Antiviral cyanuric chloride trisubstituted amine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of cyanuric chloride trisubstituted amine derivatives, and particularly relates to an antiviral cyanuric chloride trisubstituted amine derivative as well as a preparation method and application thereof. The structure of the cyanuric chloride trisubstituted amine derivative is as shown in a formula (I). The invention provides a brand new cyanuric chloride trisubstituted amine derivative which has a remarkable antiviral effect. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of tri-substituted amine derivatives of cyanuric chloride, and particularly relates to a tri-substituted amine derivative of cyanuric chloride, a preparation method and use thereof. Background Art

[0002] Through literature research, it was found that many antiviral drugs have triazine heterocyclic skeletons.

[0003] Triazines are six-membered conjugated carbon-nitrogen atom rings that are components of many pharmaceutically active substances with significant therapeutic effects. 1,3,5-triazine derivatives are reported to have a variety of biological activities and a wide range of industrial applications. The most widely studied triazine substance is 1,3,5-triazine, of which cyanuric acid chloride (2,4,6-trichloro-1,3,5-triazine, i.e., cyanuric chloride) is a very important and widely studied 1,3,5-triazine derivative. According to the different reactivity of the three chlorines of cyanuric chloride, the chlorine undergoes aromatic nucleophilic substitution with different nucleophiles to synthesize different types of compounds. The reaction characteristics of the three chlorines of cyanuric chloride with nucleophiles: the first substitution reaction is carried out at low temperature (below 0 degrees), the second substitution reaction is carried out at room temperature, and the third substitution reaction is carried out at 70-100°C. This property allows three different nucleophiles to react with the same 1,3,5-triazine core, providing a series of promising derivatives suitable for various applications. Literature survey shows that 1,3,5-triazine derivatives have multi-dimensional biological activities, such as anti-tuberculosis, anti-HIV and antiviral [1-3] , antimalarial, antitumor, antifungal, antimicrobial and herbicidal activities.

[0004] 3C protease (Picornain 3C) is a protease found in picornaviruses that can cleave peptide bonds in non-terminal sequences. 3CLpro is derived from 3C-like protease and usually exists in the form of dimers. The average molecular weight of the monomer is about 34.21 kDa. Each monomer of 3CLpro consists of three domains: domain I, domain II, and domain III. Domain III (Thr201-Val303) is a helical domain (containing five α-helices) and is the cause of 3CLpro dimerization. In addition, the enzymatic reaction activity of 3CLpro monomers is low, but the monomer usually exists in a transient state, while dimers are easier to form and have higher enzymatic reaction activity. Domain I (Phe8-Tyr101) and domain II (Lys102-Pro184) are the catalytic domains of 3CLpro and have an antiparallel β-barrel structure.

[0005] From the perspective of its mode of action, 3CLpro protease belongs to the cysteine ​​protease family and has a histidine 41-cysteine ​​145 catalytic dyad, which is used to cleave the peptide bond of substrates containing a Gln-(Ser / Ala / Gly) dipeptide structure. The imidazole group of the histidine side chain acts as a base, while the sulfhydryl group of the cysteine ​​side chain acts as a nucleophilic group to attack the amide bond of the substrate, ultimately leading to the sulfhydryl-catalyzed hydrolysis of the amide bond.

[0006] SARS-CoV-2 and SARS-CoV 3CLpro differ by only 12 amino acids, with a homology of more than 96%, and their structures are basically the same. The recognition site of 3CLpro depends on Gln at the P1 position. Since there is no protease with a similar cleavage site to 3CLpro in the human body, highly specific inhibitors can be screened; after the SARS-CoV-2 virus enters the cell, the nucleocapsid and the positive-strand RNA of the virus itself are released into the cytoplasm, and the open reading frames ORF1a and ORF1b of the positive-strand RNA are translated to produce non-structural proteins, which are cleaved by PLpro and Mpro / 3CLpro, and finally produce 16 non-structural proteins (NSP, non-structural proteins), of which 3CLpro cleavage produces 11 NSPs, so inhibiting 3CL can fundamentally inhibit the production of the virus. In summary, 3CL protease has become one of the most promising targets for the development of specific drugs against SARS-CoV-2.

[0007] Currently, Paxlovid developed by Pfizer is the world's first oral drug for 3CL protease. In order to inhibit the rapid metabolism of Paxlovid, it needs to be used in combination with ritonavir in clinical practice. With the emergence of viral immune escape, safer and more effective small molecule inhibitors still need to be explored and discovered.

[0008] References:

[0009] [1]RVPatel, P.Kumari, DPRajani, C.Pannecouque, E.deClercq, KHChikhalia, Future Med.Chem.2012,4,1053.

[0010] [2]PKPatel,D.Mahajan,C.Pannecouque,KHChikhalia,J.HeterocyclicChem.2014,51,1641.

[0011] [3]RVPatel,P.Kumari,DPRajani,KHChikhalia,Int.J.DrugDes.Dis.2012,3,739.

[0012] [4]Abe,K.et al.Sci Rep.2022;12(1):1299.

[0013] [5]Feng J, Li D, Zhang J, et al. BiochemBiophys Res Commun. 2022; 611:190-194.

[0014] [6]Zhang,L.et al.Science 2020,368,409-412. Summary of the invention

[0015] In order to solve the above problems of the prior art, the object of the present invention is to provide a tri-substituted amine derivative of cyanuric chloride, a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, so as to screen out compounds for use as antivirals having excellent properties in terms of effectiveness, safety and selectivity.

[0016] Another object of the present invention is to provide a method for preparing the derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer.

[0017] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0018] In a first aspect, the present invention provides a cyanuric chloride compound, and a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, wherein the cyanuric chloride compound has a formula (I):

[0019]

[0020] in:

[0021] R 1 Selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 alkyleneoxy-C1-C10 alkyl, substituted or unsubstituted C1-C10 alkylamino, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted C6-14 aryl, or substituted or unsubstituted C5-14 heteroaryl;

[0022] R ais selected from hydrogen, substituted or unsubstituted C1-10 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -C(=O)R 5 、-OC(=O)R 5 、-C(=O)OR 5 、-OR 5 、-SR 5 、-S(=O)R 5 、-S(=O) 2 R 5 、-S(=O) 2 N(R 5 ) 2 、-N(R 5 ) 2 、-C(=O)N(R 5 ) 2 、-NR 5 -C(=O)R 5 、-NR 5 -C(=O)OR 5 、-NR 5 -S(=O) 2 -R 5 、C(=O)-N(R 5 ) 2 、-C1-6 alkylene-N(R 5 ) 2 、-C1-6 alkylene-OR 5 、-C1-6 alkenylene-OR 5 and -O-C1-6 alkylene-N(R 5 ) 2 ; Among them, R 5 is H, guanidinyl, C1-C6 alkyl, saturated or partially unsaturated C 3-6 Cycloalkyl, saturated or partially unsaturated three- to ten-membered heterocyclic group or C6-10 aryl group;

[0023] R b is selected from hydrogen, substituted or unsubstituted C6-14 aryl, -NH-C1-6 alkylene-substituted or unsubstituted C6-14 aryl, -C1-6 alkylene-NH-substituted or unsubstituted C6-14 aryl;

[0024] R c is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C3-C7 oxacycloalkyl groups, substituted or unsubstituted C2-C8 olefin groups, substituted or unsubstituted C6-14 aryl groups, halogenated C1-10 aliphatic hydrocarbon groups, -C1-6 alkylene groups, -NH-substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic groups, -NHCH 2 RC1 , R C1 A saturated lactam ring selected from five to seven members;

[0025] X is selected from CH or N atoms;

[0026] R d Selected from hydrogen, C1-6 alkyl, C1-6 alkylene-OH, C1-6 alkylene-C(O)N(R 7 ) 2 、C(O)NH-C1-6alkylene-C(O)N(R 7 ) 2 、-C(O)OR 7 、-C(O)N(R 7 ) 2 、-C(O)-N(R 7 )-five-seven-membered heterocyclic group or -C(O)-N(R 7 )-C1-6 alkylene-five to seven-membered heterocyclic group, wherein the five to seven-membered heterocyclic group is a substituted or unsubstituted saturated or partially unsaturated group, R 7 is H, C1-C6 alkyl, saturated or partially unsaturated C3-6 cycloalkyl, or C6-10 aryl; R d Substitution on any carbon atom in the six-membered ring except the N atom and the X atom;

[0027] The above-mentioned substitution or unsubstituted means that one or more H in the group is substituted by a group selected from halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or a combination of at least two or more groups, or means -CH 2 The two H in - are replaced by oxo=O.

[0028] In a preferred embodiment of the present invention,

[0029] R 1 Selected from C1-C3 alkyl, C3-C6 cycloalkyl;

[0030] R a is selected from hydrogen, C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)OCH 3 、-OR 6 、-SR 6、-S(=O)R 6 、-S(=O) 2 R 6 、-S(=O) 2 N(R 6 ) 2 、-N(R 6 ) 2 、-C(=O)N(R 6 ) 2 、-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S(=O) 2 -R 6 、C(=O)-N(R 6 ) 2 、-C1-6 alkylene-N(R 6 ) 2 、-C1-6 alkylene-OR 6 、-C1-6 alkenylene-OR 6 and -O-C1-6 alkylene-N(R 6 ) 2 ; Among them, R 6 is H, methyl;

[0031] R b is selected from substituted or unsubstituted phenyl, -CH 2 -NH-substituted or unsubstituted phenyl;

[0032] R c is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, halogenated C1-C3 alkyl, -C1-6 alkylene, -NH-substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -NHCH 2 R C1 , R C1 A saturated lactam ring selected from five to seven members;

[0033] R d Selected from hydrogen, C1-3 alkyl, C1-3 alkylene-OH, CH 2 C(O)NHR 9 、C(O)NH(CH 2 )C(O)NHR 9 、C(O)OR 9 、C(O)NHR 9 、-C(O)-NR 9 -5-7-membered heterocyclic group or -C(O)-NR 9-C1-6 alkylene-five to seven-membered heterocyclic group, wherein the five to seven-membered heterocyclic group is substituted or unsubstituted, saturated or partially unsaturated; R 9 is H, methyl;

[0034] The above substitution or unsubstitution means that one or more H in the group is substituted by a group selected from halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or a combination of at least two or more groups, or that -CH 2 The two H in - are replaced by oxo=O.

[0035] In a further preferred embodiment of the present invention,

[0036] R 1 Selected from methyl, ethyl, propyl;

[0037] R a is selected from hydrogen, methyl, hydroxymethyl, hydroxyethyl, methylformyl;

[0038] R b Selected from unsubstituted or substituted phenyl, -CH 2 -NH-unsubstituted or substituted phenyl, R c Selected from unsubstituted or substituted phenyl, chloromethyl, oxirane, C2 olefin, -CH 2 -NH-five- to seven-membered heterocyclic group, -NHCH 2 - a five-membered saturated lactam ring, wherein the substituted phenyl group refers to the phenyl group whose H is optionally substituted by 1 to 3 halogen, hydroxy, methoxy, methyl, ethyl, trifluoro, cyano or amino groups;

[0039] R d Selected from hydrogen, methyl, CH 2 OH, CH 2 C(O)NHCH 3 、C(O)NHCH 2 C(O)NH 2 、C(O)NHCH 2 CH 2 C(O)NH 2 、C(O)OH、C(O)NHCH 3 、C(O)-NH-R d1 or C(O)NH-CH 2 R d1 ; R d1 A five- to seven-membered heterocyclic group, wherein the heterocyclic group includes one heteroatom selected from oxygen, sulfur or nitrogen, and the oxygen, sulfur or nitrogen atom is at any position in the ring. The five- to seven-membered heterocyclic group may be saturated or partially saturated. When the heterocyclic atom is selected from nitrogen atom, the heterocycle is a saturated lactam structure.

[0040] In a further preferred embodiment of the present invention, the cyanuric chloride compound has a structure shown in formula (II) to (VI),

[0041]

[0042]

[0043] Among them, R c , R d and X have the same definition as in the above general formula (I),

[0044] R f It represents one or both of hydrogen, halogen, hydroxy, methoxy, methyl, ethyl, trifluoro, cyano or amino.

[0045] In a further preferred embodiment of the present invention, wherein

[0046] R c Selected from the following groups

[0047]

[0048] R d A group selected from methyl, hydroxymethyl, hydroxyethyl and the following

[0049]

[0050] * indicates the attachment site.

[0051] In a second aspect, the present invention provides the antiviral use of the above cyanuric chloride compounds, and pharmaceutically acceptable salts thereof, tautomers thereof or stereoisomers thereof. Preferably, the virus is infected by a coronavirus, a calicivirus or a picornavirus.

[0052] The present invention also provides the use of the above-mentioned cyanuric chloride compounds, and pharmaceutically acceptable salts thereof, tautomers thereof or stereoisomers thereof in the preparation of drugs for treating viral infections.

[0053] The present invention also provides a pharmaceutical composition, characterized in that it comprises the cyanuric chloride compound according to any one of claims 1 to 6, and a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient. DETAILED DESCRIPTION

[0054] The other elements of the present invention are described below in more detail.

