Application of HPK1 inhibitors in the treatment of interferon-related diseases

Abstract

The present invention discloses a new class of compounds with HPK1 inhibitory activity, and for the first time reveals the unique mechanism relationship between HPK1 kinase and viral infection.The compounds of the present invention can be used to treat interferon-related diseases, especially viral infections.The present invention further provides a method for treating interferon-related diseases using the compounds of the present invention.

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine. Specifically, the present invention relates to the application of HPK1 inhibitors in the treatment of interferon-related diseases, particularly in the treatment of viral infections by restoring or enhancing IFN-β signaling pathway. [Background technology]

[0002] Hematopoietic progenitor kinase 1 (HPK1), also called mitogen-activated protein kinase kinase kinase kinase (MAP4K1), is a serine / threonine protein kinase. It is involved in various cellular events, including mitogen-activated protein kinase signaling, nuclear factor kappa B signaling, cytokine signaling, cell proliferation and apoptosis, T cell receptor / B cell receptor signaling, and T / B / dendritic cell-mediated immune responses. HPK1 is mainly expressed in blood cells. In T cells, HPK1 is a negative regulator of T cell receptor (TCR) signals and is involved in the inhibition of immune responses. Upon TCR activation, HPK1 is recruited to the cell membrane, where it is subsequently activated by phosphorylation at the Tyr281\Ser171\Thr165 sites. Activated HPK1 destabilizes the TCR signaling complex by phosphorylating the Ser276 site of the SLP76 protein, thereby inhibiting T cell activation and proliferation. At the same time, HPK1 activation also inhibits the secretion of interferon-gamma (IFN-γ). In a series of tumor immunity animal models, knockout / knockdown of HPK1 or the use of HPK1 inhibitors can effectively block the suppression of the immune system by HPK1, enhance the body's immunity, and thereby enhance the antitumor effect (Hernandez et al., Cell R eOn the other hand, in mice infected with lymphocytic choriomeningitis virus (LCMV), 21 days after infection, the viral titers in the plasma of HPK1 knockdown mice were significantly lower than those of wild-type mice, suggesting that inhibition of HPK1 activity may be a new antiviral therapeutic approach. A patent (WO2020255022) filed by Janssen Sciences Ireland Unlimited Company indicates that the combination of hepatitis B vaccine (HBV) and HPK1 small molecule inhibitors may be an effective treatment to cure hepatitis B.

[0003] Despite the above research foundations, so far, the intrinsic mechanism between HPK1 kinase and viral infection has not been elucidated, and at the same time, there have been no reports investigating the use of HPK1 small molecule inhibitors alone or in combination (non-vaccine adjuvants) as broad-spectrum antiviral drugs for the treatment of virus-associated diseases. Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide a series of novel HPK1 inhibitors, which can be used as therapeutic agents for interferon-related diseases, particularly viral infections. [Means for solving the problem]

[0005] In a first aspect, the present invention provides an application of HPK1 inhibitors in treating interferon-related diseases or preparing drugs for enhancing immunity. In a preferred embodiment, the interferon is IFN-β and / or IFN-γ. In a preferred embodiment, the agent is an IFN-β and / or IFN-γ signaling pathway enhancer.

[0006] In a specific embodiment, said interferon-associated disease is a viral infection. In a preferred embodiment, the viral infection is a viral infection for which IFN-β / IFN-γ has a therapeutic and / or prophylactic effect.

[0007] In a specific embodiment, the HPK1 inhibitor is a compound of formula I, or a pharma- ceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite, or derivative thereof: [ka] In the formula, Z1 is selected from N or C-RR1; Z2 and Z3 are each selected from N or C-RR2, where Z2 and Z3 are different; RR1 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 1-6 is selected from an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group; RR2 is selected from a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted sulfhydryl group; RR3 is H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl groups, substituted or unsubstituted C 1-6 is selected from an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group; RR4, RR5, RR6, and RR7 each independently represent H, a hydroxyl group, a halogen, a cyano group, or a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl groups, substituted or unsubstituted C 1-6 Alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted amido group, substituted or unsubstituted C5-10 a heteroaryl group or RR-Z-; RR8 is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or a substituted or unsubstituted hydroxyl group; Z4 is selected from -O-, -NH-, -S-, -SO-, -SO2-, a carbonyl group, a carbonylamino group or an aminocarbonyl group.

