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably, 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared by the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, it is a monospiroheterocyclyl group of 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member.

[0046] As used herein, the term "isomer" includes "tautomer", "stereoisomer", etc. "Tautomer" refers to a structural isomer having different energies and capable of interconverting through a low energy barrier. When tautomerism can exist (e.g., in a solution), the tautomers can reach a chemical equilibrium. For example, proton tautomers (also called prototropic tautomers) include, but are not limited to, keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, etc., which involve interconversion by the movement of protons. "Stereoisomer" refers to a compound having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, etc. Unless otherwise specified, all tautomeric and stereoisomeric forms of the compounds of the present invention are included within the scope of the present invention.

[0047] As used herein, the term "substituted" refers to the replacement of at least one hydrogen atom by a non-hydrogen group, provided that normal valences are maintained and a stable compound is obtained by said substitution. As used herein, a "ring double bond" is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

[0048] When a nitrogen atom is present in a compound of the present invention (e.g., an amine), other compounds of the present invention can be obtained by treating with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to convert these nitrogen atoms to N-oxides. Accordingly, when a nitrogen atom is indicated or its protection is claimed, in each case, it is considered to cover the indicated nitrogen and its N-oxide (N→O) derivatives.

[0049] When any variable appears one or more times in any composition or formula of a compound, the definition each time it appears is independent of the definitions for each other appearance. Thus, for example, if a group is said to be substituted by 0 to 3 R's, said group may optionally be substituted by up to 3 R groups, and each time R appears, it is independently selected from the definition of R. Also, combinations of substituents and / or variables are only permitted to exist if a stable compound is obtained from said combination.

[0050] When a bond attached to a substituent is shown to cross a bond connecting two atoms of a ring, said substituent can be bonded to any atom of said ring. When a substituent is shown but the atom by which it is bonded to the remainder of the compound having a given formula is not specified, said substituent can be bonded by any atom of said substituent. Combinations of substituents and / or variables are only permitted to exist if a stable compound is obtained from said combination.

[0051] The term "amino group" refers to a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group (either by itself or in combination with something) [Chem.] etc.) etc. are represented.

[0052] The term "C 1~6 alkylamino group" by itself or in combination with something represents a group in which at least one hydrogen atom of the amino group in the amino group defined above is replaced by a C 1~6 alkyl group, where the "alkyl group" is as defined above, and correspondingly, the "C 1~6 alkylamino group" includes methylamino group, ethylamino group, propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, 2-butylamino group, tert-butylamino group, n-pentylamino group, 2-pentylamino group, 3-pentylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 3-methyl-1-butylamino group, 2-methyl-1-butylamino group, n-hexylamino group, 2-hexylamino group, 3-hexylamino group, 2-methyl-2-pentylamino group, 3-methyl-2-pentylamino group, 4-methyl-2-pentylamino group, 3-methyl-3-pentylamino group, 2-methyl-3-pentylamino group, 2,3-dimethyl-2-butylamino group, 3,3-dimethyl-2-butylamino group, etc. In particular, the "C 1~6 alkylamino group" is methylamino group, ethylamino group, isopropylamino group, tert-butylamino group, etc.

[0053] The term "(C 1~6 alkyl)2amino group" by itself or in combination with something represents a group in which two hydrogen atoms of the amino group in the amino group defined above are replaced by C 1~6 alkyl groups, where the "alkyl group" is as defined above, and correspondingly, the "(C 1~6 alkyl)2amino group" includes dimethylamino group, diethylamino group, methylethylamino group, etc.

[0054] As used herein, the term "amino acid residue" refers to a residue in which the carboxy or amino group at the carbon terminus of one amino acid participates in the formation of a bond and one water molecule is lost, and the amino acid unit is called an amino acid residue.

[0055] As used herein, the term "[Cu]" herein refers to a reagent containing monovalent copper (Cu + ) or divalent copper (Cu 2+ ), for example, CuI, CuBr, CuCl, CuI2, CuBr2, CuCl2, etc.

[0056] The term "isomer" includes all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, a single stereoisomer of the compound designed in the present invention, or a mixture of its enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) all belong to the scope of the present invention.

[0057] As used herein, "pharmaceutically acceptable salt" refers to a derivative of a compound of the present invention in which the parent compound is modified by producing its salt from an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids of basic groups (e.g., amines), and alkali metal salts or organic salts of acidic groups (e.g., carboxylic acids). Pharmaceutically acceptable salts include, for example, normal non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids or quaternary ammonium salts. For example, the normal non-toxic salts are derived from, for example, the following inorganic acids, namely hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and, for example, the following organic acids, namely acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic 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, isethionic acid, etc.

[0058] The pharmaceutically acceptable salts of the present invention may be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, these salts may be prepared by reacting the free acid or base forms of these compounds in water or an organic solvent or a mixture of both with a stoichiometrically appropriate base or acid, and generally, non-aqueous media such as, for example, 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, L.V. Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosed content of which is incorporated herein by reference.

[0059] The term "solvate" refers to a compound of the present invention that is physically associated with one or more solvent molecules (whether organic or inorganic). Such physical association includes hydrogen bonding. In some cases, for example, 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 a solvate can exist as a regular arrangement and / or an irregular arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" covers both the solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, me thanolates, isopropanolates. Methods of solvation are well known in the art.

[0060] The term "ester" is used to denote organic esters and includes mono-esters, di-esters, tri-esters, and more generally polyesters.

[0061] The term "isotope derivative" refers to an isotope derivative obtained by substituting 1 to 6 hydrogen atoms in General Formula I with deuterium atoms (D), and an isotope derivative obtained by substituting 1 to 3 carbon atoms in General Formula I with carbon-14 atoms (14C).

[0062] As used herein, the term "treatment" includes any effect such as improvement of a medical condition, disease, disorder, etc., for example, alleviation, reduction, regulation, improvement or elimination, or bringing about improvement of symptoms.

[0063] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent and an inert or active carrier so that the composition is particularly suitable for diagnosis or treatment in vivo or ex vivo. Examples of bases include, but are not limited to, hydroxides of alkali metals (e.g., sodium), hydroxides of alkaline earth metals (e.g., magnesium), ammonia, etc. For therapeutic uses, salts of the compounds of the present invention are preferably those that are pharmaceutically acceptable. It should be noted that salts of non-pharmaceutical acids and bases can also be used, for example, for the manufacture or purification of pharmaceutical compounds.

[0064] Specific pharmaceutical and medical terms: As used herein, the term "cancer" refers to the abnormal growth of cells that cannot be controlled and can metastasize (spread) under certain conditions. Such cancers include, but are not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (e.g., thyroid), prostate, skin (melanoma)) or blood tumors (e.g., aleukemic leukemia).

[0065] Pharmaceutical compositions and dosages: The present invention further provides a pharmaceutical composition 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. For any of the above uses, the compounds of the present invention can be administered in any suitable manner, for example, orally (e.g., tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nano-suspensions, micro-suspensions, spray-dried dispersions), syrups and emulsions), sublingually, buccally, parenterally (e.g., subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., in the form of a sterile aqueous or non-aqueous solution or suspension for injection)), intranasally (including administration to the nasal mucosa (e.g., by inhalation spray)), topically (e.g., in the form of a cream or ointment), or rectally (e.g., in the form of a suppository). They may be administered alone, but generally are administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0066] Pharmaceutical carriers are prepared taking into account various factors within the knowledge of those skilled in the art. Such factors include, but are not limited to, the type and properties of the active pharmaceutical ingredient to be formulated, the subject to which the composition containing the active ingredient is to be administered, the intended route of administration of the composition, and the indication for treatment. Pharmaceutical carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms.

[0067] The above carriers may contain various components and additives in addition to the active pharmaceutical ingredient, and the other components, such as stabilizing agents, adhesives, etc., are used in the formulation for various reasons well known to those skilled in the art. A description of suitable pharmaceutical carriers and the factors involved in their selection can be found in a number of readily available sources, for example, Allen, L.V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0068] Note that the dosage regimen of the compounds of the present invention varies depending on known factors such as the pharmacodynamic properties of a particular agent, its mode and route of administration, the species, age, sex, health status, disease state and body weight of the subject, the nature and degree of the symptoms, the type of treatment being carried out simultaneously, the frequency of treatment, the route of administration, the renal and hepatic functions of the patient, and the desired effect. Generally, when used for a given effect, the daily oral dosage of each active ingredient is about 0.001 mg / day to about 10 - 5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably about 0.1 mg / day to about 600 mg / day. During the period of constant rate infusion, the intravenous dosage is most preferably about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention may be administered once a day for the daily dosage, or the daily dosage may be divided into 2, 3 or 4 administrations during the day.