[0055] definition

[0056] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0057] The terms "include," "comprises," "has," "contains," or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0058] As used herein, the so-called "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0059] As used herein, so-called "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the so-called "C 1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl") (e.g., CH 2 F. CHF 2 CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 The so-called "C1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0060] As used herein, the so-called "alkenyl" means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms ("C 2-6The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0061] As used herein, the so-called "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0062] As used herein, the so-called "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the so-called "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0063] As used herein, the so-called "cycloalkylene group", "cycloalkyl group" and "hydrocarbon ring" refer to a saturated (i.e., "cycloalkylene group" and "cycloalkyl group") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.

[0064] As used herein, the so-called "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered (sub)heterocyclyl" is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0065] As used herein, the so-called "(ylidene)aryl" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 6-10 "(E)aryl" and "C 6-10 The term "aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (benzene ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) substituted.

[0066] As used herein, so-called "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused. In particular, "heteroaryl" or "heteroaromatic ring" is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0067] As used herein, so-called "aralkyl" preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl may have 6-14 carbon atoms, the heteroaryl may have 5-14 ring atoms, and the alkyl may have 1-6 carbon atoms. Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0068] As a more specific explanation of the terms are as follows:

[0069] "Alkyl" refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be optionally substituted or unsubstituted.

[0070] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one CC is sp 2Double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, wherein specific examples include, but are not limited to, vinyl, allyl, butylene, etc. The alkenyl group can be optionally substituted or unsubstituted.

[0071] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.

[0072] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:

[0073]

[0074] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

[0075]

[0076] "Bridged cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

[0077]

[0078] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0079] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0080] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m The heteroatom of the ring is 1, the remaining ring atoms are carbon, and m=1 or 2. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to:

[0081]

[0082] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The so-called "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl group is C 6 -C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with heteroaryl, heterocyclic or cycloalkyl, wherein the aryl ring is connected to the parent structure, non-limiting examples include but are not limited to:

[0083]

[0084] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0085]

[0086] "Alkoxy" refers to a group of (alkyl-O-) wherein alkyl is as defined herein. 1 -C 6 Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0087] "Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0088] "Hydroxy" refers to an -OH group.

[0089] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0090] "Amino" refers to -NH 2 .

[0091] "Cyano" refers to -CN.

[0092] "Nitro" refers to -NO 2 .

[0093] "Benzyl" refers to -CH 2 -phenyl.

[0094] "Carboxy" refers to -C(O)OH.

[0095] "Acyl" refers to the acetyl group -C(O)CH 3 Type of group.

[0096] "Carboxylate" refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0097] As used herein, a so-called "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0098] As used herein, the so-called "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may also optionally contain one or more (e.g., one, two, three or four) selected from N, O, C=O, S, S=O and S(=O). 2 A ring member of which is connected to the rest of the molecule via a nitrogen atom in the nitrogen-containing heterocyclic ring and any remaining ring atoms, the nitrogen-containing heterocyclic ring is optionally benzo-fused, and is preferably connected to the rest of the molecule via a nitrogen atom in the nitrogen-containing heterocyclic ring and any carbon atom in the fused benzene ring.

[0099] By "substitution" is meant that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0100] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0101] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0102] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

[0103] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R b 、-OC(O)R b 、-NR b R b 、-C(O)NR b R b 、-NR b C(O)R b 、-S(O)NR b R b or -S(O) 2 NR b R b , where R b The definition of is as described in the general formula (I).

[0104] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0105] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0106] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g.35 S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotope-labeled reagents instead of the non-labeled reagents previously used. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .

[0107] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0108] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R b 、-OC(O)R b 、-NR b R b 、-C(O)NR b R b 、-NR b C(O)R b 、-S(O)NR b R b or -S(O) 2 NR b R b , where R bThe definition of is as described in the general formula (I).

[0109] As used herein, an "effective amount" of a compound refers to an amount sufficient to down-regulate or agonize a corresponding target.

[0110] As used herein, the "therapeutically effective dose" of a compound refers to an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease, or negatively regulate or excite a corresponding target. This dose can be used as a single dose or taken according to a regimen to be effective.

[0111] As used herein, "treating" means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.

[0112] As used herein, "amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, lasting or transitory, attributable to or associated with the administration of that composition.

[0113] The definitions and conventions used in this invention for stereochemistry are generally based on the following references:

[0114] SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present invention. Diastereomers can be separated into individual diastereomers based on their physical and chemical differences by methods such as chromatography, crystallization, distillation or sublimation. Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers. The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of rotation of the plane of polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different. Specific stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The so-called "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0115] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present invention.

[0116] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention which are safe and effective for use in humans or animals. Salts of compounds can be prepared by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, and pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).

[0117] In this article, solid lines (——), solid wedges Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0118] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0119] It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

[0120] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.

[0121] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0122] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.

[0123] For a review of suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0124] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form). The compounds of the present invention themselves may also be esters.

[0125] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0126] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750;

[0127] ARKatritzky and AJBoulton, Eds., Academic Press; and GWHCheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJBoulton, Eds., Academic Press.

[0128] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0129] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0130] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0131] The term "about" means within ±10% of the numerical value, preferably within ±5%, and more preferably within ±2%.

[0132] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0133] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition may also contain a small amount of wetting agent, emulsifier or pH buffer as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0134] Pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, local, in the form of ophthalmic preparations or by inhalation.

[0135] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0136] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0137] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, relieves to some extent one or more of the symptoms of the condition being treated.

[0138] The dosage regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0139] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For a 70kg person, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, the dosage level not higher than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0140] The content or dosage of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0141] As used herein, unless otherwise indicated, the terms "treating" and "treating" mean reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0142] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0143] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0144] Preferred compounds of the tri-substituted amine derivatives of cyanuric chloride of the present invention

[0145] The preferred compounds of the present invention are as follows:

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] Method for obtaining the compound of the present invention:

[0153] The compound represented by the general formula 1 of the present invention can be obtained by a known method, for example, by a known organic synthesis method. An exemplary synthesis route is given below, but those skilled in the art can also obtain it by other known methods.

[0154] Several feasible schemes for the synthesis of the compound are briefly described below:

[0155] Solution 1

[0156]

[0157] In the first step, the compound of general formula (I-1) is reacted with R 1 -NH 2 A substitution reaction occurs to obtain a compound of general formula (I-2);

[0158] In the second step, the compound of general formula (I-2) is reacted with R 2 -NH 2 Substitution reaction occurs to obtain a compound of general formula (IA);

[0159] In the third step, the compound of general formula (IA) is reacted with R 3a -NH 2 Substitution reaction or catalytic coupling reaction occurs to obtain a compound of general formula (IB);

[0160] The fourth step is to remove the Boc protection of the amino group of the compound of general formula (IB) under acidic conditions to obtain a compound of general formula (IC);

[0161] The fifth step is to subject the compound of the general formula (IC) to a condensation or substitution reaction under alkaline conditions to obtain a compound of the general formula (I);

[0162] Among them, R 1 , R 2 , R a , R b , R c and R d has the same definition as the above general formula (I), R 3a -NH 2 wherein X is selected from nitrogen atom.

[0163] Solution 2

[0164]

[0165] In the first step, the compound of general formula (IA) is reacted with R under alkaline conditions. 3b -NH 2 Substitution reaction or catalytic coupling reaction occurs to obtain a compound of general formula (I);

[0166] Among them, R 1 , R 2 , R a , R b , R c and R d has the same definition as the above general formula (I), R 3b -NH 2 Here, X is selected from a carbon atom or a nitrogen atom.

[0167] Option 3

[0168]

[0169] In the first step, the compound of general formula (IA) is reacted with R under alkaline conditions. 3c -NH 2 Substitution reaction or catalytic coupling reaction occurs to obtain a compound of general formula (ID);

[0170] In the second step, the ester group of the compound of general formula (ID) is hydrolyzed under alkaline conditions to obtain a compound of general formula (IE);

[0171] In the third step, the compound of general formula (IE) is subjected to condensation or substitution reaction under alkaline conditions to obtain a compound of general formula (IF)

[0172] Step 4: Deprotecting the Boc group of the compound of general formula (IF) under acidic conditions to obtain a compound of general formula (IC);

[0173] The fifth step is to subject the compound of the general formula (IC) to a condensation or substitution reaction under alkaline conditions to obtain a compound of the general formula (I);

[0174] Among them, R 1 , R 2 , R a , R b , R c and R d has the same definition as the above general formula (I), R 3b -NH 2 wherein X is selected from nitrogen atom.

[0175] Method 4:

[0176]

[0177] In the first step, the compound of general formula (IA) is reacted with R under alkaline conditions. 3d -NH 2 Substitution reaction occurs to obtain a compound of general formula (IC);

[0178] In the second step, the compound of general formula (IC) is subjected to condensation or substitution reaction under alkaline conditions to obtain a compound of general formula (I);

[0179] Among them, R 1 , R 2 , R a , R b , R c and R d has the same definition as the above general formula (I), R 3b -NH 2 wherein X is selected from nitrogen atom.

[0180] In the above preparation method, the reagent providing alkaline conditions is selected from organic bases or inorganic bases, the organic base is one or more of triethylamine, N,N-diisopropylethylamine, n-butyl lithium, diisopropyl lithium amide, bistrimethylsilyl lithium amide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic base is one or more of sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;

[0181] The reagent providing acidic conditions is one or more of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid;

[0182] The metal catalysts are palladium / carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl2 ), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex, bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 )Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) or more;

[0183] The ligand is one or more of 2-dicyclohexylphosphino-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (XantPhos), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (DavePhos), 1,1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP);

[0184] The condensing agent includes, but is not limited to, one or more of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazol L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBt) and 1-propylphosphoric anhydride (T3P).

[0185] The above reaction is preferably carried out in a solvent, and the solvent used is one or more of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.

[0186] Example

[0187] The method of the present invention is described below by means of specific embodiments to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0188] The mass spectrum was obtained by LC / MS using ESI as the ionization method.

[0189] HPLC model: Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrigeC18 (4.6*150mm, 3.5μm); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); flow rate: 1.0 mL / min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C.

[0190] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0191] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0192] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include but are not limited to Sinopharm Group, J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.

[0193] CD 3 OD: deuterated methanol

[0194] CDCl 3 : Deuterated chloroform

[0195] DMSO-d 6 : Deuterated dimethyl sulfoxide

[0196] Pd 2 (dba) 3 :Tris(dibenzylideneacetone)dipalladium

[0197] Pd(dppf)Cl 2 :[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0198] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0199] XPhos: 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0200] HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0201] DMAP: 4-dimethylaminopyridine

[0202] DMF: N, N-dimethylformamide

[0203] THF: Tetrahydrofuran

[0204] DIPEA: N, N-diisopropylethylamine

[0205] Boc: tert-butyl carbonate

[0206] Cbz: benzyl formate

[0207] DHP: 3,4-dihydro-2H-pyran

[0208] DIBAL: diisobutylaluminum hydride

[0209] TEA: triethylamine

[0210] NaBH 3 CN: Sodium cyanoborohydride

[0211] NaH: Sodium hydride

[0212] DCM: dichloromethane

[0213] PE: Petroleum ether

[0214] EA: Ethyl acetate

[0215] TLC: Thin layer chromatography

[0216] HPLC: High Performance Liquid Chromatography

[0217] purity

[0218] &:and

[0219] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0220] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0221] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.

[0222] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the system of eluent for column chromatography or the developing solvent system for thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.

[0223] Pharmaceutical Chemical Synthesis

[0224] Intermediate 1

[0225] 4-Aminomethylpyrrolidin-2-one hydrochloride IN-1

[0226]

[0227] Step 1 4-Hydroxymethyl-2-pyrrolidone IN-1b

[0228] 4-Hydroxymethyl-2-pyrrolidone IN-1a (14.83 g, 103.6 mmol) was dissolved in methanol (100 mL), cooled to 0°C, and sodium borohydride (7.87 g, 207.2 mmol) was added in batches. After addition, the temperature was raised to 25°C and the reaction was allowed to proceed for 16 h. TLC detected that the reaction was complete. The reaction solution was added with aqueous solution (10 mL), stirred for 10 minutes, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-1b (8.87 g, yield 74%) as a white solid.

[0229] LC-MS: m / z = 116.1 [M+H] +

[0230] Step 2 5-Oxopyrrolidin-3-yl)methyl 4-methylbenzenesulfonate IN-1c

[0231] Compound IN-1b (1.00 g, 8.7 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.14 g, 11.3 mmol), DMAP (0.11 g, 0.87 mmol) and p-toluenesulfonyl chloride (1.9 g, 9.6 mmol) were added in sequence, and the mixture was reacted at 25°C for 1 hour. The reaction was complete after TLC detection. Dilute hydrochloric acid (10 mL, 0.5 mol / L) solution was added to the reaction solution, stirred for 10 minutes, separated, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound IN-1c (1.70 g, yield 73%) as a white solid.

[0232] LC-MS: m / z = 270.1 [M+H] +

[0233] Step 3 4-azidomethylpyrrolidin-2-one IN-1d

[0234] Compound IN-1c (0.50 g, 1.9 mmol) was dissolved in DMF (5 mL), sodium azide (0.16 g, 2.4 mmol) was added, and the temperature was raised to 60°C for 4 hours. The reaction was complete after TLC. The reaction solution of the title compound IN-1d was directly used for the next step.

[0235] Step 4: Tert-butyl ((5-oxopyrrolidin-3-yl)methyl)carbamate IN-1e

[0236] The reaction solution of compound IN-1d was added with THF (8 mL) and H 2 O (1 mL), add triphenylphosphine (486 mg, 1.9 mmol), react at 25 ° C for 16 hours, and add (Boc) to the reaction solution 2 O (414 mg, 1.9 mmol), react at 25 ° C for 1 hour, TLC detection reaction is complete. Concentrate, add water (5 mL), extract with ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography to obtain the title compound IN-1e (280 mg, two-step yield 69%) as a white solid.