[0008] In a specific embodiment, the compound of formula I is a compound of formula I-1: [ka] In the formula, R a , R b , R c , R d One of these is R 1’ -X ’ -, and the remainder are each independently H, a hydroxyl group, a halogen, a cyano group, or a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl group or substituted or unsubstituted C 1-6 alkoxy groups, R e is H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl group or substituted or unsubstituted C 1-6 alkoxy groups, X ’ is selected from -O-, -NH-, -S-, -SO-, -SO2-, a carbonyl group, a carbonylamino group or an aminocarbonyl group; R 1’ is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or R 14’ -O-(CH2) m- where m is 0, 1, 2, 3, 4 or 5; R 14’ is a substituted or unsubstituted C1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein the heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R 2’ is selected from the following substituents: [ka] Here, Y ’ is C or N, R 7’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 8’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 R9 is a cycloalkyl group. ’ and R 10 ’ are independently H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 11’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 12’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group.

[0009] In a preferred embodiment, R 1’ is a substituted or unsubstituted 5- to 8-membered cycloalkyl group or a substituted or unsubstituted 5- to 8-membered heterocyclyl group, wherein the heterocyclyl group has 1 to 4 heteroatoms selected from O, S or N.

[0010] In a preferred embodiment, R 1’is a substituted 5- to 8-membered cycloalkyl group, 1’ teeth, [ka] where n is 1, 2, 3 or 4; R 3’ -OR 4’ or -NR 5’ R 6’ where R 4’ H, [ka] R is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group. 5’ and R 6’ are independently H, [ka] is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group, where R 5’ and R 6’ is not simultaneously a substituted or unsubstituted cycloalkyl group.

[0011] R 13’ is H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 It is a cycloalkyl group. In a preferred embodiment, the A ring is [ka] is selected from the group consisting of:

[0012] In a specific embodiment, the compound of formula I-1 is as represented by formula I-1-1: [ka] In the formula, R b , R c , R d , Re each independently represents H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl group or substituted or unsubstituted C 1-6 alkoxy groups, X ’ is selected from -O-, -NH-, -S-, -SO-, -SO2-, a carbonyl group, a carbonylamino group or an aminocarbonyl group; R 1’ is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or R 14’ -O-(CH2) m- where m is 0, 1, 2, 3, 4 or 5; R 14’ is a substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein the heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R 2’ is selected from the following substituents: [ka] Here, Y ’ is C or N, R 7’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 8’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 Cycloalkyl group, R9 ’ and R 10 ’ are independently H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8is a cycloalkyl group, R 11’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 12’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group.

[0013] In a specific embodiment, the compound of formula I-1 is as represented by formula I-1-1-1 or I-1-1-2: [ka] In the formula, R b , R c , R d , R e each independently represents H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl group or substituted or unsubstituted C 1-6 alkoxy groups, X is selected from -O-, -NH-, -S-, -SO-, -SO2-, a carbonyl group, a carbonylamino group or an aminocarbonyl group; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; R 14’ is a substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein the heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R 2’ is selected from the following substituents: [ka] Here, Y’ is C or N, R 7’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 8’ is H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 R9 is a cycloalkyl group. ’ and R 10 ’ are independently H, substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 11’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C 1-6 Alkyl group or substituted or unsubstituted C 3-8 is a cycloalkyl group, R 12’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group.