[0069] The said compounds are generally appropriately selected according to a given dosage form (e.g., oral tablets, capsules, elixirs, syrups), and are administered in the form of a mixture with appropriate pharmaceutical diluents, excipients, carriers (collectively referred to as pharmaceutical carriers herein) that conform to normal pharmaceutical practice.

[0070] The dosage form for administration (pharmaceutical composition) may contain about 0.1 mg to about 2000 mg of the active ingredient per dosage unit. In such a pharmaceutical composition, the active ingredient generally exists in a ratio of about 0.1 - 95% by weight based on the total weight of the composition.

[0071] A typical injectable preparation may be manufactured as follows. At least one compound of the present invention (250 mg) is placed in a bottle in a sterile state, freeze-dried in a sterile state and sealed. When in use, the contents of the bottle are mixed with 2 mL of physiological saline to obtain an injectable preparation.

[0072] The present invention includes pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one compound of the present invention (either alone or in combination with a pharmaceutical carrier). Optionally, the compounds of the present invention are used alone, or in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0073] Without considering the selected route of administration, the compounds of the present invention (which may be in the form of suitable hydrates) and / or the pharmaceutical compositions of the present invention are formulated in the form of pharmaceutical dosages by conventional methods known to those skilled in the art.

[0074] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient and that is non-toxic to the patient.

[0075] The selected dosage level is determined by a variety of factors including the activity of the particular compound or its ester, salt, or amide of the present invention being used, the route of administration, the duration of administration, the rate of excretion of the particular compound being used, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or substances being administered in combination with the particular compound being used, and factors well known in the medical arts such as the age, sex, weight, condition, general health, and medical history of the patient being treated.

[0076] A physician or veterinarian who is a person skilled in the art can easily determine and prescribe an effective amount of a given pharmaceutical composition. For example, in order to obtain a desired therapeutic effect, a physician or veterinarian may gradually increase the dosage from a pharmaceutical composition containing a compound of the present invention at a dosage lower than a predetermined level until the desired effect is achieved. Generally, an appropriate daily dosage of the compound of the present invention is the amount of the compound at the lowest dosage effective to obtain a therapeutic effect. Such an effective dosage is generally determined by the above factors. Generally, the oral, intravenous, intramuscular injection, intraventricular or subcutaneous dosage range of the compound of the present invention for a patient is about 0.01 to about 1000 mg / kg body weight / day. If necessary, the active compound in an effective daily dosage may be administered in two, three, four, five, six or more divided dosages at appropriate intervals throughout the day, and is optionally administered in the form of a unit dosage form. In some embodiments of the present invention, the drug is administered once a day.

[0077] The compound of the present invention may be administered alone, but preferably, the compound is administered in the form of a pharmaceutical preparation (composition).

[0078] The features of the present invention mentioned above, or the features mentioned in the examples, can be combined without limitation. All the features disclosed in this specification may coexist in any form of composition, and each feature disclosed in the specification may be replaced by alternative features that can achieve the same, equivalent or similar purpose. Therefore, unless otherwise specifically explained, the disclosed features are only general examples of equivalent or similar features.

[0079] The present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, deuteride, isomer, solvate, prodrug or isotope-labeled compound thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0080] Preferably, at least one of the C, G, and I is an N atom. For example, any one of C, G, and I is an N atom, or two of C, G, and I are N atoms (that is, 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.

[0081] Preferably, at least one of the 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.

[0082] Preferably, the I, J, and K are all N atoms, or the I, M, and K are all N atoms.

[0083] Preferably, each R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently hydrogen, deuterium, unsubstituted or substituted C 1~6 alkyl group, unsubstituted or substituted C 2~6 alkenyl group, unsubstituted or substituted C 2~6 alkynyl group, unsubstituted or substituted C 3~7 cycloalkyl group, unsubstituted or substituted 3- to 7-membered cycloheteroalkyl group, halogen, -OH, unsubstituted or substituted C 1~6 alkoxy group, unsubstituted or substituted C 6~10 arylethyl group, unsubstituted or substituted 5- to 10-membered arylheteroethyl group, unsubstituted or substituted C 6~10An aryl ether group, an unsubstituted or substituted 5- to 10-membered aryl heteroether group, -CN, -NH2, -NO2, -N3, a boronic acid group, an unsubstituted or substituted boronic acid ester group, a carboxy group, an ester group, an unsubstituted or substituted carbamoyl group, an unsubstituted or substituted C 6~10 An aryl group, an unsubstituted or substituted 5- to 10-membered aryl hetero group, an unsubstituted or substituted thioether group, an unsubstituted or substituted sulfoxide group, an unsubstituted or substituted sulfone group, an unsubstituted or substituted sulfonamide group,

Chemical formula

[0084] Preferably, the W is a direct bond, an unsubstituted or substituted aryl group, an aryl hetero group, a cycloalkyl group, a cycloheteroalkyl group, a bridged cycloalkyl group, a bridged cycloheteroalkyl group, a spirocycloalkyl group, a spirocycloheteroalkyl group, an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, -N(R 12 R 13 ), an aminoalkyl group, an aminoalkylamino group, unsubstituted or substituted

Chemical formula

[0085] Preferably, the W is a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, a substituted or unsubstituted -amino-C 1~6 alkyl group, and the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, -N3, boric acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, alkylamino group, and is substituted by a substituent selected therefrom.

[0086] Preferably, in the W, the atom connected to the ring containing J and K is N.

[0087] Preferably, W is selected from a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, and the 5- to 7-membered heterocycloalkyl group contains at least one nitrogen atom. More preferably, the 5- to 7-membered heterocycloalkyl group is a piperidinyl group or a piperazinyl group.

[0088] Preferably, the Q is -H, -NH2, -OH, -C 1~6 alkyl-HNC(=O)H, unsubstituted or substituted C 1~6 alkylhydroxy group, unsubstituted or substituted C 2~6 alkenylhydroxy group, unsubstituted or substituted C 2~6 alkynylhydroxy group, unsubstituted or substituted alkylamino group, sulfonamide group, and sulfonylhydrazide group. The substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered hetero cycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, -N3, boric acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, and is substituted by a substituent selected from an alkylamino group.

[0089] Preferably, W and Q may be connected or condensed to form a ring, and the ring is a substituted or unsubstituted 5- to 7-membered cycloalkyl group, a substituted or unsubstituted 5- to 7-membered cycloheteroalkyl group, a substituted or unsubstituted C 6~10 aryl group, a substituted or unsubstituted 5- to 10-membered aryl hetero group.

[0090] More preferably, the substitution is hydrogen, deuterium, halogen, C 1~6 alkyl group, C 2~6 alkenyl group, C2~6 alkynyl group, C 1~6 haloalkyl group, C 1~6 haloalkenyl group, C 1~6 haloalkynyl group, C 3~7 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, halogen, -OH, C 1~6 alkoxy group, C 1~6 haloalkoxy group, -CN, -NH2, -NO2, N3, boronic acid group, carboxy group, ester group, formamide group, C 1~6 alkylamide group, C 6~10 aryl group, 5- to 10-membered aryl hetero group, alkylamino group, and is substituted by a substituent selected therefrom.

[0091] Preferably, the compound having the structure of Formula I is

Chemical formula

[0092] Preferably, the compound having the structure of Formula I is

Chemical formula

[0093] In a preferred embodiment, the present invention also provides the following compound or a pharmaceutically acceptable salt, ester, deuteride, isomer, solvate, prodrug or isotope-labeled compound thereof, and the compound is selected from the following. [Table 2] JPEG0007710756000021.jpg195130JPEG0007710756000022.jpg189139JPEG0007710756000023.jpg199142JPEG0007710756000024.jpg199139

[0094] The present invention also provides a pharmaceutical composition, which comprises any one of the above compounds or a pharmaceutically acceptable salt, ester, deuteride, isomer, solvate, prodrug or isotope-labeled compound thereof, and a pharmaceutically acceptable excipient.