[0237] 1 H NMR (400 MHz, DMSO-d 6 )δ7.45(s,1H),6.98(t,J=4.4Hz,1H),3.25(t,J=8.4Hz,1H),2.96-2.90(m,3H),2.38-2.46(m,1H),2.19(dd,J 1 =9.2Hz,J 2 =16.8Hz,1H),1.87(dd,J 1 =6.0Hz,J 2 =16.4Hz,1H),1.38(s,9H).

[0238] Step 5: 4-aminomethylpyrrolidin-2-one hydrochloride IN-1

[0239] Add dioxane hydrochloride (2 mL) to a dichloromethane (1 mL) solution of compound IN-1e (150 mg, 0.70 mmol), react at 25°C for 1 hour, and the reaction is complete as determined by TLC. Filter, wash the filter cake with dichloromethane (1 mL), and dry to obtain the title compound IN-1 (100 mg, yield 95%) as a white solid.

[0240] Intermediate 2

[0241] 3-Amino-3-(2-chlorophenyl)propan-1-ol hydrochloride IN-2

[0242]

[0243] Step 1: 3-amino-3-(2-chlorophenyl)propionic acid IN-2b

[0244] o-Chlorobenzaldehyde IN-2a (7.00 g, 49.8 mmol) was dissolved in ethanol (20 mL), malonic acid (10.36 g, 99.6 mmol) and ammonium acetate (7.68 g, 99.6 mmol) were added, and the mixture was reacted at 80°C for 16 hours. The mixture was cooled to 25°C, filtered, and the filter cake was dissolved in sodium hydroxide solution (10 mL, 1 mol / L). After the solution was clear, the pH was adjusted to 7-8 with 1N dilute hydrochloric acid, filtered, and the filter cake was washed with water (2 mL) and dried to obtain the title compound IN-2b (2.55 g, yield 26%) as a white solid.

[0245] LC-MS: m / z = 200.1 [M+H] +

[0246] Step 2 3-(tert-Butyloxycarbonyl)amino)-3-(2-chlorophenyl)propanoic acid IN-2c

[0247] Compound IN-2b (1.10 g, 5.5 mmol) was dissolved in DMF (10 mL) and water (10 mL), and DIPEA (1.42 g, 11.0 mmol) and (Boc) were added. 2 O (1.32 g, 6.1 mmol), reacted at 30 ° C for 16 hours, TLC showed that the reaction was complete. The reaction solution was added with water (20 mL), extracted with ethyl acetate (10 mL x 2), the ethyl acetate phase was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was slurried with petroleum ether (10 mL), filtered and dried to obtain the title compound IN-2c (1.17 g, yield 71%) as a white solid.

[0248] LC-MS: m / z=244.1[M+H] +

[0249] Step 3 1-(2-chlorophenyl)-3-hydroxypropylcarbamic acid tert-butyl ester IN-2d

[0250] Compound IN-2c (0.53 g, 1.8 mmol) was dissolved in THF (5 mL), the temperature was controlled at 0-5°C, borane tetrahydrofuran solution (3 mL, 1 mol / L) was added dropwise, and the mixture was reacted at 25°C for 16 h. TLC showed that the reaction was complete. Methanol (2 mL) was added to quench the mixture, and the mixture was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound IN-2d (190 mg, yield 38%) as a colorless oil.

[0251] LC-MS: m / z = 230.1 [M+H] +

[0252] 1 H NMR (400 MHz, DMSO-d 6 )δ7.48-7.43(m,2H),7.38-7.31(m,2H),7.25-7.21(m,1H),5.02-4.96(m,1H ),4.52(t,J=9.6Hz,1H),3.45-3.42(m,2H),1.76-1.65(m,2H),1.35(s,9H).

[0253] Step 4: 3-amino-3-(2-chlorophenyl)propan-1-ol hydrochloride IN-2

[0254] Compound IN-2d (150 mg, 0.5 mmol) was added with 1,4-dioxane hydrochloride solution (2 mL, 4 mol / L) and reacted at 25 °C for 1 h. TLC showed that the reaction was complete. The crude product was concentrated and slurried with PE / EA = 1 / 1 (2 mL). The crude product was filtered and dried to obtain the title compound IN-2 (110 mg, yield 99%) as a white solid.

[0255] Intermediate 3

[0256] 3-Amino-4-(2-chlorophenyl)aminobutan-1-ol hydrochloride IN-3

[0257]

[0258] The first step (tert-butyloxycarbonyl)-homoserine benzyl ester IN-3b

[0259] (tert-Butyloxycarbonyl)-homoserine IN-3a (5 g, 22.81 mmol) was dissolved in DMF (20 mL), ethanol (30 mL) and water (20 mL), and sodium hydroxide (0.96 g, 23.96 mmol) and benzyl bromide (4.09 g, 23.91 mmol) were added in sequence, and the mixture was reacted at 25°C for 16 hours. The reaction was complete when detected by TLC. Water (50 mL) was added to the reaction solution, and the pH was adjusted to about 3 with dilute hydrochloric acid (1 mol / L), and extracted with EA (30 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate (30 mL), washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3b (4.31 g, yield 59.5%) as a colorless oil.

[0260] LC-MS: m / z = 308.2 [MH] -

[0261] (tert-Butyloxycarbonyl)-homoserine can be DL-(tert-Butyloxycarbonyl)-homoserine or D-(tert-Butyloxycarbonyl)-homoserine or L-(tert-Butyloxycarbonyl)-homoserine

[0262] Step 2 N-tert-Butyloxycarbonylbenzyl-O-(tetrahydropyran-2-yl)-homoserine benzyl ester IN-3c

[0263] Compound IN-3b (3.78 g, 12.2 mmol) was dissolved in toluene (30 mL), and DHP (1.34 g, 15.9 mmol) and p-toluenesulfonic acid (0.21 g, 1.2 mmol) were added in sequence. The mixture was reacted at 25°C for 1 hour. The reaction was complete after TLC detection. Saturated sodium bicarbonate (30 mL) was added to the reaction solution, stirred for 10 minutes, separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography to obtain the title compound IN-3c (3.42 g, yield 71.3%) as a colorless oil.

[0264] Step 3 tert-Butyl 1-oxo-4-(tetrahydropyran-2-yl)oxy)butane-2-carbamate IN-3d

[0265] Compound IN-3c (4.50 g, 11.4 mmol) was dissolved in THF (40 mL), and DIBAL (23 mL, 1 mol / L n-hexane solution) was added dropwise at -78°C. After the addition was completed, the mixture was reacted at -78°C for 2 hours. The reaction was complete by TLC. Methanol (10 mL) was added dropwise at -78°C to quench the mixture, and water (40 mL) was added. The mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-3d (2.22 g, yield 67.5%) as a colorless oil.

[0266] Step 4: tert-Butyl (1-((2-chlorophenyl)amino)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)carbamate IN-3e

[0267] Compound IN-3d (1.00 g, 3.5 mmol) was dissolved in methanol (20 mL), o-chloroaniline (0.67 g, 5.2 mmol) was added, and the mixture was reacted at 25°C for 1 hour. Sodium cyanoborohydride (0.66 g, 10.4 mmol) was added, and the mixture was reacted at 25°C for 16 hours. TLC detected that the reaction raw materials were left and the reaction was stopped. Water (10 mL) was added to the reaction solution, and the mixture was concentrated, extracted with EA (10 mL × 2), washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-3e (406 mg, yield 29.2%) as a colorless oil.

[0268] Step 5: 3-amino-4-((2-chlorophenyl)amino)butan-1-ol hydrochloride IN-3

[0269] Compound IN-3e (200 mg, 0.5 mmol) was dissolved in dioxane hydrochloride (1 mL, 4 mol / L) and reacted at 25 °C for 1 hour. TLC showed that the reaction was complete. The crude product was concentrated and slurried with PE / EA = 1 / 1 (2 mL). The crude product was filtered and dried to obtain the title compound IN-3 (120 mg, yield 96%) as a white solid.

[0270] LC-MS: m / z = 215.1 [M+H] +

[0271] Intermediate 4

[0272] 3-Amino-4-(2-chlorophenyl)aminobutan-1-ol hydrochloride IN-4

[0273]

[0274] Step 1 Dimethyl 2-(cyanomethyl)malonate IN-4b

[0275] At 0°C, NaH (60%, 6.06 g, 152 mmol) was suspended in tetrahydrofuran (100 mL), dimethyl malonate IN-4a (20 g, 151 mmol) was added, and stirred for 15 min. Bromoacetonitrile (9.08 g, 75.7 mmol) was slowly added dropwise. After completion, the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. Water was added to quench the mixture, and the mixture was extracted with EA (150 mL), washed with water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain the title compound IN-4b (7.0 g, yield 27.02%) as a colorless oily liquid.

[0276] 1 HNMR (400MHz, DMSO-d6) δ3.82 (s, 6H), 3.76 (t, J = 7.2Hz, 1H), 2.94 (d, J = 7.2Hz, 2H).

[0277] Step 2: 2-Oxopyrrolidine-3-carboxylic acid methyl ester IN-4c

[0278] Triethylamine (0.1 g, 0.99 mmol) was added to a methanol (20 mL) solution of compound IN-4b (2.0 g, 11.7 mmol) and Raney nickel (0.2 g, 3.34 mmol), and the hydrogen was replaced. The mixture was stirred at room temperature overnight. TLC showed that the reaction was complete. The mixture was filtered and dried by spin drying. The crude product was separated and purified by column chromatography to obtain the title compound IN-4c (1.4 g, yield 83.67%) as a white solid.

[0279] LC-MS: m / z = 144.1. [M+H] +

[0280] Step 3 3-Hydroxymethylpyrrolidin-2-one IN-4d

[0281] Compound IN-4c (2.72 g, 19.0 mmol) was dissolved in isopropanol (20 mL), cooled to 0°C, and sodium borohydride (1.44 g, 37.9 mmol) was added in batches. After addition, the temperature was raised to 25°C and the reaction was complete for 2 h. TLC detected that the reaction was complete. Water (5 mL) was added to the reaction solution, stirred for 10 minutes, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4d (1.49 g, yield 68%) as a white solid.

[0282] Step 4: (2-oxopyrrolidin-3-yl)methyl 4-methylbenzenesulfonate IN-4e

[0283] Compound IN-4d (1.38 g, 12.0 mmol) was dissolved in dichloromethane (5 mL), triethylamine (1.58 g, 15.6 mmol), DMAP (0.15 g, 1.2 mmol) and p-toluenesulfonyl chloride (2.51 g, 13.2 mmol) were added in sequence, and the mixture was reacted at 25°C for 4 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4e (2.46 g, yield 76%) as a white solid.

[0284] Step 5: 3-azidomethylpyrrolidin-2-one IN-4f

[0285] Compound IN-4e (2.46 g, 9.1 mmol) was dissolved in DMF (8 mL), sodium azide (0.77 g, 9.1 mmol) was added, and the temperature was raised to 60°C for 16 hours. The reaction was complete after TLC. The reaction solution of the title compound IN-4f was directly used for the next step.

[0286] Step 6: Tert-butyl ((2-oxopyrrolidin-3-yl)methyl)carbamate IN-4g

[0287] Compound IN-4f (reaction solution) was added with THF (30 mL) and water (3 mL), and triphenylphosphine (4.79 g, 18.2 mmol) was added, and the mixture was reacted at 25°C for 2 hours. (Boc) was added to the reaction solution. 2 O (1.99 g, 9.1 mmol), react at 25°C for 1 hour, and the reaction is complete after TLC detection. Concentrate, add water (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography to obtain the title compound IN-4g (1.01 g, two-step yield 51%) as a white solid.

[0288] Step 7: 3-aminomethylpyrrolidin-2-one hydrochloride IN-4

[0289] Add dioxane hydrochloride (2 mL) to a solution of compound IN-4g (300 mg, 1.4 mmol) in dichloromethane (2 mL), react at 25°C for 1 hour, and the reaction is complete as determined by TLC. Filter, wash the filter cake with dichloromethane (1 mL), and dry to obtain the title compound IN-4 (200 mg, yield 96%) as a white solid.

[0290] Example 1

[0291] 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((5-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 1

[0292]

[0293] Step 1 4,6-dichloro-N-methyl-1,3,5-triazine-2-amine 1b

[0294] Methylamine hydrochloride (1.83 g, 27.11 mmol) was added to a solution of cyanuric chloride 1a (5.0 g, 27.11 mmol) and DIPEA (7.01 g, 54.22 mmol) in tetrahydrofuran (100 mL) at 0°C. The mixture was reacted for 1 hour. TLC showed that the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA=10 / 1) to obtain the title compound 1b (2.1 g, yield 43.27%) as a white solid.

[0295] LC-MS: m / z=179.0 [M+H] +

[0296] Step 2 3-(4-chloro-6-methylamino)-1,3,5-triazin-2-ylamino)-3-(2-chlorophenyl)propan-1-ol 1c

[0297] Compound IN-2 (47 mg, 0.21 mmol) was dissolved in THF (2 mL), and DIPEA (55 mg, 0.42 mmol) and compound 1b (50 mg, 0.28 mmol) were added in sequence, and reacted at 25°C for 3 h. The reaction was complete by TLC. The crude product was concentrated and purified by preparative plate to obtain the title compound 1c (71 mg, yield 77%) as a white solid.