[0014] In specific embodiments, the compound is selected from the group consisting of: [ka]

[0015] [ka]

[0016] [ka]

[0017] [ka]

[0018] [ka]

[0019] In a specific embodiment, the compound of formula I is a compound of formula I-2: [ka] In the formula: R1, R2, R3, R4 and R5 each independently represent a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 1-6 an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group, and R1 and R2 are not hydrogen; R6 is, [ka] and X is O, NH or S, Y is O, NH or S, and the A ring is a substituted or unsubstituted C 3-6 Cycloalkyl group or substituted or unsubstituted C 6-10 Aryl group or substituted or unsubstituted C 5-10 Heteroaryl groups, which refer to aryl groups containing one or more N, O or S heteroatoms, and R7 is a halogen, a cyano group, a hydroxyl group, an amino group, an amide group, a branched or linear C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Heterocyclyl group, C 6-10 Aryl group, C 5-10 Heteroaryl groups or single or multiple substitutions on the various rings, including -C(O)R', where R' is C 3-6 Heterocyclyl group, C 6-10 Aryl group or C 5-10 A heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Heterocyclyl group, C 6-10Aryl groups and C 5-10 The heteroaryl group may further include various single or multiple substitutions including hydrogen, hydroxyl, halogen, cyano, amino, -CHF2, -CF3, -CH3, -CH2CH2OH, or -CONH2; or R7 and ring A together form a substituted or unsubstituted fused, bridged, heterobridged, spiro, or heterospiro ring; R8, R9 and R 10 are each independently i. Hydrogen, hydroxyl group, halogen, cyano group, amino group, di(C 1-6 alkyl)amino group, mono(C 1-6 alkyl)amino group or C 1-6 Alkoxy groups, ii. Hydrogen, hydroxyl group, halogen, cyano group, amino group, -CHF2, -CF3, di(C 1-6 alkyl)amino group, mono(C 1-6 alkyl)amino group, C 3-6 Cycloalkyl group or C 1-6 Branched or linear C further containing a variety of single or multiple substitutions, including alkoxy groups. 1-6 Alkyl group, C 2-6 Alkenyl group or C 2-6 Alkynyl groups, iii. Hydrogen, C 1-6 C with various single or multiple substitutions including alkyl, hydroxyl, halogen, cyano, amino, -CHF2 or -CF3 3-6 Cycloalkyl groups, C 3-6 Heterocyclyl group, C 6-10 Aryl group or C 5-10 heteroaryl groups.

[0020] In a specific embodiment, the compound of formula I-2 is as represented by formula I-2-1: [ka] In the formula, R1, R2, R6, R8, R9 and R 10 are each as defined above. In a specific embodiment, the compound of formula I-2 is as represented by formula I-2-2: [ka] In the formula, R1, R2, R6 and R8 are each as defined above. In a preferred embodiment, X is NH.

[0021] In a specific embodiment, the compound of formula I-2 is as represented by formula I-2-3: [ka] In the formula, R1, R2, R8 and ring A are each as defined above.

[0022] In a preferred embodiment, the A ring is [ka] is selected from Here, Z is O or S.

[0023] In a preferred embodiment, R7 is a halogen, a cyano group, a hydroxyl group, an amino group, an amido group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a vinyl group, an ethynyl group, [ka] is selected from.

[0024] In a preferred embodiment, the A ring and R7 together represent: [ka] and forming an optionally substituted fused ring, bridged ring, heterobridged ring, spiro ring, or heterospiro ring group selected from the group consisting of:

[0025] In a preferred embodiment, R1 is an amino group, a hydroxyl group, a cyano group, a methoxy group or a halogen substituent. In preferred embodiments, R8 is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a vinyl group, an ethynyl group, or a substituted or unsubstituted aryl group (preferably phenyl) or a 5-membered heteroaryl group. In preferred embodiments, R8 is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, or a substituted or unsubstituted phenyl group.

[0026] In specific embodiments, the compound is selected from the following: [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5]

[0027] In a specific embodiment, the compound is [ka] It is.