[0095] In a preferred embodiment, the form of the pharmaceutical composition is any one of an aqueous dispersant, liquid, jelly, syrup, elixir, slurry, suspension, aerosol, release control agent, rapid dissolution agent, effervescent tablet, lyophilized preparation, tablet, powder, pill, sugar-coated tablet, capsule, delayed release preparation, sustained release preparation, pulsatile release agent, multiparticulate preparation or immediate release preparation.

[0096] The present invention also provides the use of any one of the above compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or any one of the above pharmaceutical compositions, in the manufacture of a drug for treating CTLA-4 related diseases.

[0097] In a preferred embodiment, the CTLA-4 related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, and organ transplant rejection reactions.

[0098] In a more preferred embodiment, the cancer is skin cancer, bladder cancer, breast cancer, pancreatic cancer, bone cancer, brain cancer, neuroblastoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, choriocarcinoma, pancreatic cancer, urinary tract cancer, brain tumor (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral primitive neuroectodermal tumor), 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 cancer, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma (including chondrosarcoma, histiocytic sarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, but not limited thereto), melanoma, hemangioma, keloid, squamous cell cancer, astrocytoma, lymphoma (including non-Hodgkin lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin disease, central nervous system lymphoma, but not limited thereto), respiratory system cancer (including lung cancer, but not limited thereto, e.g., small cell and non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma), head and neck cancer (including head cancer, neck cancer, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer and / or oropharyngeal cancer, lip cancer and oral cancer, but not limited thereto), bladder cancer, breast cancer (including invasive ductal carcinoma, invasive lobular carcinoma, non-invasive ductal carcinoma, non-invasive lobular carcinoma, but not limited thereto), gastrointestinal cancer (including anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, rectal cancer, gastric cancer, small intestine cancer, salivary gland cancer, but not limited thereto), thyroid cancer, parathyroid cancer and its distant metastases, pancreatic cancer, liver cancer (including hepatocellular carcinoma, fibrolamellar or non-fibrolamellar hepatocellular carcinoma, cholangiocarcinoma, mixed type of hepatocellular carcinoma and cholangiocarcinoma, but not limited thereto), leukemia (including acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, but not limited thereto), brain cancer (including brainstem and pituitary glioma, medulloblastoma, cerebellar and cerebral astrocytoma, ependymoma and primitive neuroectodermal tumor, pinealoma, but not limited thereto), genital cancer (prostate cancer, testicular cancer, ovarian cancer,Selected from related cancers such as endometrial cancer, cervical cancer, endometrial cancer, vaginal cancer and vulvar cancer (including, but not limited to, these), uterine sarcoma, urethral cancer, eye tumors (including, but not limited to, intraocular melanoma, retinoblastoma), skin cancer (including, but not limited to, Kaposi's sarcoma, squamous cell carcinoma, malignant melanoma, Merkel cell carcinoma, non-melanoma skin cancer), renal parenchymal cancer, kidney cancer (also called renal cell cancer and adrenal cancer), etc.

[0099] The features of the present invention mentioned above, or the features mentioned in the examples, can be combined without limitation. All the features disclosed in this specification may coexist in any form of composition, and each feature disclosed in the specification may be replaced by alternative features that can achieve the same, equivalent or similar purposes. Therefore, unless otherwise specifically explained, the disclosed features are only general examples of equivalent or similar features.

[0100] The present invention will be further described below using specific examples. It should be understood that these examples are only for explaining the present invention and do not limit the scope of the present invention. The experimental methods without showing specific conditions in the following examples are carried out under normal conditions or the conditions recommended by the manufacturer. Unless otherwise specifically explained, all percentages, ratios, proportions, or parts are based on weight.

[0101] In the present invention, the unit of weight / volume percentage is a matter well-known to those skilled in the art, for example, it refers to the weight of the solute in 100 mL of solution.

[0102] Unless otherwise defined, all technical terms and scientific terms used in this specification have the same meaning as the general understanding of those skilled in the art. Also, any methods and materials similar to or equivalent to those described can be used in the method of the present invention. The preferred embodiments and materials described in this specification are only exemplary.

[0103] The following examples are only for illustration and explanation and do not limit the scope of the claims provided here.

[0104] 1 The 1H NMR spectra were obtained on a Bruker-400 or OXFORD-AS500 nuclear magnetic resonance spectrometer. The chemical shift is in parts per million, and the internal standard substance is tetramethylsilane. The coupling constant (J) is about 0.1 Hz. The explanations of the abbreviations used are as follows: s: singlet, d: doublet, t: triplet, q: quartet, qu: quintet, m: multiplet, brs: broad singlet. In mass spectrometry, a Quattro Micro (trademark) API triple quadrupole mass spectrometer was used.

[0105] Example 1: Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 1)

Chemical formula

[0106] 1 1H NMR (400 MHz, CDCl3) δ 9.51 (d, J = 4.0 Hz, 1H), 8.95 (d, J = 4.0 Hz, 1H), 8.73 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.68 - 7.60 (m, 1H).

[0107]

Chemical formula

[0108] 1 H 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). MS-ESI: 320.5 [M + H] + 。

[0109] Example 2: Preparation of N-((1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)formamide (Compound 2)

Chemical Structure

[0110] 11H 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). MS-ESI: 348.6 [M+H] + .

[0111] Example 3: Preparation of (1-(4-(quinolin-6-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 3)

Chemical Structure

[0112] 1 1H 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). MS-ESI: 242.4 [M+H] + .

[0113]

Chemical Structure

[0114] 1 H NMR(400MHz,DMSO-d6)δ 8.95(dd,J=4.0,2.0Hz,1H),8.77(d,J=4.0Hz,1H),8.55-8.44(m,3H),8.12(d,J=8.0Hz,1H),7.59(dd,J=8.0,4.0Hz,1H),7.32(d,J=4.0Hz ,1H),4.85(d,J=12.0Hz,2H),2.93(td,J=12.0,4.0Hz,2H),2.53(d,J=4.0Hz,2H),1.89-1.76(m,2H),1.70-1.57(m,1H),1.20-1.06(m,2H). MS-ESI: 320.5 [M+H] + .

[0115] Example 4: Preparation of N-((1-(4-(quinolin-6-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)formamide (Compound 4) [ka] The synthesis of compound 4 was the same as that of compound 2 in Example 2, except that 6-(2-chloropyrimidin-4-yl)quinoline was substituted for 3-(2-chloropyrimidin-4-yl)quinoline. The yield was 56%.

[0116] 11H 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 = 12.0 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 2.93 (t, J = 12.0 Hz, 2H), 1.78 - 1.70 (m, 3H), 1.20 - 1.05 (m, 2H). MS-ESI: 348.6 [M+H] + 。

[0117] Example 5: Preparation of (1-(4-(quinolin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 5)

Chem.

[0118] MS-ESI: 235.4 [M+H] + 。

[0119] (1-(4-(quinolin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine

Chem.

[0120] 1 H NMR (400 MHz, CDCl3) δ 8.50 (t, J = 6.8 Hz, 2H), 8.25 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.2 Hz, 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). MS-ESI: 320.5 [M + H] + 。

[0121] Example 6: Preparation of (1-(4-(quinoxalin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 6)

Chemical formula

[0122] MS-ESI: 243.2 [M+H] + 。

[0123]

Chem.

[0124] MS-ESI: 321.2 [M+H] + 。

[0125] Example 7: Preparation of (1-(4-(6-fluoroquinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 7)

Chem.

[0126] 1 H NMR (400 MHz, CD3OD) δ 9.54 (d, J = 4.0 Hz, 1H), 9.13 (d, J = 4.0 Hz, 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). MS-ESI: 260.3 [M+H] + 。

[0127]

Chem.