[0298] LC-MS: m / z=328.1[M+H] +

[0299] Step 3 Benzyl 4-(((5-oxopyrrolidin-3-yl)methyl)carbamoyl)piperidine-1-carboxylate 1e

[0300] Compound IN-1 (100 mg, 0.66 mmol) was dissolved in dichloromethane (5 mL), and N-Cbz-4-piperidinic acid 1d (175 mg, 0.7 mmol), HATU (278 mg, 0.7 mmol), and DIPEA (257 mg, 2.0 mmol) were added in sequence, and reacted at 25°C for 2 hours. The reaction was complete after TLC detection. The crude product was concentrated and purified by silica gel column chromatography to obtain the title compound 1e (65 mg, yield 27%) as a white solid.

[0301] LC-MS: m / z = 360.2 [M+H] +

[0302] Step 4: N-(5-oxopyrrolidin-3-yl)methylpiperidine-4-carboxamide 1f

[0303] Compound 1e (60 mg, 0.17 mmol) was dissolved in methanol (5 mL), palladium carbon (20 mg, 10%) was added, hydrogen was replaced 3 times, and the mixture was reacted at 25°C for 2 hours. The reaction was complete after TLC detection. The mixture was filtered, the filter cake was washed with methanol (1 mL), and the filtrate was concentrated to obtain the title compound 1f (37 mg, yield 97%) as a colorless oily solid.

[0304] LC-MS: m / z = 226.2 [M+H] +

[0305] Step 5: 1-(4-(1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-(5-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 1

[0306] Compound 1c (55 mg, 0.16 mmol) was dissolved in THF (1 mL), potassium carbonate (69 mg, 0.50 mmol) and compound 1f (37 mg, 0.16 mmol) were added, and the mixture was reacted at 95°C for 16 h in a sealed tube. The reaction was complete according to TLC. The crude product was concentrated and purified by preparative plate to obtain the title compound 1 (25 mg, yield 30%) as a light yellow solid.

[0307] LC-MS: m / z=517.3[M+H] +

[0308] 1 H NMR (400 MHz, DMSO-d 6 )δ7.90-7.84(m,1H),7.48-7.16(m,6H),6.51-6.32(m,1H),5.52-5.42(m,1H),4.55(s,3H),3.51-3.45(m,2H),3.2 5(t,J=8.4Hz,1H),3.06-3.05(m,2H),2.93-2.89(m,1H),2.76-2.62(m,5H),2.29-2.15(m,3H),1.88-1.31(m,7H).

[0309] Example 2

[0310] 1-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((5-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 2

[0311]

[0312] Step 1 (S)-3-((4-chloro-6-(methylamino)-1,3,5-triazin-2-yl)amino)-4-((2-chlorophenyl)amino)butan-1-ol 2a

[0313] Compound IN-3 (188 mg, 0.75 mmol) was dissolved in tetrahydrofuran (5 mL), and compound 1b (135 mg, 0.8 mmol) and DIPEA (258 mg, 2.0 mmol) were added in sequence, and the mixture was reacted at 25°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was separated and purified by preparative plate to obtain the title compound 2a (66 mg, yield 24.6%) as a white solid.

[0314] LC-MS: m / z=357.2[M+H] +

[0315] Step 2 1-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((5-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 2

[0316] Compound 2a (60 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and compound 1f (41 mg, 0.18 mmol) and potassium carbonate (99 mg, 0.72 mmol) were added in sequence, and the mixture was sealed and reacted at 95°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was separated and purified by preparative plate to obtain the title compound 2 (17 mg, yield 18.5%) as a white solid.

[0317] LC-MS: m / z=546.3[M+H] +

[0318] 1 H NMR (400 MHz, DMSO-d 6 )δ8.07-8.00(m,2H),7.48(s,1H),7.21(d,J=7.6Hz,1H),7.12(t,J=8.0Hz,1H),6.80(d,J=8.0Hz,1H),6.57(t,J=7.2Hz,1H),5. 47(br,1H),4.64-4.42(m,4H),3.32-3.24(m,4H),3.10-2.78(m,8H),2.45-2.29(m,1H),2.19(m,1H),1.84(m,5H),1.48(m,2H).

[0319] Example 3

[0320] 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 3

[0321]

[0322] Step 1 Benzyl 4-(((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperidine-1-carboxylate 3a

[0323] Compound IN-4 (100 mg, 0.66 mmol) was dissolved in dichloromethane (5 mL), and N-Cbz-4-piperidinic acid 1d (175 mg, 0.7 mmol), HATU (278 mg, 0.7 mmol), and DIPEA (257 mg, 2.0 mmol) were added in sequence, and reacted at 25°C for 2 hours. The reaction was complete after TLC detection. The crude product was concentrated and purified by silica gel column chromatography to obtain the title compound 3a (77 mg, yield 32%) as a white solid.

[0324] LC-MS: m / z = 360.2 [M+H] +

[0325] Step 2 N-(2-oxopyrrolidin-3-yl)methylpiperidine-4-carboxamide 3b

[0326] Compound 3a (70 mg, 0.20 mmol) was dissolved in methanol (5 mL), palladium carbon (20 mg, 10%) was added, hydrogen was replaced 3 times, and the reaction was carried out at 25°C for 2 hours. The reaction was complete after TLC detection. The filter cake was filtered and washed with methanol (1 mL). The filtrate was concentrated to obtain the title compound 3b (43 mg, yield 95%) as a colorless oily solid. LC-MS: m / z = 226.2 [M+H] + .

[0327] Step 3 1-(4-(1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-(2-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 3

[0328] Compound 1c (65 mg, 0.19 mmol) was dissolved in THF (1 mL), potassium carbonate (69 mg, 0.50 mmol) and compound 3b (43 mg, 0.19 mmol) were added, and the mixture was reacted at 95°C for 16 h in a sealed tube. The reaction was complete according to TLC. The crude product was concentrated and purified by preparative plate to obtain the title compound 3 (32 mg, yield 33%) as a light yellow solid. LC-MS: m / z = 517.3 [M+H] + .

[0329] 1H NMR (400 MHz, DMSO-d 6 )δ7.86-7.76(m,1H),7.51-7.10(m,6H),6.46-6.33(m,1H),5.62-5.48(m,1H),4.51(s,3H),3.55-3.41(m,2H),3 .29-3.21(m,1H),3.00-3.02(m,2H),2.92-2.86(m,1H),2.80-2.72(m,5H),2.31-2.11(m,3H),1.87-1.28(m,7H).

[0330] Example 4

[0331] 1-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide

[0332]

[0333] Step 1-(4-((1-((2-chlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((5-oxopyrrolidin-3-yl)methyl)piperidine-4-carboxamide 4

[0334] Compound 2a (70 mg, 0.20 mmol) was dissolved in tetrahydrofuran (2 mL), and compound 3b (50 mg, 0.22 mmol) and potassium carbonate (99 mg, 0.72 mmol) were added in sequence, and the mixture was sealed and reacted at 95°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was separated and purified by preparative plate to obtain the title compound 4 (32 mg, yield 29.3%) as a white solid.

[0335] LC-MS: m / z=546.3[M+H] +

[0336] 1 H NMR (400 MHz, DMSO-d 6)δ8.12-8.06(m,2H),7.51(s,1H),7.23-7.13(m,2H),6.82(d,J=8.0Hz,1H),6.63(t,J=7.2Hz,1H),5.56(br,1H),4 .71-4.62(m,4H),3.39-3.31(m,4H),3.13-2.64(m,8H),2.51-2.38(m,1H),2.25(m,1H),1.79(m,5H),1.51(m,2H).

[0337] Example 5

[0338] 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-4-(4-fluorobenzoyl)-N-((5-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 5

[0339]

[0340] Step 1-(tert-Butyl) 2-methyl 4-(4-fluorobenzoyl) piperazine-1,2-dicarboxylate 5c

[0341] At 25 degrees, TEA (0.52 g, 5.15 mmol) was added to a DMF (10 mL) solution of N-1-Boc-2-piperazinecarboxylic acid methyl ester 5a (0.5 g, 2.05 mmol), p-fluorobenzoic acid 5b (0.33 g, 2.42 mmol) and HATU (1.56 g, 4.1 mmol), and the mixture was reacted at 25 degrees for 18 hours. TLC showed that the reaction was complete, and water (40 mL) was added to quench the reaction. The mixture was extracted with EA (40 mL x 2), washed with water (40 mL x 2), and the EA phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated and purified by column chromatography to obtain the title compound 5c (0.48 g, yield 63.9%) as a white solid.

[0342] LC-MS: m / z=311.1 [M-55] +

[0343] Step 2 1-(tert-Butyloxycarbonyl)-4-(4-fluorobenzoyl)piperazine-2-carboxylic acid 5d

[0344] At 25 degrees, sodium hydroxide (33 mg, 0.83 mmol) was added to a mixed solvent of tetrahydrofuran (3 mL) and water (2 mL) of compound 5c (200 mg, 0.55 mmol), and the mixture was reacted at 25 degrees for 2 hours. TLC showed that the reaction was complete. Water (10 mL) was added, and the aqueous phase was washed with ethyl acetate. The pH of the aqueous phase was adjusted to 2 with 1N hydrogen chloride, filtered, and the filter cake was washed with water. After drying, the title compound 5d (176 mg, yield 90.8%) was obtained as a white solid.

[0345] LC-MS: m / z = 297.1 [M-55] +

[0346] Step 3 4-(4-fluorobenzoyl)-2-(((5-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 5e

[0347] At 25 degrees, DIPEA (129 mg, 1 mmol) was added to a DMF (6 mL) solution of compound 5d (176 mg, 0.50 mmol), compound IN-1 (60 mg, 0.40 mmol) and HATU (285 mg, 0.75 mmol), and the mixture was reacted at 25 degrees for 2 hours. TLC showed that the reaction was complete, and water (10 mL) was added to quench the mixture. The mixture was extracted with EA (10 mL x 2), washed with water (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified using a silica gel thick preparation plate to obtain the title compound 5e (120 mg, yield 53.5%) as a white solid.

[0348] LC-MS: m / z = 449.3 [M+1] +

[0349] Step 4: 4-(4-Fluorobenzoyl)-N-((5-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 5f

[0350] At 25 degrees, 1,4-dioxane hydrochloride (4M, 2 mL) was added to a solution of compound 5e (120 mg, 0.27 mmol) in dichloromethane (1 mL), and the mixture was stirred at 25°C for 1 hour. TLC indicated that the reaction of the raw material was complete. The reaction solution was concentrated to obtain the title compound 5f hydrochloride (103 mg, yield 99.2%).

[0351] Step 5 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-4-(4-fluorobenzoyl)-N-((5-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 5

[0352] In a sealed tube, compound 5f (103 mg, 0.27 mmol), compound 1c (115 mg, 0.36 mmol) and potassium carbonate (122 mg, 0.88 mmol) in THF (7.5 mL) were reacted at 95 ° C for 16 hours. The reaction was completed after monitoring by TLC. The mixture was cooled to room temperature, filtered, and dried to obtain a crude product. The crude product was purified by silica gel thick preparation plate to obtain the title compound 5 (21 mg, yield 12.1%) as a white solid.

[0353] LC-MS: m / z = 640.3 [M+1] +

[0354] 1 HNMR (400MHz, CD 3 OD)δ9.27(s,1H),7.10-7.39(m,8H),5.02-5.47(m,1H),4.05-4.29(m,2H),3.31-3.57(m,5H),1.83-3.12(s,12H),1.22-1.28(m,2H).

[0355] Example 6

[0356] 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-4-(4-fluorobenzoyl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 6

[0357]

[0358] Step 1 4-(4-fluorobenzoyl)-2-(((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 6a

[0359] At 25 degrees, DIPEA (129 mg, 1 mmol) was added to a DMF (6 mL) solution of compound 5d (176 mg, 0.50 mmol), compound IN-4 (60 mg, 0.40 mmol) and HATU (285 mg, 0.75 mmol), and the reaction was carried out at 25 degrees for 2 hours. TLC showed that the reaction was complete, and water (10 mL) was added to quench, and EA (10 mL x2) was used for extraction, and the mixture was washed with water (10 mL x2), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by silica gel thick preparation plate to obtain the title compound 6a (137 mg, yield 61%) as a white solid.

[0360] LC-MS: m / z = 449.3 [M+1] +

[0361] Step 2 4-(4-Fluorobenzoyl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 6b

[0362] At 25°C, 1,4-dioxane hydrochloride (4M, 2 mL) was added to a solution of compound 6a (137 mg, 0.31 mmol) in dichloromethane (1 mL). The mixture was stirred at 25°C for 1 hour. TLC indicated that the reaction was complete. The reaction solution was concentrated to obtain the title compound 6b hydrochloride (116 mg, yield 99%).

[0363] Step 3 1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-4-(4-fluorobenzoyl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 6

[0364] In a sealed tube, compound 6b (116 mg, 0.33 mmol), compound 1c (130 mg, 0.40 mmol) and potassium carbonate (137 mg, 0.99 mmol) in THF (7.5 mL) were reacted at 95 degrees for 16 hours. TLC monitored the complete reaction of the raw materials. The mixture was cooled to room temperature, filtered, and dried to obtain a crude product. The crude product was purified by silica gel thick preparation plate to obtain the title compound 6 (36 mg, yield 17%) as a white solid.