[0028] In a specific embodiment, the virus is selected from the group consisting of Hepatitis B virus, Measles virus, Sindbis virus, West Nile virus, Dengue virus, Herpes simplex virus, Human cytomegalovirus (HCMV), Ebola virus, Hepatitis C virus (HCV), Influenza A virus, Severe acute respiratory syndrome virus (SARS-CoV), Zika virus, Human immunodeficiency virus (HIV), Feline infectious peritonitis virus, Mouse hepatitis virus, Canine coronavirus, Feline calicivirus, Feline leukemia virus, Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus, Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea Virus, Porcine Hemagglutinating Encephalomyelitis Virus, Bovine Coronavirus, and the like, preferably Feline Infectious Peritonitis Virus, Mouse Hepatitis Virus,Virus), herpes simplex virus, severe acute respiratory syndrome virus, Zika virus, feline infectious peritonitis virus, canine coronavirus, feline calicivirus, avian infectious bronchitis virus, and porcine epidemic diarrhea virus.

[0029] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite or derivative thereof and one or more other antiviral agents, and optionally a pharma- ceutically acceptable excipient.

[0030] In a third aspect, the present invention provides a compound of the invention for use as a treatment for an interferon-associated disease.

[0031] In a fourth aspect, the present invention provides a method of treating an interferon-associated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention. Effect of the Invention

[0032] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief description of the drawings]

[0033] [Figure 1] We show that overexpression of HPK1 can significantly inhibit the IFN-β signaling pathway induced by SeV virus. [Diagram 2] 13 shows that overexpression of HPK1 at different doses can dose-dependently inhibit IFN-β expression induced by SeV. [Diagram 3] This shows that overexpression of HPK1 at different doses can inhibit ISRE expression induced by SeV in a dose-dependent manner. [Figure 4] 1 shows that HPK1 small molecule inhibitors restore IFN-β expression inhibited by HPK1. [Diagram 5] 1 shows that compound C2 restores IFN-β expression inhibited by HPK1 in a dose-dependent manner. [Figure 6] We show that HPK1 inhibitors significantly reduce viral expression levels in liver tissue of MHV-infected C57 mouse models. [Figure 7] FIG. 1 shows that oral administration of different doses of C1 compound (twice daily) has a dose-dependent inhibitory effect on the viral content in the liver of MHV-infected C57 mice. [Figure 8] FIG. 1 shows that oral administration (twice daily) of different doses of C1 compound has a dose-dependent inhibitory effect on alanine aminotransferase (ALT) in serum of MHV-infected C57 mice. [Figure 9] The synthetic route of compound DD02001H is shown. [Figure 10] The synthetic route of compound DD02013H is shown. [Figure 11] The synthetic route of compound DD02014H is shown. [Figure 12] The synthetic route of compound DD02006H is shown. [Figure 13] The synthetic route of compound DD02008H is shown. [Figure 14] The synthetic route of compound DD02015H is shown. [Figure 15] The synthetic route of compound DD02021H is shown. [Figure 16] The synthetic route of compound DD02018H is shown. [Figure 17] The synthetic route of compound DD02002H is shown. [Figure 18] The synthetic route of compound DD02019H is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] After extensive and detailed research, the present inventors have unexpectedly discovered a series of highly active and highly selective HPK1 small molecule inhibitors. The present inventors further elaborate the unique mechanistic relationship between HPK1 kinase and viral infection, and at the same time evaluate the antiviral effects of these HPK1 small molecule inhibitors as monotherapy at the cell and animal model levels. Research results show that HPK1 small molecule inhibitors, either as single agents or as compositions, are promising as a new type of broad-spectrum antiviral therapy in the treatment of virus-related diseases. Based on this basis, the present invention has been completed.