[0128] 1 H NMR (400MHz, CD3OD) δ 9.51(d,J=4.0Hz,1H),8.97(d,J=4.0Hz,1H),8.44(d,J=8.0Hz,1H),8.15-8. 10(m,1H),7.76(dd,J=12.0,4.0Hz,1H),7.66(td,J=8.0,4.0Hz,1H),7.25(d ,J=4.0Hz,1H),4.96(d,J=12.0Hz,2H),3.00(td,J=12.0,4.0Hz,2H),2.66(d ,J=8.0Hz,2H),1.89(d,J=12.0Hz,2H),1.86-1.72(m,1H),1.30-1.18(m,2H). MS-ESI: 338.4 [M+H] + .

[0129] Example 8: (1-(3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinolin-2-yl)piperidin-4-yl)methylamine (compound 8) [ka] Except for replacing the quinolin-3-ylboronic acid in Example 1 with the compound (2-fluoroquinolin-3-yl)boronic acid, the synthesis of the compound 3-(2-chloropyrimidin-4-yl)-6-fluoroquinoline was the same as that of the compound 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 42%.

[0130] 1 H NMR(400MHz,CD3OD)δ 9.28(d,J=8.0Hz,1H),8.82(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),8.05(dd,J=8.0,4.0Hz,1H),7.97-7.85(m,2H),7.69(t,J=8.0Hz,1H). MS-ESI: 260.3 [M+H] + 。

[0131]

Chem.

[0132] 1 H NMR (400 MHz, CD3OD) δ 8.40 - 8.32 (m, 2H), 7.81 (dd, J = 8.0, 4.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 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). MS-ESI: 432.5 [M+H] + 。

[0133] Example 9: Preparation of (1-(4-(2-Methoxyquinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 9)

Chem.

[0134] 11H 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). MS-ESI: 272.3 [M + H] + .

[0135]

Chem.

[0136] 1 1H 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 = 16.0 Hz, 2H), 1.78 - 1.60 (m, 1H), 1.31 - 1.17 (m, 2H). MS-ESI: 350.4 [M + H] + .

[0137] Example 10: Preparation of 3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinolin-2-ol (Compound 10)

Chem.

[0138] 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). MS-ESI: 336.4 [M+H] + 。

[0139] Example 11: Preparation of (1-(4-(quinolin-3-yl-2-d)pyrimidin-2-yl)piperidin-4-yl)methylamine (Compound 11)

Chemical formula

[0140] 1 H 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). MS-ESI: 243.2 [M+H] + 。

[0141]

Chem.

[0142] 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 = 4.0 Hz, 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). MS-ESI: 321.3 [M+H] + 。

[0143] Example 12: Preparation of (1-(4-(quinolin-3-yl)pyridin-2-yl)piperidin-4-yl)methylamine (Compound 12)

Chem.

[0144] 11H 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 = 8.0 Hz, 1H). MS-ESI: 241.2 [M+H] + 。

[0145]

Chem.

[0146] 1 1H 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 = 4.0 Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H), 1.75 - 1.65 (m, 1H), 1.26 - 1.14 (m, 2H). MS-ESI: 319.3 [M+H] + 。

[0147] Example 13: Preparation of 2-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin- 4-yl)-4H-benzo[b]pyran-4-one (Compound 13)

Chem.

[0148] MS-ESI: 351.2[M+H] + 。

[0149] ((1-(4-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamic acid tert-butyl

Chemical formula

[0150] 1 H NMR(400MHz,CDCl3)δ 8.21(dd,J=8.0,0.6Hz,1H),6.35(d,J=4.0Hz,1H),4.79(d,J=16.0Hz,2H),4.65(s,1H),4.54(d,J=4.0Hz,2H),3.73 - 3.71(m,1H),3.05 - 3.02(m,2H),2.86(t,J=12.0,7.6Hz,2H),1.79 - 1.75(m,2H),1.45(s,9H),1.18(dd,J=12.2,3.8Hz,2H). MS-ESI: 323.4 [M+H] + 。

[0151] ((1-(4-Formylpyrimidin-2-yl)piperidin-4-yl)methyl)carbamic acid tert-butyl

Chem.

[0152] 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). MS-ESI: 321.6 [M+H] + 。

[0153] ((1-(4-(1-Hydroxy-3-(2-hydroxyphenyl)-3-oxopropyl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamic acid tert-butyl

Chem.

[0154] MS-ESI: 457.5[M+H] + 。

[0155] ((1-(4-(4-Oxo-4H-chromen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamic acid tert-butyl

Chemical Structure

[0156] 1 H NMR(400MHz,CDCl3)δ 8.41(d,J=4.0Hz,1H),7.82 - 7.79(m,1H),7.71 - 7.67(m,1H),7.32(d,J=8.0Hz,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). MS-ESI: 437.4 [M + H] + .

[0157]

Chem.

[0158] 1 H NMR (400 MHz, CD3OD) δ 8.44 (d, J = 4.0 Hz, 1H), 7.81 (t, J = 7.4 Hz, 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). MS-ESI: 337.3 [M + H] + .

[0159] Example 14: Preparation of (1-(6-(quinolin-3-yl)pyridin-2-yl)piperidin-4-yl)methylamine (Compound 14)

Chem.

[0160] 1 1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.33 (m, 1H), 6.77 (d, J = 12.0 Hz, 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).

[0161]

Chemical Structure

[0162] 11H 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 = 4.0 Hz, 3H), 1.95 - 1.85 (d, J = 11.3 Hz, 3H), 1.33 - 1.14 (m, 2H). MS-ESI: 319.3 [M+H] + 。

[0163] Example 15: Preparation of (1-(3-(quinolin-3-yl)phenyl)piperidin-4-yl)methylamine (Compound 15)

Chem.

[0164] 1 1H 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).

[0165]

Chem.

[0166] 1 1H 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).

[0167] Example 16: Preparation of 3-(2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)quinolin-2-amine (Compound 16)

Chemical Structure

[0168] 1 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 4.0 Hz, 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). MS-ESI: 257.3 [M+H] + .

[0169] [Chemical formula] The synthesis of Compound 16 was the same as that of Compound 1 in Example 1, except that 3-(2-chloropyrimidin-4-yl)quinolin-2-amine was used to replace 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 82%.

[0170] 1 1H 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, 4.0 Hz, 2H). MS-ESI: 335.4 [M+H] + .

[0171] Example 17: Preparation of 1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-amine (Compound 17) [Chemical formula] The synthesis of Compound 17 was the same as that of Compound 1 in Example 1, except that piperidin-4-amine was used to replace piperidin-4-ylmethylamine in Example 1. The yield was 65%.

[0172] 1 1H 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 = 4.0 Hz, 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). MS-ESI: 306.3 [M + H] + 。

[0173] Example 18: Preparation of 3-(2-(Piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 18)

Chem.

[0174] MS-ESI: 392.2 [M + H] + 。

[0175]

Chem.

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 4.0 Hz, 1H), 9.15 (d, J = 4.0 Hz, 1H), 8.60 (d, J = 8.0 Hz, 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). MS-ESI: 292.2 [M+H] + 。

[0177] Example 19: Preparation of 2-(1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)ethylamine (Compound 19)

Chemical Structure

[0178] 11H 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 = 12.0 Hz, 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). MS-ESI: 334.2 [M+H] + .

[0179] Example 20: Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin -4-yl)methanol (Compound 20) [Chemical formula] The synthesis of Compound 20 was the same as that of Compound 1 in Example 1, except that piperidin-4-ylmethylamine in Example 1 was replaced by piperidin-4-ylmethanol. The yield was 83%.

[0180] 1 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). MS-ESI: 321.2 [M+H] + .

[0181] Example 21: Preparation of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)ethanol (Compound 21)

Chem.

[0182] 1 H 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 = 8.0 Hz, 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). MS-ESI: 335.3 [M+H] + 。

[0183] Example 22: Preparation of 3-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 22)

Chem.

[0184] 11H 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 = 5.2 Hz, 1H), 4.72 (d, J = 12.4 Hz, 2H), 2.81 - 2.74 (m, 2H), 2.45 (t, J = 12.0 Hz, 2H), 1.09 (s, 3H), 1.07 (s, 3H). MS-ESI: 320.2 [M+H] + 。

[0185] Example 23: Preparation of 3-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 23)

Chem.