[0365] LC-MS: m / z = 640.3 [M+1] +

[0366] 1 HNMR (400MHz, CD 3 OD)δ9.29(s,1H),7.09-7.41(m,8H),5.05-5.52(m,1H),4.03-4.32(m,2H),3.29-3.51(m,5H),1.90-3.26(s,12H),1.23-1.27(m,2H).

[0367] Example 7

[0368] 1-(2-Chloroacetyl)-4-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 7

[0369]

[0370] Step 1 4-Benzyl 1-tert-butyl 2-((2-oxopyrrolidin-3-ylmethyl)carbamoyl)piperazine-1,4-dicarboxylate 7b

[0371] Compound IN-4 (250 mg, 1.7 mmol) and 4-(benzyloxy)carbonyl)-1-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid 7a (0.61 g, 1.7 mmol) were dissolved in DCM (5 mL), HATU (0.80 g, 2.1 mmol) and DIPEA (0.73 g, 5.6 mmol) were added, and the mixture was reacted at 40°C for 4 hours. The reaction was complete after TLC detection. Water (10 mL) was added for quenching, and DCM (10 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7b (577 mg, yield 74%) as a colorless oil.

[0372] LC-MS: m / z=461.3[M+H] +

[0373] Step 2 Tert-butyl 2-((2-oxopyrrolidin-3-yl)methyl)carbamoylpiperazine-1-carboxylate 7c

[0374] Compound 7b (577 mg, 1.25 mmol) was added with methanol (10 mL), palladium carbon (100 mg, 10%), and hydrogen was replaced 3 times. The reaction was carried out at 25°C for 2 hours. The reaction was complete after TLC detection. The filter cake was washed with methanol (1 mL), and the filtrate was concentrated to obtain the title compound 7c (370 mg, yield 91%) as a colorless oily solid.

[0375] Step 3 4-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 7d

[0376] Compound 7c (137 mg, 0.38 mmol) was dissolved in THF (2 mL), and compound 2a (150 mg, 0.46 mmol) and potassium carbonate (0.21 g, 1.52 mmol) were added. The mixture was reacted at 95 °C in a sealed tube for 16 hours. The reaction was complete when detected by TLC. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography to obtain the title compound 7d (190 mg, yield 77%) as a white solid. LC-MS: m / z=647.4 [M+H] + .

[0377] Step 4: 4-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 7e

[0378] Compound 7d (70 mg, 0.11 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 25°C for 1 hour. The reaction was complete after TLC detection. The reaction solution was concentrated to obtain the title compound 7e hydrochloride (crude) as a white solid.

[0379] Step 5 1-(2-chloroacetyl)-4-(4-(((S)-1-((2-chlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 7

[0380] Compound 7e (crude product) was dissolved in DCM (2 mL), triethylamine (45 mg, 0.44 mmol) was added, chloroacetyl chloride (12 mg, 0.11 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. The reaction was complete after TLC detection. The reaction solution was concentrated and purified by Pre-TLC to obtain the title compound 7 (20 mg, two-step yield 29%) as a white solid.

[0381] LC-MS: m / z=623.3[M+H] +

[0382] 1 H NMR (400 MHz, DMSO-d 6 )δ8.20-8.05(m,1H),7.63(s,1H),7.44-6.53(m,7H),5.59-5.33(m,1H),4.97-4.12( m,7H),3.75-3.48(m,4H),3.24-2.76(m,10H),2.41-2.29(s,1H),1.96-1.63(m,4H).

[0383] Example 8

[0384] 1-(2-Chloroacetyl)-4-(4-(((S)-1-((2,3-dichlorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 8

[0385]

[0386] Step 1 Tert-butyl (2S)-1-((2,3-dichlorophenyl)amino)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)carbamate 8b

[0387] 2,3-Dichloroaniline 8a (1.0 g, 6.17 mmol) was dissolved in methanol (30 mL), compound IN-3d (1.95 g, 6.79 mmol) was added, and the mixture was reacted at 25 °C for 1 hour. NaBH 3 CN (0.58 g, 9.26 mmol), react at 25°C for 16 hours, TLC shows that the reaction of the raw material is complete. Add water to quench (10 mL), concentrate, extract with EA (10 mL × 2), wash with saturated sodium chloride (10 mL), dry with anhydrous sodium sulfate, filter, concentrate, and the crude product is subjected to silica gel column chromatography to obtain the title compound 8b (1.31 g, yield 49%) as a colorless oil.

[0388] Step 2 (S)-3-Amino-4-((2,3-dichlorophenyl)amino)butan-1-ol hydrochloride 8c

[0389] Compound 8b (500 mg, 1.15 mmol) was added to dioxane hydrochloride solution (1 mL, 4 mol / L) and reacted at 25°C for 1 hour. The reaction was complete after TLC detection. The reaction solution was concentrated to obtain the title compound 8c (crude product) as a colorless oil.

[0390] Step 3 (S)-3-((4-chloro-6-(methylamino)-1,3,5-triazin-2-yl)amino)-4-((2,3-dichlorophenyl)amino)butan-1-ol 8d

[0391] Compound 8c (crude product) was dissolved in THF (5 mL), and compound 1b (0.23 g, 1.27 mmol) and TEA (0.29 g, 2.88 mmol) were added in sequence. The mixture was reacted at 25°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 8d (326 mg, two-step yield 72%) as a white solid.

[0392] Step 4: tert-butyl 4-(4-(((S)-1-((2,3-dichlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-2-((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylate 8e

[0393] Compound 8d (300 mg, 0.77 mmol) was dissolved in THF (2 mL), and compound 7c (275 mg, 0.84 mmol) and potassium carbonate (423 mg, 3.1 mmol) were added in sequence. The mixture was reacted at 95 °C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography to obtain the title compound 8e (381 mg, yield 73%) as a white solid.

[0394] LC-MS: m / z=681.3[M+H] +

[0395] Step 5: 4-(4-(((S)-1-((2,3-dichlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 8f

[0396] Compound 8e (100 mg, 0.15 mmol) was added to a dioxane hydrochloride solution (2 mL, 4 mol / L) and reacted at 25°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 8f hydrochloride (crude) as a white solid.

[0397] Step 6 1-(2-chloroacetyl)-4-(4-(((S)-1-((2,3-dichlorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 8

[0398] Compound 8f hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (59 mg, 0.59 mmol) was added, chloroacetyl chloride (17 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and Pre-TLC was used to obtain the title compound 8 (32 mg, two-step yield 32%) as a white solid.

[0399] LC-MS: m / z=657.2[M+H] +

[0400] 1 H NMR (400 MHz, DMSO-d 6 )δ8.32-8.15(m,1H),7.80(s,1H),7.59-6.66(m,6H),5.57-5.31(m,1H),4.89-4.02( m,7H),3.81-3.51(m,4H),3.25-2.81(m,10H),2.38-2.26(m,1H),2.01-1.62(m,4H).

[0401] Example 9

[0402] 1-(2-Chloroacetyl)-4-(4-(((S)-1-((2-fluorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 9

[0403]

[0404] First step: tert-Butyl (2S)-1-((2-fluorophenyl)amino)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)carbamate 9b

[0405] o-Fluoroaniline 9a (0.46 g, 4.14 mmol) was dissolved in methanol (20 mL), compound IN-3d (1.00 g, 3.48 mmol) was added and reacted at 25 °C for 1 hour, and NaBH 3 CN (0.52 g, 8.34 mmol), react at 25°C for 16 hours, TLC shows that the reaction of the raw material is complete. Add water to quench (10 mL), concentrate, extract with EA (10 mL × 2), wash with saturated sodium chloride (10 mL), dry with anhydrous sodium sulfate, filter, concentrate, and the crude product is subjected to silica gel column chromatography to obtain the title compound 9b (455 mg, yield 43%) as a colorless oil.

[0406] Step 2 (S)-3-Amino-4-((2-fluorophenyl)amino)butan-1-ol hydrochloride 9c

[0407] Compound 9b (357 mg, 0.93 mmol) was added to dioxane hydrochloride solution (1 mL, 4 mol / L) and reacted at 25°C for 1 hour. The reaction was complete after TLC detection. The reaction solution was concentrated to obtain the title compound 9c (crude product) as a colorless oil.

[0408] Step 3 (S)-3-((4-chloro-6-(methylamino)-1,3,5-triazin-2-yl)amino)-4-((2-fluorophenyl)amino)butan-1-ol 9d

[0409] Compound 9c (crude product) was dissolved in THF (5 mL), and compound 1b (0.25 g, 1.40 mmol) and DIPEA (0.48 g, 3.72 mmol) were added in sequence, and the mixture was reacted at 25°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9d (158 mg, two-step yield 50%) as a white solid.

[0410] LC-MS: m / z=341.2[M+H] +

[0411] Step 4: tert-butyl 4-(4-(((S)-1-((2-fluorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-(((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylate 9e

[0412] Compound 9d (120 mg, 0.35 mmol) was dissolved in THF (2 mL), and compound 7c (140 mg, 0.43 mmol) and potassium carbonate (0.19 g, 1.41 mmol) were added in sequence. The mixture was reacted at 95°C for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 9e (192 mg, yield 87%) as a white solid. LC-MS: m / z = 631.4 [M+H] + .

[0413] Step 5: 4-(4-(((S)-1-((2-fluorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 9f

[0414] Compound 9e (75 mg, 0.12 mmol) was added to a dioxane hydrochloride solution (2 mL, 4 mol / L) and reacted at 25°C for 1 hour. The reaction was complete after TLC detection. The reaction solution was concentrated to obtain the title compound 9f hydrochloride (crude product) as a white solid.

[0415] Step 6 1-(2-chloroacetyl)-4-(4-(((S)-1-((2-fluorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 9

[0416] Compound 9f hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (49 mg, 0.48 mmol) was added, chloroacetyl chloride (14 mg, 0.12 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and Pre-TLC was used to obtain the title compound 9 (205 mg, two-step yield 34%) as a white solid.

[0417] LC-MS: m / z=607.4[M+H] +

[0418] 1 H NMR (400 MHz, DMSO-d 6 )δ8.19-7.97(m,1H),7.63-6.53(m,8H),5.47-5.31(m,1H),5.01-4.26(m,7H) ,3.83-3.46(m,4H),3.31-2.71(m,10H),2.39-2.30(m,1H),1.99-1.69(m,4H).

[0419] Example 10

[0420] 1-(2-Chloroacetyl)-4-(4-(((S)-1-((2,3-difluorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 10

[0421]

[0422] First step: tert-butyl (2S)-1-((2,3-difluorophenyl)amino)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)carbamate 10b

[0423] 2,3-Difluoroaniline 10a (500 mg, 3.1 mmol) was dissolved in methanol (20 mL), compound IN-3d (0.98 g, 3.39 mmol) was added and reacted at 25 °C for 1 hour, and NaBH 3 CN (0.29 g, 4.63 mmol), react at 25°C for 16 hours, TLC shows that the reaction of the raw material is complete. Add water to quench (10 mL), concentrate, extract with EA (10 mL × 2), wash with saturated sodium chloride (10 mL), dry with anhydrous sodium sulfate, filter, concentrate, and the crude product is subjected to silica gel column chromatography to obtain the title compound 10b (810 mg, yield 61%) as a colorless oil.

[0424] Step 2 (S)-3-Amino-4-((2,3-difluorophenyl)amino)butan-1-ol hydrochloride 10c

[0425] Compound 10b (400 mg, 0.92 mmol) was added to dioxane hydrochloride solution (1 mL, 4 mol / L) and reacted at 25°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 10c (crude product) as a colorless oil.

[0426] Step 3 (S)-3-((4-chloro-6-(methylamino)-1,3,5-triazin-2-yl)amino)-4-((2,3-difluorophenyl)amino)butan-1-ol 10d

[0427] Compound 10c (crude product) was dissolved in THF (5 mL), and compound 1b (181 mg, 1.01 mmol) and DIPEA (233 mg, 2.3 mmol) were added in sequence, and the mixture was reacted at 25°C for 16 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 10d (257 mg, two-step yield 71%) as a white solid.

[0428] Step 4: 4-(4-(((S)-1-((2,3-difluorophenyl)amino)-4-hydroxybutan-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-2-((2-oxopyrrolidin-3-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 10e

[0429] Compound 10d (150 mg, 0.42 mmol) was dissolved in THF (2 mL), and compound 7c (150 mg, 0.46 mmol) and potassium carbonate (0.23 g, 1.67 mmol) were added in sequence. The reaction was carried out at 95° C. for 16 hours. TLC detected that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 10e (163 mg, yield 60%) as a white solid. LC-MS: m / z=649.3[M+H] +

[0430] Step 5: 4-(4-(((S)-1-((2,3-difluorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 10f

[0431] Compound 10e (100 mg, 0.15 mmol) was added to a dioxane hydrochloride solution (2 mL, 4 mol / L) and reacted at 25°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 10f hydrochloride (crude product) as a white solid.

[0432] Step 6: 1-(2-chloroacetyl)-4-(4-(((S)-1-((2,3-difluorophenyl)amino)-4-hydroxybutyl-2-yl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 10

[0433] Compound 10f hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (62 mg, 0.62 mmol) was added, chloroacetyl chloride (17 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. The reaction was complete after TLC detection. The reaction solution was concentrated, and Pre-TLC was used to obtain the title compound 10 (26 mg, two-step yield 27%) as a white solid.