[0035] Definition of Terms The terms used herein are the same as or similar to those conventionally understood by those skilled in the art. For ease of understanding, some terms used herein are defined as follows:

[0036] The term "alkyl group" as used herein refers to branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12, 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. The numeric position, represented as a subscript following the symbol "C", indicates the number of carbon atoms that can be contained in a particular group. For example, "C 1-6 "Alkyl group" refers to straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0037] The term "alkenyl group" as used herein refers to a straight or branched chain hydrocarbon group having at least one double bond. The alkenyl group may be optionally substituted with one or more substituents and includes groups having "cis" and "trans" orientations, or "E" and "Z" orientations. Examples include, but are not limited to, vinyl groups, allyl groups, and the like.

[0038] The term "alkynyl group" as used herein generally refers to a branched or straight chain hydrocarbon group having at least one triple bond. An alkynyl group may be optionally substituted. In this application, "C 2-3 Alkynyl group, C 2-4 Alkynyl group, C 2-5 Alkynyl group, C 2-6 Alkynyl group, C 2-7 Alkynyl group" and "C 2-8 The term "alkynyl group" typically refers to an alkynyl group containing at least 2 and at most 3, 4, 5, 6, 7, or 8 carbon atoms, respectively. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.

[0039] The term "cycloalkyl group" as used herein refers to a group obtained by removing one hydrogen atom from a cyclic hydrocarbon molecule. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl groups. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups.

[0040] As used herein, the term "heteroatom" refers to oxygen (O), sulfur (S) or nitrogen (N). "Halo" and "halogen" refer to F, Cl, Br or I. Correspondingly, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogens.

[0041] As used herein, the term "cyano group" refers to a -CN group. The term "amino group" refers to a -NH2 group.

[0042] The term "heterocycloalkyl group" or "heterocyclyl group" as used herein refers to a cycloalkyl group containing 1 to 4 heteroatoms (monocyclic), 1 to 6 heteroatoms (bicyclic), or 1 to 9 heteroatoms (tricyclic), selected from O, S, or N. A heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms in each ring of a heterocycloalkyl group may be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolyl, THF, tetrahydrothienyl, thienyl, and the like.

[0043] The term "aromatic ring" or "aryl group" as used herein refers to a group obtained by losing one hydrogen atom from a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. The aryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each aryl ring may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0044] The term "aromatic heterocycle" or "heteroaryl group" as used herein refers to an "aromatic ring" or "aryl group" having at least one heteroatom (O, S or N) in at least one ring, said heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms independently selected from O, S or N. Each ring of the heteroatom-containing heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents. Non-limiting examples of heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolyl, indazolyl, and the like.

[0045] The term "alkoxy group" as used herein refers to an -O-alkyl group that may be optionally substituted with one or more substituents.

[0046] As used herein, "(CO)" and "C(O)" represent carbonyl moieties. Examples of suitable carbonyl moieties include, but are not limited to, ketone and aldehyde moieties.

[0047] As used herein, the term "alkylamino group" refers to an amino group substituted with one or two alkyl groups. The term "aminoalkyl group" refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups. The alkyl group portion optionally bears one or more substituents.

[0048] As used herein, the term "spirocyclyl group" refers to a polycyclic group in which two carbocyclic rings share one carbon atom. A heterospirocyclyl group refers to a polycyclic group in which two monocyclic rings share one carbon atom, where the two rings can contain one or more heteroatoms.

[0049] The term "bridged ring group" as used herein refers to a cyclic group in which any two carbocyclic rings share two carbon atoms that are not directly bonded, and depending on the number of rings formed, can be classified as bicyclic, tricyclic, tetracyclic, etc. A "hetero bridged ring group" refers to a polycyclic heterocyclyl group, and the two rings of the polycyclic heterocyclyl group share two non-adjacent carbon atoms or heteroatoms.

[0050] The term "fused ring group" as used herein refers to a polycyclic organic compound formed by two or more carbon rings that share the ends of the rings. A "fused heterocyclic ring group" refers to a polycyclic heterocyclyl group in which two rings share two adjacent carbon atoms or heteroatoms.