[0186] 1 1H NMR (400 MHz, CD3OD) δ 9.56 (d, J = 4.0 Hz, 1H), 9.05 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.86 - 3.79 (m, 4H), 2.41 - 2.34 (m, 4H), 2.20 (s, 3H). MS-ESI: 306.4 [M+H] + 。

[0187] Example 24: Preparation of 3-(2-(1,4-diazepan-1-yl)pyrimidin-4-yl)quinoline (Compound 24)

Chem.

[0188] MS-ESI: 406.3 [M+H] + .

[0189] [ka] The synthesis of compound 24 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)-1,4-diazane-1-carboxylate was substituted for tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 84%.

[0190] 1 H NMR(400MHz,CDCl3)δ 9.59(d,J=4.0Hz,1H),8.75(d,J=4.0Hz,1H),8.45(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.82-7.74(m,1H) ),7.60(t,J=8.0Hz,1H),7.07(d,J=8.0Hz,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). MS-ESI: 306.2 [M+H] + .

[0191] Example 25: Preparation of 3-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)quinoline (Compound 25) [ka] Except for replacing piperidin-4-ylmethylamine in Example 1 with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the synthesis of tert-butyl 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)piperidin-4-yl)methylamine in Example 1. The yield was 41%.

[0192] MS-ESI: 418.2 [M+H] + .

[0193] [ka] The synthesis of compound 25 was the same as that of compound 18 in Example 18, except that tert-butyl 8-(4-(quinolin-3-yl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was substituted for tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 63%.

[0194] 1 H NMR(400MHz,CDCl3)δ 9.56(d,J=4.0Hz,1H),8.76(d,J=4.0Hz,1H),8.46(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.78(t,J= 8.0Hz,1H), 7.61(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),3.22(d,J=12.0Hz,2H),2.84(d,J=12.0Hz,2H),2.20-1.99(m,6H). MS-ESI: 318.2 [M+H] + .

[0195] Example 26: Preparation of N-(4-(quinolin-3-yl)pyrimidin-2-yl)ethane-1,2-diamine (Compound 26) [Chemical formula] (2-((4-(Quinolin-3-yl)pyrimidin-2-yl)amino)ethyl)carbamic acid tert-butyl was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1, except that piperidin-4-ylmethylamine in Example 1 was replaced with (2-aminoethyl)carbamic acid tert-butyl. The yield was 64%.

[0196] MS-ESI: 366.2 [M+H] + 。

[0197] [Chemical formula] (2-((4-(Quinolin-3-yl)pyrimidin-2-yl)amino)ethyl)carbamic acid tert-butyl was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18 was replaced with (2-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)ethyl)carbamic acid tert-butyl. The yield was 79%.

[0198] 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.78 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 12.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 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). MS-ESI: 266.2 [M+H] + 。

[0199] Example 27: Preparation of N-(4-(quinolin-3-yl)pyrimidin-2-yl)propane-1,3-diamine (Compound 27) [Chemical formula] Except for replacing piperidin-4-ylmethylamine in Example 1 with tert-butyl (2-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)propyl)carbamate, the synthesis of tert-butyl (2-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1 was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine in Example 1. The yield was 50%.

[0200] MS-ESI: 380.2 [M+H] + .

[0201] [ka] The synthesis of compound 27 was the same as that of compound 18 in Example 18, except that tert-butyl (2-((4-(quinolin-3-yl)pyrimidin-2-yl)amino)propyl)carbamate was used to replace tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 98%.

[0202] 1 H NMR(400MHz,CDCl3)δ 9.54(s,1H),8.78(d,J=4.0Hz,1H),8.41(d,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.81-7.75(m,1H),7.60( t,J=8.0Hz,1H),7.11(d,J=4.0Hz,1H),5.68(s,1H),3.67-3.62(m,2H),2.88(t,J=8.0Hz,2H),1.82(p,J=8.0Hz,2H),1.41(s,2H). MS-ESI: 280.3 [M+H] + .

[0203] Example 28: Preparation of 7-(2-(piperazin-1-yl)pyrimidin-4-yl)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridine (Compound 28)

Chem.

[0204] 1 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 5.2 Hz, 1H), 6.52 (d, J = 5.2 Hz, 1H), 3.85 - 3.72 (m, 4H), 3.52 - 3.41 (m, 4H), 1.48 (s, 9H).

[0205] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)2,3-dihydro-[1,4]dioxine[2,3-b]pyridine

Chem.

[0206] 11H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.26 (s, 1H), 4.48 - 4.41 (m, 2H), 4.27 - 4.20 (m, 2H), 1.33 (s, 12H). MS-ESI: 264.4 [M+H] + .

[0207] tert-Butyl 4-(4-(2,3-dihydro-[1,4]dioxo[2,3-b]pyridin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chem.

[0208] 1 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 5.2 Hz, 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). MS-ESI: 400.5 [M+H] + .

[0209]

Chem.

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 5.2 Hz, 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).

[0211] Example 29: Preparation of 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperazin-1-yl)pyrimidine (Compound 29)

Chemical Structure

[0212] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 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). MS-ESI: 399.5 [M+H] + 。

[0213]

Chem.

[0214] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 2.2 Hz, 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). MS-ESI: 299.5 [M+H] + 。

[0215] Example 30: Preparation of 4-(5,6-dimethoxy-pyridin-3-yl)-2-piperazin-1-yl-pyrimidine (Compound 30)

Chem.

[0216] 1 1H 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). MS-ESI: 266.4 [M+H] + .

[0217] tert-Butyl 4-[4-(5,6-dimethoxy-pyridin-3-yl)-pyrimidin-2-yl]-piperazine-1-carboxylate [Chemical formula] The synthesis of tert-butyl 4-[4-(5,6-dimethoxy-pyridin-3-yl)-pyrimidin-2-yl]-piperazine-1-carboxylate was the same as that of tert-butyl 4-(4-(2,3-dihydro-[1,4] dioxo[2,3-b]pyridin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 28, except that 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was used to replace 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine. The yield was 54%.

[0218] 1 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 5.2 Hz, 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). MS-ESI: 402.5 [M+H] + .

[0219] [Chemical formula] The synthesis of compound 30 was the same as that of compound 18 in Example 18, except that tert-butyl 4-[4-(quinolin-3-yl)pyrimidin-2-yl]piperazine-1-carboxylate in Example 18 was replaced by tert-butyl 4-[4-(5,6-dimethoxypyridin-3-yl)pyrimidin-2-yl]piperazine-1-carboxylate. The yield was 40%.

[0220] 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). MS-ESI: 302.4 [M+H] + 。

[0221] Example 31: Preparation of 4-(3,4-dimethoxyphenyl)-2-piperazin-1-yl-pyrimidine (Compound 31)

Chemical formula

[0222] 11H 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). MS-ESI: 401.5 [M+H] + .

[0223]

Chem.

[0224] 1 1H 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). MS-ESI: 301.5 [M+H] + .

[0225] Example 32: Preparation of 3-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indole (Compound 32)

Chem.

[0226] 1 H NMR (400 MHz, CDCl3) δ 8.40 - 8.36 (m, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.19 (s, 2H), 7.39 - 7.5 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 3.93 (t, J = 8.0 Hz, 4H), 3.57 (t, J = 8.0 Hz, 4H), 1.71 (s, 9H), 1.51 (s, 9H). MS-ESI: 480.6 [M+H] + 。

[0227] tert-butyl 3-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indole-1-carboxylate

Chemical Structure

[0228] 11H NMR (400 MHz, CDCl3) δ 8.39 - 8.36 (m, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 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). MS-ESI: 380.5 [M+H] + 。

[0229]

Chem.

[0230] 1 1H 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). MS-ESI: 280.5 [M+H] + 。

[0231] Example 33: Preparation of 4-(Benzofuran-3-yl)-2-(piperazin-1-yl)pyrimidine (Compound 33)

Chem.

[0232] 1 H NMR(400MHz,CDCl3)δ 8.36(d,J=5.1Hz,1H),8.23(q,J=4.3,3.4Hz,2H),7.67-7.50(m,1H),7.43-7.30(m,2H ),6.89(d,J=5.1Hz,1H),4.01-3.85(m,4H),3.57(dd,J=6.5,4.0Hz,4H),1.50(s,9H). MS-ESI: 381.5 [M+H] + .

[0233] [ka] The synthesis of compound 33 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-(benzofuran-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate was replaced with tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 86%.