[0434] LC-MS: m / z=625.3[M+H] +

[0435] 1 H NMR (400 MHz, DMSO-d 6)δ8.31-8.15(m,1H),7.83(s,1H),7.65-6.61(m,6H),5.58-5.26(m,1H),5.12-4.09( m,7H),3.79-3.42(m,4H),3.41-2.86(m,10H),2.43-2.29(m,1H),2.01-1.68(m,4H).

[0436] Embodiment 11

[0437] 4-(2-Chloroacetyl)-1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(thiophen-2-ylmethyl)piperazine-2-carboxamide 11

[0438]

[0439] The first step is 1-tert-butyl 3-methyl 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)piperazine-1,3-dicarboxylate 11b

[0440] Compound 1c (214 mg, 0.7 mmol) was dissolved in THF (2 mL), potassium carbonate (360 mg, 2.6 mmol) and 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate 11a (320 mg, 1.3 mmol) were added, and the mixture was reacted at 90°C for 1 h. TLC showed that the reaction was complete. Water was added to quench the mixture (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 11b (80 mg, yield 23%) as a colorless oil.

[0441] LC-MS: m / z=536.3[M+H] +

[0442] Step 2: 4-tert-Butyloxycarbonyl-1-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)piperazine-2-carboxylic acid 11c

[0443] Compound 11b (80 mg, 0.2 mmol) was dissolved in THF (2 mL), methanol (2 mL) and water (2 mL), sodium hydroxide (12 mg, 0.3 mmol) was added, and the mixture was reacted at 10°C for 1 h. TLC showed that the reaction was complete. The mixture was concentrated, water (5 mL) was added, pH was adjusted to 3 with 1N dilute hydrochloric acid, and extracted with DCM (10 mL×2). The organic phase was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 11c (53 mg, yield 68%) as a white solid.

[0444] Step 3: 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-3-(thiophen-2-ylmethyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 11e

[0445] Compound 11c (53 mg, 0.1 mmol) was dissolved in DCM (5 mL), and thiophene-2-methylamine 11d (17 mg, 0.2 mmol), HATU (46 mg, 0.1 mmol) and DIPEA (51 mg, 0.4 mmol) were added, and the mixture was reacted at 10°C for 16 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the solution was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 11e (61 mg, yield 99%) as a white solid.

[0446] LC-MS: m / z=617.3[M+H] +

[0447] Step 4: 1-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-thiophen-2-ylmethylpiperazine-2-carboxamide hydrochloride 11f

[0448] Compound 11e (61 mg, 0.1 mmol) was dissolved in dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 11f hydrochloride (crude product).

[0449] LC-MS: m / z = 515.2 [MH] -

[0450] Step 5: 4-(2-chloroacetyl)-1-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-thiophen-2-ylmethylpiperazine-2-carboxamide 11

[0451] Compound 11f hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (40 mg, 0.4 mmol) was added, chloroacetyl chloride (11 mg, 0.1 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and TLC prepared the title compound 11 (35 mg, two-step yield 60%) as a white solid.

[0452] LC-MS: m / z = 593.2 [M+H] +

[0453] 1 H NMR (400 MHz, DMSO-d 6 )δ8.59-8.48(m,1H),7.62-6.53(m,10H),5.53-5.15(m,2H),5.55-4.08(m,8H),3.47(s,2H),3.82-2.63(m,5H),1.85-1.73(m,2H).

[0454] Example 12

[0455] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(thiophen-2-ylmethyl)piperazine-2-carboxamide 12

[0456]

[0457] The first step is tert-butyl 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)piperazine-1,2-dicarboxylate 12a

[0458] Compound 1c (300 mg, 0.9 mmol) was dissolved in toluene (2 mL), 1-(tert-butyl) 2-methylpiperazine-1,2-dicarboxylate 5a (440 mg, 1.8 mmol) and DIPEA (470 mg, 3.6 mmol) were added, and the mixture was reacted at 120°C for 1 h. TLC showed that the reaction was complete. Water (5 mL) was added for quenching, and ethyl acetate (5 mL × 2) was used for extraction. The organic phase was washed with saturated sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 12a (430 mg, yield 88%) as a colorless oil.

[0459] LC-MS: m / z=536.3[M+H] +

[0460] Step 2 1-tert-Butyloxycarbonyl-4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)piperazine-2-carboxylic acid 12b

[0461] Compound 12a (430 mg, 0.8 mmol) was dissolved in THF (3 mL), methanol (3 mL) and water (3 mL), sodium hydroxide (64 mg, 1.6 mmol) was added, and the mixture was reacted at 10°C for 1 h. TLC showed that the reaction was complete. The mixture was concentrated, water (5 mL) was added, pH was adjusted to 3 with 1N dilute hydrochloric acid, and extracted with DCM (10 mL×2). The organic phase was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 12b (340 mg, yield 83%) as a white solid.

[0462] Step 3 4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-methylamino-1,3,5-triazin-2-yl)-2-(thiophen-2-ylmethyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 12c

[0463] Compound 12b (340 mg, 0.7 mmol) was dissolved in DCM (5 mL), and thiophene-2-methylamine 11d (150 mg, 1.3 mmol), HATU (310 mg, 0.8 mmol) and DIPEA (350 mg, 2.7 mmol) were added in sequence, and the mixture was reacted at 10°C for 16 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12c (291 mg, yield 70%) as a white solid.

[0464] Step 4: 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-thiophen-2-ylmethylpiperazine-2-carboxamide hydrochloride 12d

[0465] Compound 12c (90 mg, 0.1 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 12d hydrochloride (crude product).

[0466] Step 5 1-(2-chloroacetyl)-4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-thiophen-2-ylmethylpiperazine-2-carboxamide 12

[0467] Compound 12d hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (61 mg, 0.6 mmol) was added, chloroacetyl chloride (17 mg, 0.2 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and TLC prepared the title compound 12 (25 mg, two-step yield 60%) as a white solid.

[0468] LC-MS: m / z = 593.2 [M+H] +

[0469] 1H NMR (400MHz, DMSO-d 6 )δ8.79-8.57(m,1H),7.49-7.19(m,6H),6.89(s,2H),6.52-6.42(m,1H),5.50-5.44(m,1H),4 .78-4.14(m,8H),3.70-3.48(m,4H),3.18-2.97(m,2H),2.71-2.61(m,3H),1.83-1.77(m,2H).

[0470] Embodiment 13

[0471] 4-(2-Chloroacetyl)-1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(tetrahydrofuran-3-yl)piperazine-2-carboxamide 13

[0472]

[0473] First step 4-(4-((1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-3-(tetrahydrofuran-3-yl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 13b

[0474] Compound 11c (200 mg, 0.38 mmol) and 3-aminotetrahydrofuran 13a (40 mg, 0.46 mmol) were dissolved in DCM (5 mL), HATU (219 mg, 0.57 mmol) and triethylamine (78 mg, 0.77 mmol) were added, and the mixture was reacted at 25 degrees for 3 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 13b (175 mg, yield 77%) as a white solid.

[0475] Step 2 1-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-N-tetrahydrofuran-3-yl)piperazine-2-carboxamide hydrochloride 13c

[0476] Compound 13b (70 mg, 0.12 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 13c hydrochloride (crude product).

[0477] Step 3 4-(2-chloroacetyl)-1-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-tetrahydrofuran-3-yl)piperazine-2-carboxamide 13

[0478] Compound 13c (crude product) was dissolved in DCM (5 mL), triethylamine (49 mg, 0.48 mmol) was added, chloroacetyl chloride (14 mg, 0.12 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to TLC to obtain the title compound 13 (20 mg, two-step yield 29%) as a white solid.

[0479] LC-MS: m / z = 567.2 [M+H] +

[0480] 1 H NMR (400 MHz, DMSO-d 6 )δ8.27-8.15(m,1H),7.47-7.19(m,5H),6.43(s,1H),5.42(s,1H),4.71-4.16(m,6H),3 .71-3.65(m,5H),3.47(s,3H),3.09-2.86(m,2H),2.72-2.60(m,3H),2.01-1.60(m,5H).

[0481] Embodiment 14

[0482] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(tetrahydrofuran-3-yl)piperazine-2-carboxamide 14

[0483]

[0484] First step 4-(4-((1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-2-(tetrahydrofuran-3-yl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 14b

[0485] Compound 12b (200 mg, 0.38 mmol) and 3-aminotetrahydrofuran 14a (40 mg, 0.46 mmol) were dissolved in DCM (5 mL), HATU (219 mg, 0.57 mmol) and triethylamine (78 mg, 0.77 mmol) were added, and the mixture was reacted at 25 degrees for 3 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 14b (153 mg, yield 68%) as a white solid.

[0486] Step 2 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-N-tetrahydrofuran-3-yl)piperazine-2-carboxamide hydrochloride 14c

[0487] Compound 14b (90 mg, 0.15 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 14c hydrochloride (crude product).

[0488] Step 3 1-(2-chloroacetyl)-4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-tetrahydrofuran-3-yl)piperazine-2-carboxamide 14

[0489] Compound 14c (crude product) was dissolved in DCM (5 mL), triethylamine (61 mg, 0.60 mmol) was added, chloroacetyl chloride (17 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to TLC to obtain the title compound 14 (48 mg, two-step yield 56%) as a white solid.

[0490] LC-MS: m / z = 567.2 [M+H] +

[0491] 1 H NMR (400 MHz, DMSO-d 6 )δ8.28-8.04(m,1H),7.47-7.19(m,5H),6.43(s,1H),5.42(s,1H),4.74-4.16(m,6H),3 .71-3.57(m,5H),3.47(s,3H),3.09-2.86(m,2H),2.72-2.61(m,3H),2.01-1.58(m,5H).

[0492] Embodiment 15

[0493] 1-(2-Chloroacetyl)-4-(4-(((S)-1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((tetrahydrofuran-2-yl)methyl)piperazine-2-carboxamide 15

[0494]

[0495] First step 4-(4-((1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-2-((tetrahydrofuran-2-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 15b

[0496] Compound 12b (200 mg, 0.38 mmol) and tetrahydrofurfurylamine 15a (47 mg, 0.46 mmol) were dissolved in DCM (5 mL), HATU (219 mg, 0.57 mmol) and triethylamine (78 mg, 0.77 mmol) were added, and the mixture was reacted at 25°C for 3 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the solution was separated. The aqueous phase was extracted with DCM (10 mL×2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 15b (189 mg, yield 82%) as a white solid.

[0497] LC-MS: m / z=605.4[M+H] +

[0498] Step 2 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-N-(tetrahydrofuran-2-yl)methyl)piperazine-2-carboxamide hydrochloride 15c

[0499] Compound 15b (90 mg, 0.2 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 15c hydrochloride (crude product).

[0500] Step 3 1-(2-chloroacetyl)-4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-(tetrahydrofuran-2-yl)methyl)piperazine-2-carboxamide 15

[0501] Compound 15c (crude product) was dissolved in DCM (5 mL), triethylamine (61 mg, 0.6 mmol) was added, chloroacetyl chloride (17 mg, 0.2 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to TLC to obtain the title compound 15 (26 mg, two-step yield 30%) as a white solid.

[0502] LC-MS: m / z = 581.2 [M+H] +

[0503] 1 H NMR (400 MHz, DMSO-d 6 )δ8.12-7.98(m,1H),7.49-7.19(m,5H),6.49(s,1H),5.50(s,1H),4.74(s,1H),4.58-4.55(m,2H),4.43-4.39(m ,1H),4.17(s,1H),3.17-3.47(m,7H),3.21-2.95(m,5H),2.71(d,J=4.0Hz,2H),2.61(s,1H),1.82-1.57(m,6H).

[0504] Example 16

[0505] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropylamino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(tetrahydro-2H-pyran-3-yl)piperazine-2-carboxamide 16

[0506]

[0507] First step 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-2-(tetrahydro-2H-pyran-3-yl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 16b

[0508] Compound 12b (200 mg, 0.38 mmol) and tetrahydro-2H-pyran-3-amine 16a (47 mg, 0.46 mmol) were dissolved in DCM (5 mL), HATU (219 mg, 0.57 mmol) and triethylamine (78 mg, 0.77 mmol) were added, and the mixture was reacted at 25 degrees for 3 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 16b (171 mg, yield 74%) as a white solid.

[0509] Step 2 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-N-tetrahydro-2H-pyran-3-yl)piperazine-2-carboxamide hydrochloride 16c

[0510] Compound 16b (90 mg, 0.15 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 16c hydrochloride (crude product).

[0511] Step 3 1-(2-chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropylamino)-6-(methylamino)-1,3,5-triazine-2-yl)-N-(tetrahydro-2H-pyran-3-yl)piperazine-2-carboxamide 16

[0512] Compound 16c (crude product) was dissolved in DCM (5 mL), triethylamine (61 mg, 0.60 mmol) was added, chloroacetyl chloride (17 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to TLC to obtain the title compound 16 (34 mg, two-step yield 39%) as a white solid.

[0513] LC-MS: m / z = 581.2 [M+H] +

[0514] 1 H NMR (400 MHz, DMSO-d 6 )δ8.02-7.73(m,1H),7.47-7.15(m,5H),6.41(s,1H),5.43(s,1H),4.74-4.02(m, 6H),3.64-3.48(m,6H),3.17-2.86(m,5H),2.73-2.61(m,3H),1.82-1.44(m,6H).