[0234] 1 H NMR(400MHz,CDCl3)δ 8.35(d,J=5.1Hz,1H),8.24(d,J=10.3Hz,2H),7.65-7.50(m,1H),7.43-7.31( m,2H),6.86(d,J=5.1Hz,1H),3.98-3.89(m,4H),3.01(dd,J=6.0,4.2Hz,4H). MS-ESI: 281.4 [M+H] + .

[0235] Example 34: Preparation of 3-methoxy-5-(2-piperazin-1-yl-pyrimidin-4-yl) )-pyridin-2-ol (Compound 34)

Chemical formula

[0236] 1 H NMR (400 MHz, DMSO) δ 8.31 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 2.2 Hz, 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). MS-ESI: 288.4 [M+H] + .

[0237] Example 35: Preparation of 3-(4-(piperazin-1-yl)-1,3,5-triazin-2-yl)quinoline (Compound 35)

Chemical formula

[0238] MS-ESI: 300.3 [M+H] + .

[0239] tert-Butyl 4-(4-(quinolin-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate [Chemical formula] The synthesis of tert-butyl 4-(4-(quinolin-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1, except that tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate was used instead of quinoline-3-boronic acid in Example 1. The yield was 42%.

[0240] 1 H NMR (400 MHz, CDCl3) δ 9.92 (d, J = 4.0 Hz, 1H), 9.25 (d, J = 4.0 Hz, 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). MS-ESI: 393.4 [M+H] + .

[0241] [Chemical formula] The synthesis of Compound 35 was the same as that of Compound 18 in Example 18, except that tert-butyl 4-(4-(quinolin-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate was used to replace tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 72%.

[0242] 11H 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). MS-ESI: 293.4 [M+H] + 。

[0243] Example 36: Preparation of 2-(Piperazin-1-yl)-4-(quinolin-3-yl)quinazoline (Compound 36)

Chemical formula

[0244] 1 1H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 4.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 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). MS-ESI: 292.4 [M+H] + 。

[0245] tert-Butyl 4-(4-(quinolin-3-yl)quinazolin-2-yl)piperazine-1-carboxylate

Chemical formula

[0246] 1 H NMR(400MHz,CDCl3)δ 9.30(d,J=2.0Hz,1H),8.54(d,J=2.0Hz,1H),8.22(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,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). MS-ESI: 442.5 [M+H] + .

[0247] [ka] The synthesis of compound 36 was the same as that of compound 18 in Example 18, except that compound 4-(4-(quinolin-3-yl)quinazolin-2-yl)piperazine-1-carboxylate tert-butyl was used instead of 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl in Example 18. The yield was 82%.

[0248] 1 H NMR(400MHz,DMSO-d6)δ 9.23(d,J=4.0Hz,1H),8.80(d,J=2.0Hz,1H),8.20-8.13(m,2H),7.95-7.85(m,2H),7.80-7.7 0(m,2H),7.62(d,J=8.0Hz,1H),7.28(t,J=8.0Hz,1H),3.96-3.84(m,4H),2.92-2.81(m,4H). MS-ESI: 342.3 [M+H] + .

[0249] Example 37: Preparation of 2-(Piperazin-1-yl)-4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazoline (Compound 37)

Chem.

[0250] 1 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 2.81 (t, J = 8.0 Hz, 2H), 2.00 - 1.87 (m, 2H), 1.82 - 1.69 (m, 2H). MS-ESI: 296.4 [M+H] + 。

[0251] 4-(4-(Quinolin-3-yl)-5,6,7,8-tetrahydroquinazolin-2- yl)piperazine-1-carboxylic acid tert-butyl

Chem.

[0252] 1 H NMR(400MHz,CDCl3)δ 9.14(d,J=4.0Hz,1H),8.33(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,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=8.0Hz,2H),2.70(t,J=8.0Hz,2H),1.95-1.83(m,2H),1.79-1.67(m,2H),1.48(s,9H). MS-ESI: 446.6 [M+H] + .

[0253] [ka] The synthesis of compound 37 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-(quinolin-3-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine-1-carboxylate was replaced with tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 73%.

[0254] 11H 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 = 8.0 Hz, 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). MS-ESI: 346.5 [M+H] + 。

[0255] Example 38: Preparation of 3-(5-amino-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 38)

Chemical formula

[0256] 1 1H NMR (400 MHz, CDCl3) δ 9.19 (d, J = 2.2 Hz, 1H), 8.76 (d, J = 2.2 Hz, 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). MS-ESI: 257.3 [M+H] + 。

[0257] tert-Butyl 4-(5-amino-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical formula

[0258] 1 H NMR(400MHz,DMSO-d6)δ 9.36(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,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). MS-ESI: 407.4 [M+H] + .

[0259] [ka] The synthesis of compound 38 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(5-amino-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate was substituted for tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 63%.

[0260] 1 H NMR(400MHz,DMSO)δ 9.32(d,J=2.2Hz,1H),8.82(d,J=2.2Hz,1H),8.18(s,1H),8.09-8.03(m,2H),7.81(t,J=7. 6Hz,1H), 7.66(t,J=7.6Hz,1H),4.80(s,2H),3.59(t,J=5.0Hz,4H),2.82(t,J=5.0Hz,4H). MS-ESI: 307.4 [M+H] + 。

[0261] Example 39: Preparation of 3-(6-Methoxy-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 39)

Chem.

[0262] 1 1H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 2.4 Hz, 1H), 8.90 (d, J = 2.4 Hz, 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). MS-ESI: 272.3 [M+H] + 。

[0263] tert-Butyl 4-(4-Methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chem.

[0264] 1 H NMR(400MHz,DMSO-d6)δ 9.58(d,J=2.2Hz,1H),9.07(d,J=2.2Hz,1H),8.12(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.90-7.78(m, 1H),7.68(t,J=7.4Hz,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). MS-ESI: 422.5 [M+H] + .

[0265] [ka] The synthesis of compound 39 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate was replaced with tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18. The yield was 60%.

[0266] 1 H NMR(400MHz,DMSO)δ 9.56(d,J=2.2Hz,1H),9.04(d,J=2.2Hz,1H),8.12(d,J=8.4Hz,1H),8.07(d,J=8.4Hz,1H),7.82(t,J=8. 4Hz,1H), 7.67(t,J=8.4Hz,1H),6.87(s,1H),3.92(s,3H),3.82(t,J=5.0Hz,4H),2.81(t,J=5.0Hz,4H). MS-ESI: 322.5 [M+H] + .

[0267] Example 40: Preparation of 3-(2-(Piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)quinoline (Compound 40)

Chem.

[0268] 1 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).

[0269] tert-Butyl 4-(4-(quinolin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate

Chem.

[0270] 11H 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).

[0271]

Chem.

[0272] 1 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). MS-ESI: 360.3 [M + H] + .

[0273] Example 41: Preparation of 3-(5-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-7-yl)quinoline (Compound 41)

Chem.

[0274] 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).

[0275] tert-Butyl 3-(7-(quinolin-3-yl)imidazo[1,2-c]pyrimidin-5-yl)piperazine-1-carboxylate

Chemical formula

[0276] 11H 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).

[0277]

Chem.

[0278] 1 1H NMR (400 MHz, DMSO) δ 9.68 (d, J = 2.0 Hz, 1H), 9.07 (d, J = 2.0 Hz, 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). MS-ESI: 331.5 [M + H] + .

[0279] Example 42: Preparation of 3-(6-cyano-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 42)

Chem.

[0280] 1 1H 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). MS-ESI: 224.3 [M-100] + 。

[0281] tert-Butyl 4-(4-cyano-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical Structure

[0282] 1 1H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 1.8 Hz, 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). MS-ESI: 417.5 [M+H] + 。

[0283]

Chem.

[0284] 1 H NMR(400MHz, DMSO-d6) δ 9.62(d, J = 2.0Hz, 1H), 9.19(s, 1H), 8.13(d, J = 8.2Hz, 1H), 8.10(d, J = 8.4Hz, 1H), 7.99(s, 1H), 7.88(t, J = 7.4Hz, 1H), 7.71(t, J = 7.4Hz, 1H), 3.87 - 3.75(m, 4H), 2.88 - 2.76(m, 4H). MS-ESI: 317.4[M + H] + 。

[0285] Example 43: Preparation of 3-(5-methoxy-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 43)

Chem.