[0515] Embodiment 17

[0516] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperazine-2-carboxamide 17

[0517]

[0518] First step 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester 17b

[0519] Compound 12b (200 mg, 0.38 mmol) and 4-aminotetrahydropyran 17a (47 mg, 0.46 mmol) were dissolved in DCM (5 mL), HATU (219 mg, 0.57 mmol) and triethylamine (78 mg, 0.77 mmol) were added, and the mixture was reacted at 25°C for 3 hours. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the solution was separated. The aqueous phase was extracted with DCM (10 mL×2), and the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 17b (155 mg, yield 67%) as a white solid.

[0520] Step 2 4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazin-2-yl)-N-tetrahydro-2H-pyran-4-yl)piperazine-2-carboxamide hydrochloride 17c

[0521] Compound 17b (90 mg, 0.15 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 17c hydrochloride (crude product).

[0522] Step 3 1-(2-chloroacetyl)-4-(4-(1-(2-chlorophenyl)-3-hydroxypropylamino)-6-methylamino-1,3,5-triazine-2-yl)-N-tetrahydro-2H-pyran-4-yl)piperazine-2-carboxamide 17

[0523] Compound 17c hydrochloride (crude product) was dissolved in DCM (5 mL), triethylamine (61 mg, 0.60 mmol) was added, chloroacetyl chloride (17 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to TLC to obtain the title compound 17 (53 mg, two-step yield 61%) as a white solid.

[0524] LC-MS: m / z = 581.2 [M+H] +

[0525] 1 H NMR (400 MHz, DMSO-d 6)δ7.99-7.86(m,1H),7.47-7.17(m,5H),6.42(s,1H),5.43(s,1H),4.72-4.17(m,6H),3 .80-3.68(m,4H),3.48(s,2H),3.35-3.09(m,5H),2.72-2.61(m,3H),1.82-1.34(m,6H).

[0526] Embodiment 18

[0527] 1-(4-(4-(Benzylamino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)-2-chloroethane-1-one 18

[0528]

[0529] Step 1 2 -Benzyl-6-chloro-N 4 -Methyl-1,3,5-triazine-2,4-diamine 18b

[0530] Compound benzylamine 18a (132 mg, 1.23 mmol) was dissolved in THF (5 mL), and DIPEA (289 mg, 2.23 mmol) and compound 1b (200 mg, 1.28 mmol) were added in sequence, and reacted at 25°C for 3 h. The reaction was complete by TLC. The crude product was concentrated and purified by preparative plate to obtain the title compound 18b (211 mg, 75.6%) as a white solid.

[0531] Step 2N 2 -Benzyl-N 4 -methyl-6-(piperazin-1-yl)-1,3,5-triazine-2,4-diamine 18d

[0532] Compound 18b (100 mg, 0.4 mmol) and compound 18c (345 mg, 4 mmol) were dissolved in THF (1 mL) and reacted at 95°C for 16 h in a sealed tube. TLC showed that the reaction was complete. The crude product was concentrated and purified by preparative plate to obtain the title compound 18d (83 mg, yield 69%) as a light yellow solid.

[0533] Step 3 1-(4-(4-(Benzylamino)-6-(methylamino)-1,3,5-triazine-2-yl)piperazin-1-yl)-2-chloroethane-1-one 18

[0534] Compound 18d (60 mg, 0.2 mmol) was dissolved in DCM (3 mL), triethylamine (30 mg, 0.3 mmol) was added, chloroacetyl chloride (25 mg, 0.22 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC to obtain the title compound 19 (23 mg, yield 31%) as a white solid.

[0535] LC-MS: m / z=376.2[M+H] +

[0536] 1 H NMR (400 MHz, DMSO-d 6 )δ7.44-7.17(m,6H),6.67(s,1H),4.41(s,4H),3.72-3.62(m,4H),3.45(s,4H),2.72(d,J=4.0Hz,3H).

[0537] Embodiment 19

[0538] 2-Chloro-1-(4-(4-((2-chlorobenzyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 19

[0539]

[0540] The experimental operation was the same as in Example 18, except that compound 19a was used in place of compound benzylamine 18a in the first step, and the second and third steps were operated in the same manner. Compound 19 was obtained after post-treatment. LC-MS: m / z=410.1 [M+H] + .

[0541] Embodiment 20

[0542] 2-((4-(4-(2-chloroacetyl)piperazin-1-yl)-6-(methylamino)-1,3,5-triazin-2-yl)amino)-2-(2-chlorophenyl)acetate 20

[0543]

[0544] The experimental operation was the same as that of Example 18, except that compound 20a was used in place of compound benzylamine 18a in the first step. The second and third steps were operated in the same manner, and compound 20 was obtained after post-treatment.

[0545] LC-MS: m / z=468.1[M+H] +

[0546] 1 H NMR (400 MHz, DMSO-d 6)δ7.47-7.35(m,2H),7.24-7.18(m,2H),6.26-5.79(m,2H),5.10-4.78(m,2H),4.09(s,2H),3.90-3.37(m,11H),2.90(d,J=4.0Hz,3H).

[0547] Embodiment 21

[0548] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 21

[0549]

[0550] The experimental operation was the same as that of Example 18, except that compound 21a was used in place of compound benzylamine 18a in the first step. The second and third steps were performed in the same manner, and compound 21 was obtained after post-treatment.

[0551] LC-MS: m / z=424.1[M+H] +

[0552] 1 H NMR (400 MHz, DMSO-d 6 )δ7.36-7.30(m,2H),7.20-7.10(m,2H),5.48-5.37(m,1H),4.07(s,2H),3.87-3.29(m,8H),2.88(s,3H),1.45(d,J=8.0Hz,3H).

[0553] Embodiment 22

[0554] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-3-methylpiperazin-1-yl)ethan-1-one 22

[0555]

[0556] Step 1 tert-Butyl 4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-methylpiperazine-1-carboxylate 22b

[0557] Compound 21b (200 mg, 0.67 mmol) was dissolved in toluene (5 mL), and compound 22a (148 mg, 0.74 mmol) and DIPEA (174 mg, 1.34 mmol) were added, and the mixture was reacted at 120°C for 5 h. TLC showed that the reaction was complete. Water (5 mL) was added for quenching, and ethyl acetate (5 mL×2) was used for extraction. The organic phase was washed with saturated sodium chloride (5 mL×2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 22b (186 mg, yield 60%) as a colorless oil.

[0558] Step 2N 2 -(1-(2-chlorophenyl)ethyl)-N 4 -methyl-6-(3-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine 22c

[0559] Compound 22b (80 mg, 0.17 mmol) was added to a dioxane hydrochloride solution (2 mL) and reacted at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain the title compound 22c hydrochloride (crude product).

[0560] Step 3 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazine-2-yl)-3-methylpiperazin-1-yl)ethan-1-one 22

[0561] Compound 22c hydrochloride (crude product) was dissolved in DCM (2 mL), triethylamine (70 mg, 0.7 mmol) was added, chloroacetyl chloride (22 mg, 0.19 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC to obtain the title compound 22 (28 mg, two-step yield 37%) as a white solid.

[0562] LC-MS: m / z=438.2[M+H] +

[0563] Embodiment 23

[0564] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-methylpiperazin-1-yl)ethan-1-one 23

[0565]

[0566] The experimental operation was the same as in Example 22, except that compound 23a was used instead of compound 22a in the first step. The second and third steps were operated in the same manner, and compound 23 was obtained after post-treatment. LC-MS: m / z=438.2 [M+H] + .

[0567] Embodiment 24

[0568] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one 24

[0569]

[0570] The experimental operation was the same as in Example 22, except that compound 24a was used instead of compound 22a in the first step. The second and third steps were operated in the same manner. After post-treatment, compound 24 was obtained. LC-MS: m / z=454.1 [M+H] + .

[0571] Embodiment 25

[0572] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazine-2-carboxylic acid 25

[0573]

[0574] The experimental operation was the same as in Example 22, except that compound 25a was used instead of compound 22a in the first step. The second and third steps were operated in the same manner. After post-treatment, compound 25 was obtained. LC-MS: m / z=468.1 [M+H] + .

[0575] Embodiment 26

[0576] 2-Chloro-1-(4-(4-(methylamino)-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 26

[0577]

[0578] The experimental operation was the same as that of Example 22, except that compound 26a was used instead of compound 22a in the first step. The second step was performed in the same manner as the third step, and compound 26 was obtained after post-treatment.

[0579] LC-MS: m / z = 458.2 [M+H] +

[0580] 1 H NMR (400 MHz, DMSO-d 6)δ7.63-7.57(m,2H),7.48(t,J=8.0Hz,3H),7.30(t,J=8.0Hz,3H),5.48-5.3 7(m,1H),4.08(s,2H),3.77-3.42(m,8H),2.89(s,3H),1.47(d,J=8.0Hz,3H).

[0581] Embodiment 27

[0582] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 27

[0583]

[0584] The experimental operation was the same as that of Example 18. The operation of the first step of this example was the same as that of the second step of Example 18, and compound 1c was used instead of compound 18b. The operation of the second step of this example was the same as that of the third step of Example 18, and compound 27 was obtained after post-treatment.

[0585] LC-MS: m / z=454.2[M+H] +

[0586] 1 H NMR (400 MHz, DMSO-d 6 )δ7.62-7.48(m,2H),7.38-7.35(m,1H),7.31-7.27(m,1H),7.22-7.18(m,1H),6.63-6.54(m,1H),5.52-5. 45(m,1H),4.59(s,1H),4.42(s,2H),3.63-3.36(m,8H),2.74-2.63(m,3H),1.82-1.78(m,2H),1.24(s,2H).

[0587] Embodiment 28

[0588] 2-Chloro-1-(4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-2-methylpiperazin-1-yl)ethan-1-one 28

[0589]

[0590] The experimental operation was the same as that of Example 22, except that compound 1c was used instead of compound 21b in the first step. The second and third steps were operated in the same manner, and compound 28 was obtained after post-treatment.

[0591] LC-MS: m / z = 468.2 [M+H] +

[0592] 1 H NMR (400 MHz, DMSO-d 6 )δ7.49-7.45(m,1H),7.38-7.35(m,1H),7.30-7.27(m,1H),7.21-7.19(m,1H),6.58-6.43(m,1H),5.53-5.43(m, 1H),4.57-4.17(m,6H),3.60-3.34(m,3H),2.93(s,2H),2.72-2.62(m,3H),1.83-1.77(m,2H),1.25-1.02(m,5H).

[0593] Embodiment 29

[0594] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-methylpiperazine-2-carboxamide 29

[0595]

[0596] The experimental operation was the same as that of Example 12. The operation of the first step of this example was the same as that of the third step of Example 12. Compound 29a was used instead of compound 11d. The operation of the second step of this example was the same as that of the fourth step of Example 12. The operation of the third step was the same as that of the fifth step of Example 12. Compound 29 was obtained by post-treatment. LC-MS: m / z=511.2 [M+H] + .

[0597] Embodiment 30

[0598] 2-(4-(2-chloroacetyl)-1-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-2-yl 30

[0599]

[0600] The experimental operation was the same as that of Example 11. The operation of the first step of this example was the same as that of the first step of Example 11, using compound 30a instead of compound 11a. The operation of the second step of this example was the same as that of the second step of Example 11. The operation of the third step was the same as that of the third step of Example 11, using compound 29a instead of compound 11d. The operations of the fourth and fifth steps were the same as those of the fourth and fifth steps of Example 11. Compound 30 was obtained after post-treatment. LC-MS: m / z=525.2 [M+H]+ .

[0601] Embodiment 31

[0602] N-(2-amino-2-oxoethyl)-1-(2-chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazine-2-carboxamide 31

[0603]

[0604] The experimental operation was the same as that in Example 12. The operation of the first step was the same as that of the third step in Example 12, using compound 31a instead of compound 11d. The operation of the second step was the same as that of the fourth step in Example 12, and the operation of the third step was the same as that of the fifth step in Example 12, followed by post-treatment to obtain compound 31.

[0605] LC-MS: m / z = 554.2 [M+H] +

[0606] 1 H NMR (400 MHz, DMSO-d 6 )δ8.43-8.17(m,1H),7.49-7.07(m,7H),6.75-6.32(m,1H),5.59-5.37(m,1H),4.78-4. 02(m,6H),3.81-3.34(m,6H),3.36-3.07(m,1H),2.72-2.50(m,3H),1.90-1.78(m,2H).

[0607] Embodiment 32

[0608] N-(3-amino-3-oxopropyl)-1-(2-chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazine-2-carboxamide 32

[0609]

[0610] The experimental operation was the same as that of Example 12. The operation of the first step of this example was the same as that of the third step of Example 12. Compound 32a was used instead of compound 11d. The operation of the second step of this example was the same as that of the fourth step of Example 12. The operation of the third step was the same as that of the fifth step of Example 12. Compound 32 was obtained by post-treatment. LC-MS: m / z=568.2 [M+H] + .

[0611] 1H NMR (400 MHz, DMSO-d 6 )δ8.29-7.89(m,1H),7.59-7.15(m,5H),7.05-6.30(m,2H),5.60-5.37(m,1H),4.95-4.02(m,6H) ,3.81-3.42(m,4H),3.26-3.07(m,4H),2.82-2.58(m,3H),2.32-2.06(m,2H),1.93-1.78(m,2H).