[0286] 11H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 2.2 Hz, 1H), 8.95 (d, J = 1.8 Hz, 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). MS-ESI: 272.3 [M+H] + 。

[0287] tert-Butyl 4-(5-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chem.

[0288] 1 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). MS-ESI: 422.5 [M+H] + 。

[0289]

Chem.

[0290] 1 H NMR(400MHz,DMSO-d6)δ 9.48(d,J=2.2Hz,1H),8.96(d,J=1.8Hz,1H),8.44(s,1H),8.11(d,J=7.8Hz,1H),8.06(d,J=8.4H z,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). MS-ESI: 322.5 [M+H] + .

[0291] Example 44: Preparation of 3-(6-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 44) [ka] Except for replacing 2,4-dichloropyrimidine with 4,6-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. The yield was 60%.

[0292] 1 H NMR(400MHz,DMSO-d6)δ 9.68(d,J=4.0Hz,1H),9.27(d,J=4.0Hz,1H),9.20(d,J=4.0Hz,1H),8.58(d,J= 2.0Hz, 1H), 8.13 (dd, J=20.0, 8.0Hz, 2H), 7.94-7.86 (m, 1H), 7.77-7.69 (m, 1H). MS-ESI: 242.4 [M+H] + .

[0293] tert-Butyl 4-(6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Chem.

[0294] 1 H NMR(400MHz,DMSO-d6)δ 9.64(d,J=2.0Hz,1H),9.12(d,J=2.0Hz,1H),8.68(s,1H),8.10(t,J=8.0Hz,2H),7.84(t,J=8.0Hz,1H),7.69(t,J=8.0Hz,1H),7.60(s,1H),3.82-3.75(m,4H),3.50-3.44(m,4H),1.44(s,9H). MS-ESI:392.4[M+H] + 。

[0295]

Chem.

[0296] 11H 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). MS-ESI: 292.5 [M+H] + 。

[0297] Example 45: Preparation of 3-(9-methyl-2-(piperazin-1-yl)-9H-purin-6-yl)quinoline (Compound 45)

Chem.

[0298] 1 1H NMR (400 MHz, 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). MS-ESI: 296.3 [M+H] + 。

[0299] tert-Butyl 4-(9-methyl-6-(quinolin-3-yl)-9H-purin-2-yl)piperazine-1-carboxylate

Chem.

[0300] 1 H NMR(400MHz,DMSO-d6)δ 10.14(d,J=2.1Hz,1H),9.67(d,J=2.2Hz,1H),8.29(s,1H),8.18(d,J=8.0Hz,1H),8.10(d,J=8.8Hz,1H),7.86(t,J=8.6Hz,1H),7.70(t,J=8.0Hz,1H),3.96-3.89(m,4H),3.73(s,3H),3.55-3.47(m,4H). MS-ESI:446.5[M+H] + 。

[0301]

Chemical formula

[0302] 11H 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 = 5.0 Hz, 4H), 3.72 (s, 3H), 2.86 (t, J = 5.0 Hz, 4H). MS-ESI: 346.4 [M+H] + 。

[0303] Example 46: Preparation of 3-(5-Fluoro-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 46)

Chemical Structure

[0304] MS-ESI: 260.7 [M+H] + 。

[0305] tert-Butyl 4-(5-fluoro-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical Structure

[0306] 1 H 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). MS-ESI: 410.5 [M+H] + 。

[0307]

Chem.

[0308] 1H NMR(400MHz,DMSO-d6)δ 9.46(s,1H),8.97(s,1H),8.59(d,J=4.0Hz,1H),8.18(d,J=8.0Hz,1H),8.10(d,J= 8.0Hz, 1H), 7.92-7.84 (m, 1H), 7.70 (m, 1H), 3.77-3.70 (m, 4H), 2.84-2.76 (m, 4H). MS-ESI: 310.4 [M+H] + .

[0309] Example 47: Preparation of 2-(piperazin-1-yl)-6-(quinolin-3-yl)pyrimidin-4-amine (Compound 47) [ka] Compound 4-(4-amino-6-chloropyrimidin-2-yl)piperazine-1-carboxylate tert-butyl (395 mg, 1.26 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (254 mg, 2.52 mmol) was added. Di-tert-butyl dicarbonate (412 mg, 1.89 mmol) was slowly added dropwise in an ice bath, and after the addition was completed, the temperature was gradually raised to room temperature and reacted. After reacting for 1 hour, TLC monitoring showed that there was almost no reaction, so DMAP (40 mg, 0.33 mmol) was added and the reaction continued at room temperature. TLC monitoring showed that the reaction was almost complete. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 487 mg of the desired product was obtained, with a yield of 93%.

[0310] 1 H NMR (400MHz, 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).

[0311] 4-(4-((tert-butoxycarbonyl)amino)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl [ka] 4-(4-((tert-Butoxycarbonyl)amino)-6-chloropyrimidin-2 -yl)piperazine-1-carboxylic acid tert-butyl, except that 2,4-dichloropyrimidine in Example 1 was replaced with 4-(4-((tert-butoxycarbonyl)amino)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl and ethanol was replaced with 1,4-dioxane, the synthesis of 4-(4-((tert-butoxycarbonyl)amino)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl was the same as that of 3-(2-chloropyrimidin-4-yl)quinoline in Example 1. The yield was 92%.

[0312] 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).

[0313]

Chemical Structure

[0314] 11H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 2.0 Hz, 1H), 8.86 (d, J = 2.0 Hz, 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). MS-ESI: 307.4 [M+H] + .

[0315] Example 48: Preparation of 6-(Piperazin-1-yl)-2-(quinolin-3-yl)pyrimidin-4-amine (Compound 48)

Chem.

[0316] 1 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 1H), 3.56 - 3.48 (m, 8H), 1.48 (s, 9H).

[0317] tert-Butyl 4-(6-amino-2-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Chem.

[0318] 1 H NMR (400 MHz, CDCl3) δ 9.84 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 12.0 Hz, 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).

[0319]

Chemical formula

[0320] MS-ESI: 307.3 [M + H] + .

[0321] Example 49: Preparation of 4-(2-(piperazin-1-yl)-6-(quinolin-3-yl)pyrimidin-4-yl)morpholine (Compound 49)

Chemical formula

[0322] 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). MS-ESI: 384.4 [M+H] + 。

[0323] tert-Butyl 4-(4-morpholino-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chem.

[0324] 11H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 1.6 Hz, 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). MS-ESI: 477.5 [M+H] + 。

[0325]

Chem.

[0326] 1 1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 2.1 Hz, 1H), 9.03 (d, J = 1.8 Hz, 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). MS-ESI: 377.5 [M+H] + 。

[0327] Example 50: Preparation of 3-(5-cyclopropyl-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 50)

Chem.

[0328] 1 H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 1.7 Hz, 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). MS-ESI: 282.4 [M + H] + 。

[0329] tert-Butyl 4-(5-cyclopropyl-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical formula

[0330] 11H NMR (400 MHz, CDCl3) δ 9.37 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.8 Hz, 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).

[0331] [Chemical formula] The synthesis of compound 50 was the same as that of compound 18 in Example 18, except that tert-butyl 4-(4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate in Example 18 was replaced by tert-butyl 4-(5-cyclopropyl-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate. The yield was 81%.

[0332] 1 1H 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). MS-ESI: 331.4 [M+H] + .

[0333] Example 51: Preparation of 3-(6-(4-methoxyphenyl)-2-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 51) [Chemical formula] 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, except that 2,4-dichloropyrimidine in Example 1 was replaced by 2,4-dichloro-6-(4-methoxyphenyl)pyrimidine. The yield was 88%.

[0334] 1 H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 4.0 Hz, 1H), 8.99 (d, J = 4.0 Hz, 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). MS-ESI: 348.4 [M + H] + 。

[0335] tert-Butyl 4-(4-(4-methoxyphenyl)-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical formula

[0336] 11H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 4.0 Hz, 1H), 8.84 (d, J = 4.0 Hz, 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). MS - ESI: 498.4 [M + H] + 。

[0337]

Chem.

[0338] 1 1H NMR (400 MHz, DMSO-d6) δ 9.73 (d, J = 4.0 Hz, 1H), 9.23 (d, J = 4.0 Hz, 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 = 8.0 Hz, 2H), 3.96 - 3.87 (m, 4H), 3.86 (s, 3H), 2.89 - 2.82 (m, 4H), 1.23 (s, 1H). MS - ESI: 398.4 [M + H] + 。

[0339] Example 52: Preparation of 3-(1-methyl-6-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)quinoline (Compound 52)

Chem.

[0340] MS-ESI: 296.2 [M+H] + 。

[0341] tert-Butyl 4-(1-methyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate

Chemical formula

[0342] MS-ESI: 296.2 [M+H] + 。

[0343]

Chemical formula

[0344] 1 1H 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). MS-ESI: 346.4 [M+H] + 。

[0345] Example 53: Preparation of 3-(5-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)quinoline (Compound 53)

Chemical Structure

[0346] 1 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 4.0 Hz, 1H), 8.95 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 16.0, 4.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.66 - 7.62 (m, 1H), 2.53 (s, 3H). MS-ESI: 256.3 [M+H] + 。

[0347] tert-Butyl 4-(5-methyl-6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Chemical Structure

[0348] 1 H NMR(400MHz,CDCl3)δ 9.15(d,J=8.0Hz,1H),8.76(s,1H),8.44-8.43(m,1H),8.16(d,J=2.0Hz,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).

[0349]

Chemical Structure

[0350] 1 H NMR(400MHz,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=8.0Hz,1H),3.42-3.35(m,4H),2.85(t,J=8.0Hz,4H),2.27(s,3H). MS-ESI:306.3[M+H]+ .

[0351] Example 54: Detection of the Activity of a CTLA-4 Small Molecule Degrader (Protein-Protein Interaction Reporter System Detection Method, Preliminary Screening Based on the Expression Level of CTLA-4 Protein) HEK293 cells were seeded in a 96-well plate. After 24 hours, the LRBA and CTLA-4 reporter systems were co-transfected into the HEK293 cells. After another 24 hours, different compounds with final concentrations of 0.01, 0.033, 0.10, 0.33, 1.00, 3.33, 10.00, 33.33, and 100.00 μM, respectively, were added. Twenty-four hours after the addition of the drug, the cell culture medium was removed, and the cells were washed with ice-cold PBS. Then, the activity of the compounds was detected using a dual-luciferase assay kit, and the IC 50 was calculated based on the detection results.

[0352] For compounds with high activity (IC 50 <200 nM), the degradation effect on CTLA-4 protein was further detected by Western Blot.

[0353] IC 50 : Concentration of the compound that inhibits 50% of the activity of the reporter system IC 50 was divided into four levels according to its magnitude. ++++: IC 50 <200 nM, +++: IC 50 is 200 - 1000 nM, ++: IC 50 is 1000 - 2000 nM, +: IC 50 >2000 nM.

[0354] The IC 50 of the compounds of the present invention is as shown in Table 1 below.

Table 3

[0355] Example 55: In Vivo Activity Study Using a Transplanted Tumor Model (MC-38) 1. Cell culture: Mouse colon cancer MC-38 cells were cultured adherently in vitro. The culture conditions were as follows: 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin were added to RPMI-1640 medium, and the cells were cultured in a 5% CO2 incubator at 37°C. Subculture was performed at a normal frequency of 2 - 3 times per week. When the cell density reached 80% - 90% and the cell number reached the requirement, the cells were collected, counted, and the cell concentration was adjusted in preparation for inoculation.

[0356] 2. Animals: C57BL / 6 mice, female, 7 weeks old, body weight 18 - 20 g, 8 mice per group.

[0357] 3. Tumor inoculation: 0.02 mL (0.2×10 6 cells) of MC-38 cells were subcutaneously inoculated into the right dorsum of each mouse. On the 7th day after inoculation, the tumor volume of the animals was measured, and then random grouping was performed based on the tumor volume size to start administration.

[0358] 4. Experimental indicators: The experimental indicators were to examine whether tumor growth was inhibited, delayed, or cured. The tumor diameter was measured with calipers 2 - 3 times per week. The formula for calculating the tumor volume was V = 0.5a×b 2 , where a and b represent the major axis and minor axis of the tumor, respectively. The antitumor effect of the compound was expressed as TGI (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) was TGI (%) = [(1 - (average tumor volume at the end of administration in the treatment group - average tumor volume at the start of administration in the treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0359] 5. Animal experiment grouping, administration plan, and experimental results:

Table 4

[0360] In addition, all of the above examples are illustrative and are not intended to cover all possible embodiments included in the claims. Various modifications and changes can be made to the above examples without departing from the scope of the present disclosure. Similarly, each technical feature of the above examples can be combined without limitation to form another embodiment of the present invention that is not clearly described. Therefore, the above examples merely show some embodiments of the present invention and do not limit the protection scope of the present invention patent.

Claims

Claim 1 A compound or a pharmaceutically acceptable salt, solvate or isotopically labeled compound thereof, characterized by being selected from the following. 【Table 1】 Claim 2 A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate or isotopically labeled compound thereof according to Claim 1, and a pharmaceutically acceptable excipient. Claim 3 The form of the pharmaceutical composition is any one of an aqueous dispersant, liquid, jelly, syrup, elixir, slurry, suspension, aerosol, controlled release agent, rapidly dissolving agent, effervescent tablet, lyophilized preparation, tablet, powder, pill, sugar-coated tablet, capsule, delayed release preparation, sustained release preparation, pulse release agent, multi-particle preparation or immediate release preparation. The pharmaceutical composition according to Claim 2. Claim 4 Use of the compound or a pharmaceutically acceptable salt, solvate or isotopically labeled compound thereof according to Claim 1, or the pharmaceutical composition according to Claim 2 or 3, in the manufacture of a drug for treating CTLA-4 related diseases. Claim 5 The use according to Claim 4, wherein the CTLA-4 related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, and organ transplant rejection reactions. Claim 6 The cancer includes skin cancer, bladder cancer, breast cancer, pancreatic cancer, bone cancer, brain cancer, neuroblastoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, choriocarcinoma, pancreatic cancer, urinary tract cancer, brain tumor (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral primitive neuroectodermal tumor), 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 cancer, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma (including chondrosarcoma, histiocytic sarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, but not limited thereto), melanoma, hemangioma, keloid, squamous cell cancer, astrocytoma, lymphoma (including non-Hodgkin lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin disease, central nervous system lymphoma, but not limited thereto), respiratory system cancer (including lung cancer, but not limited thereto, e.g., small cell and non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma), head and neck cancer (including head cancer, neck cancer, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer and / or oropharyngeal cancer, lip cancer and oral cancer, but not limited thereto), bladder cancer, breast cancer (including invasive ductal carcinoma, invasive lobular carcinoma, non-invasive ductal carcinoma, non-invasive lobular carcinoma, but not limited thereto), gastrointestinal cancer (including anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, rectal cancer, gastric cancer, small intestine cancer, salivary gland cancer, but not limited thereto), thyroid cancer, parathyroid cancer and its distant metastatic foci, pancreatic cancer, liver cancer (including hepatocellular carcinoma, fibrolamellar or non-fibrolamellar hepatocellular carcinoma, cholangiocarcinoma, mixed type of hepatocellular carcinoma and cholangiocarcinoma, but not limited thereto), leukemia (including acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, but not limited thereto), brain cancer (including brainstem and pituitary glioblastoma, medulloblastoma, cerebellar and cerebral astrocytoma, ependymoma and primitive neuroectodermal tumor, pinealoma, but not limited thereto), genital cancer (prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer,The use according to claim 5, characterized in that it is selected from related cancers such as endometrial cancer, vaginal cancer and vulvar cancer, uterine sarcoma (including but not limited to these), urethral cancer, eye tumors (including but not limited to intraocular melanoma, retinoblastoma), skin cancer (including but not limited to Kaposi's sarcoma, squamous cell carcinoma, malignant melanoma, Merkel cell carcinoma, non-melanoma skin cancer), renal parenchymal cancer, kidney cancer (also called renal cell carcinoma and adrenal cancer).

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