[0612] Embodiment 33

[0613] 1-(2-Chloroacetyl)-4-(4-((1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 33

[0614]

[0615] The test operation is the same as that of Example 12. The operation of the first step of this example is the same as that of the third step of Example 12, and compound IN-4 is used instead of compound 11d. The operation of the second step of this example is the same as that of the fourth step of Example 12, and the operation of the third step is the same as that of the fifth step of Example 12. Compound 33 is obtained by post-treatment.

[0616] LC-MS: m / z = 594.2 [M+H] +

[0617] 1 H NMR (400 MHz, DMSO-d 6 )δ8.2-7.9(m,1H),7.73-7.13(m,6H),6.70-6.35(m,1H),5.56-5.35(m,1H),5.05-3.95(s,7H) ,3.83-3.42(m,4H),3.25-2.82(m,6H),2.77-2.58(m,3H),241-2.18(m,1H),1.85-1.61(m,3H).

[0618] Embodiment 34

[0619] (4-(4-((1-(2-chlorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)(oxiran-2-yl)methanone 34

[0620]

[0621] Compound 21c (200 mg, 0.29 mmol) and oxirane formic acid (31 mg, 0.35 mmol) were dissolved in DCM (5 mL), HATU (164 mg, 0.43 mmol) and triethylamine (58 mg, 0.57 mmol) were added, and the mixture was reacted at 25°C for 1 hour. TLC showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and the solution was separated. The aqueous phase was extracted with DCM (10 mL×2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column to obtain the title compound 34 (38 mg, yield 31.6%) as a white solid. LC-MS: m / z=418.2 [M+H] + .

[0622] Embodiment 35

[0623] 1-(4-(4-(methylamino)-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)prop-2-en-1-one 35

[0624]

[0625] The first step of the test was the same as the third step of Example 26. In the first step, acryloyl chloride was used instead of chloroacetyl chloride. After post-treatment, compound 35 was obtained. LC-MS: m / z=436.2 [M+H] + .

[0626] Embodiment 36

[0627] 2-(1-(2-chloroacetyl)-4-(4-((1-(-2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-2-yl 36

[0628]

[0629] The experimental operation was the same as that of Example 11. The operation of the first step of this example was the same as that of the first step of Example 11, using compound 36a instead of compound 11a. The operation of the second step of this example was the same as that of the second step of Example 11. The operation of the third step was the same as that of the third step of Example 11, using compound 29a instead of compound 11d. The operations of the fourth and fifth steps were the same as those of the fourth and fifth steps of Example 11. Compound 36 was obtained after post-treatment. LC-MS: m / z=525.2 [M+H] + .

[0630] Embodiment 37

[0631] 2-Chloro-1-(4-(4-(methylamino)-6-((1-phenylethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 37

[0632]

[0633] The experimental operation was the same as that of Example 18, except that compound 37a was used in place of compound benzylamine 18a in the first step. The second step was the same as the third step, and compound 37 was obtained after post-treatment.

[0634] LC-MS: m / z=390.2[M+H] +

[0635] 1 H NMR (400 MHz, DMSO-d 6 )δ7.31-7.27(m,4H),7.23-7.20(m,1H),7.07-6.97(m,1H),5.16-5.03(m,1H) ,4.08(s,2H),3.76-3.45(m,8H),2.88(d,J=8.0Hz,3H),1.49(d,J=4.0Hz,3H).

[0636] Embodiment 38

[0637] 2-Chloro-1-(4-(4-((1-(2-fluorophenyl)ethyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethan-1-one 38

[0638]

[0639] The experimental operation was the same as that of Example 18, except that compound 38a was used in place of compound benzylamine 18a in the first step. The second and third steps were performed in the same manner, and compound 38 was obtained after post-treatment.

[0640] LC-MS: m / z = 408.2 [M+H] +

[0641] 1 H NMR (400 MHz, DMSO-d 6 )δ7.32-7.26(m,1H),7.20-7.15(m,1H),7.07-6.97(m,1H),5.40-5.30(m,1H) ,4.08(s,2H),3.76-3.58(m,8H),2.87(d,J=8.0Hz,3H),1.49(d,J=8.0Hz,3H).

[0642] Embodiment 39

[0643] 1-(2-Chloroacetyl)-4-(4-(((S)-1-(2-chlorophenyl)-3-hydroxypropyl)amino)-6-(methylamino)-1,3,5-triazin-2-yl)-N-((2-oxopyrrolidin-3-yl)methyl)piperazine-2-carboxamide 39

[0644]

[0645] The experimental operation of 39a is the same as that of Example 1, except that compound S-IN-2 is used instead of compound benzylamine IN-2 in the first step, the experimental operation of 39c is the same as that of implementation 12, and compound 39a is used instead of compound 1c in the second step. The experimental operation of 39 is the same as that of implementation 33, and compound 39c is used instead of compound 12b in the fourth step, and compound 39 is obtained after post-treatment.

[0646] LC-MS: m / z = 594.2 [M+H] +

[0647] Pharmacological activity test

[0648] Test Example 1 Evaluation of the inhibitory activity of 3CL protease of novel coronavirus

[0649] The fluorescence resonance energy transfer method was used to evaluate the inhibitory activity of the measured compounds on the SARS-CoV-2 3CL protease. The volume of the entire enzymatic reaction system was 120 μL, the final concentration of the protease was 30 nM, and the final concentration of the substrate was 20 μM. The buffer of the reaction system included 50 mM Tris pH 7.3 and 1 mM EDTA. SARS-CoV-2 3CL protease and samples such as compounds or mixtures of different concentrations were added to a 96-well plate, incubated at 30 ° C for 10 min, added the substrate and quickly placed in the microplate reader for reading. The excitation light and emission light were 340 nm and 405 nm, respectively. The test time was 3.5 min, and the fluorescence value was read every 30 s. The final result was to fit the reaction rate with the reading of the first 2 min, and compared with the control group (DMSO) to calculate the inhibition rate. The results are shown in Table 1 (the concentrations of the tested compounds were 10 μM and 1 μM).

[0650] Table 1 Inhibition rate of the compounds of the present invention on the activity of 3CL protease of novel coronavirus

[0651]

[0652]

[0653] Conclusion: The compounds of the present invention have a significant inhibitory effect on the enzymatic activity of SARS-CoV-2 3CL protease.

[0654] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the antiviral tri-substituted amine derivative of cyanuric chloride and its preparation method and application, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0655] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0656] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A cyanuric chloride compound, and a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof, characterized in that: The cyanuric chloride compound has the formula (I): in: R 1 Selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 alkyleneoxy-C1-C10 alkyl, substituted or unsubstituted C1-C10 alkylamino, substituted or unsubstituted C1-C6 alkanoyl, substituted or unsubstituted C6-14 aryl, or substituted or unsubstituted C5-14 heteroaryl; R a is selected from hydrogen, substituted or unsubstituted C1-10 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -C(=O)R 5 、-OC(=O)R 5 、-C(=O)OR 5 、-OR 5 、-SR 5 、-S(=O)R 5 、-S(=O)2R 5 、-S(=O)2N(R 5 )2、-N(R 5 )2, -C(=O)N(R 5 )2.-NR 5 -C(=O)R 5 、-NR 5 -C(=O)OR 5 、-NR 5 -S(=O)2-R 5 、C(=O)-N(R 5 )2, -C1-6 alkylene-N(R 5 )2, -C1-6 alkylene-OR 5 、-C1-6 alkenylene-OR 5 and -O-C1-6 alkylene-N(R 5 )2; where R 5 is H, guanidinyl, C1-C6 alkyl, saturated or partially unsaturated C 3-6 Cycloalkyl, saturated or partially unsaturated three- to ten-membered heterocyclic group or C6-10 aryl group; R b is selected from hydrogen, substituted or unsubstituted C6-14 aryl, -NH-C1-6 alkylene-substituted or unsubstituted C6-14 aryl, -C1-6 alkylene-NH-substituted or unsubstituted C6-14 aryl; R c is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C7 oxacycloalkyl, substituted or unsubstituted C2-C8 olefin, substituted or unsubstituted C6-14 aryl, halogenated C1-10 aliphatic hydrocarbon, -C1-6 alkylene-NH-substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic, -NHCH2R C1 , R C1 A saturated lactam ring selected from five to seven members; X is selected from CH or N atoms; R d Selected from hydrogen, C1-6 alkyl, C1-6 alkylene-OH, C1-6 alkylene-C(O)N(R 7 )2、C(O)NH-C1-6 alkylene-C(O)N(R 7 )2. -C(O)OR 7 、-C(O)N(R 7 )2、-C(O)-N(R 7 )-five-seven-membered heterocyclic group or -C(O)-N(R 7 )-C1-6 alkylene-five to seven-membered heterocyclic group, wherein the five to seven-membered heterocyclic group is a substituted or unsubstituted saturated or partially unsaturated group, R 7 is H, C1-C6 alkyl, saturated or partially unsaturated C3-6 cycloalkyl, or C6-10 aryl; R d Substitution on any carbon atom in the six-membered ring except the N atom and the X atom; The above-mentioned substitution or unsubstitution means that one or more H in the group is replaced by a group selected from one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or means that two H in -CH2- in the group are replaced by oxo=O.

2. The cyanuric chloride compound according to claim 1, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer, wherein: R 1 Selected from C1-C3 alkyl, C3-C6 cycloalkyl; R a is selected from hydrogen, C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)O CH3、-OR 6 、-SR 6 、-S(=O)R 6 、-S(=O)2R 6 、-S(=O)2N(R 6 )2、-N(R 6 )2, -C(=O)N(R 6 )2.-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S(=O)2-R 6 、C(=O)-N(R 6 )2, -C1-6 alkylene-N(R 6 )2, -C1-6 alkylene-OR 6 、-C1-6 alkenylene-OR 6 and -O-C1-6 alkylene-N(R 6 )2; Among them, R 6 is H, methyl; R b Selected from substituted or unsubstituted phenyl, -CH2-NH-substituted or unsubstituted phenyl; R c is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, halogenated C1-C3 alkyl, -C1-6 alkylene, -NH-substituted or unsubstituted saturated or partially unsaturated C3-10 heterocyclic group, -NHCH2R C1 , R C1 A saturated lactam ring selected from five to seven members; R d Selected from hydrogen, C1-3 alkyl, C1-3 alkylene-OH, CH2C(O)NHR 9 、C(O)NH(CH2)C(O)NHR 9 、C(O)OR 9 、C(O)NHR 9 、-C(O)-NR 9 -5-7-membered heterocyclic group or -C(O)-NR 9 -C1-6 alkylene-five to seven-membered heterocyclic group, wherein the five to seven-membered heterocyclic group is substituted or unsubstituted, saturated or partially unsaturated; R 9 is H, methyl; The above-mentioned substitution or unsubstitution means that one or more H in the group is replaced by a group selected from one or a combination of at least two of halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or two H in -CH2- in the group are replaced by oxo=O.

3. The cyanuric chloride compound according to claim 1, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer, R1 is selected from methyl, ethyl, propyl; R a is selected from hydrogen, methyl, hydroxymethyl, hydroxyethyl, methylformyl; R b is selected from unsubstituted or substituted phenyl, -CH2-NH-unsubstituted or substituted phenyl, R c Selected from unsubstituted or substituted phenyl, chloromethyl, oxirane, C2 olefin, -CH2-NH-five- to seven-membered heterocyclic group, -NHCH2-five-membered saturated lactam ring, wherein the substituted phenyl means that the H on the phenyl group is optionally substituted by 1 to 3 halogen, hydroxy, methoxy, methyl, ethyl, trifluoro, cyano or amino groups; R d Selected from hydrogen, methyl, CH2OH, CH2C(O)NHCH3, C(O)NHCH2C(O)NH2, C(O)NHCH2CH2C(O)NH2, C(O)OH, C(O)NHCH3, C(O)-NH-R d1 or C(O)NH-CH2R d1 ; R d1 A five- to seven-membered heterocyclic group, wherein the heterocyclic group includes one heteroatom selected from oxygen, sulfur or nitrogen, and the oxygen, sulfur or nitrogen atom is at any position in the ring. The five- to seven-membered heterocyclic group may be saturated or partially saturated. When the heterocyclic atom is selected from nitrogen atom, the heterocycle is a saturated lactam structure.

4. The cyanuric chloride compound according to claim 1, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer, wherein the cyanuric chloride compound has a structure represented by formula (II) to (VI), in, R c , R d and X have the same definition as in the above general formula (I), R f It represents one or both of hydrogen, halogen, hydroxy, methoxy, methyl, ethyl, trifluoro, cyano or amino.

5. The cyanuric chloride compound according to claim 1, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer, wherein: R c Selected from the following groups R d A group selected from methyl, hydroxymethyl, hydroxyethyl and the following * indicates the attachment site.

6. The cyanuric chloride compound according to claim 1, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer, wherein the cyanuric chloride compound is the following specific compound:

7. The antiviral use of the cyanuric chloride compound according to any one of claims 1 to 6, and its pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

8. The method according to claim 7, wherein the virus is a coronavirus, a calicivirus or a picornavirus infection.

9. Use of the cyanuric chloride compound according to any one of claims 1 to 6, and its pharmaceutically acceptable salt, its tautomer or its stereoisomer in the preparation of a drug for treating viral infection.

10. A pharmaceutical composition, characterized in that The invention comprises the cyanuric chloride compound as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient.

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