[0051] The term "isomer" or "stereoisomer" as used herein refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0052] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via different energy barriers. For example, prototropic tautomers (also called protic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via rearrangement of some of the bonding electrons.

[0053] The term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. The term "enantiomer" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate."

[0054] The term "prevention and / or treatment" as used herein includes not only prevention and / or treatment of a disease, but also generally includes prevention of the onset of a disease, delay or reversal of the progression of a disease, prevention or delay of onset of one or more symptoms associated with a disease, reduction and / or alleviation of one or more symptoms associated with a disease, reduction in the severity and / or duration of a disease and / or any symptoms associated therewith, and / or prevention of further increase in the severity of a disease and / or any symptoms associated therewith, prevention, reduction or reversal of any physiological damage caused by a disease, and any pharmacological effect generally beneficial to the patient receiving treatment. The compounds or compositions of the present application need not form a viable therapeutic agent to achieve a complete cure or eradication of any symptoms or manifestations of a disease. As will be appreciated in the relevant art, a drug used as a therapeutic agent may reduce the severity of a particular pathology, but need not eliminate all symptoms of a disease to be considered a useful therapeutic agent. Similarly, a treatment administered prophylactically need not be completely effective in preventing the onset of a condition to constitute a viable prophylactic agent. It may be sufficient to simply reduce the impact of the disease in a subject (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood that the disease will occur or worsen. As used herein, the term "prevention and / or treatment" includes prevention and / or treatment of disease by various means, for example, prevention and / or treatment of disease can be achieved by improving the subject's immunity.

[0055] As used herein, the term "dosing" or "administration" includes any means by which the compound is introduced into a subject to achieve its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.

[0056] The term "effective amount" as used herein includes an amount at a dosage and time period necessary to effectively achieve a desired result. An effective amount of a compound can vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to obtain an optimal therapeutic response. A "therapeutically effective amount" refers to an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disease, (ii) relieves, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disease, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disease described in the present application.

[0057] The term "subject" or "patient" as used herein refers to animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0058] The term "inhibit" as used herein means to reduce the activity of the target enzyme compared to the activity of the enzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" means a reduction in HPK1 activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, or a reduction in HPK1 activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%, or a reduction in HPK1 activity of about 95% to 100%, such as a reduction in activity of 95%, 96%, 97%, 98%, 99%, or 100%, etc.

[0059] Compounds of the Invention The present invention provides a series of compounds with HPK1 inhibitory activity. The compounds of the present invention can improve or restore the expression or production of interferon in a subject, thereby enhancing the immunity of the subject, and further treat and / or prevent disease. For example, the HPK1 inhibitory activity compounds of the present invention can enhance IFN-β-mediated antiviral effect and / or enhance IFN-γ-mediated T cell activation, thereby treating and / or preventing viral infection. In another embodiment, the HPK1 inhibitory activity compounds of the present invention can also be used to improve the immunity of a subject.

[0060] In a specific embodiment, the present invention provides a compound according to formula I, [ka] Each of the substituents in the formula is as defined above.

[0061] In a preferred embodiment, the compound of the present invention is a compound represented by the following formula I-1: [ka] Each of the substituents in the formula is as defined above.

[0062] In a further preferred embodiment, the compound represented by formula I-1 may be a compound represented by formula I-1-1, [ka] Each of the substituents in the formula is as defined above.

[0063] In a more preferred embodiment, the compound represented by formula I-1-1 may be a compound represented by formula I-1-1-1 or I-1-1-2, [ka] Each of the substituents in the formula is as defined above.

[0064] In another preferred embodiment, the compound of the present invention may be a compound represented by formula I-2: [ka] Each of the substituents in the formula is as defined above.

[0065] In a further preferred embodiment, the compound of the present invention may be a compound represented by formula I-2-1, I-2-2 or I-2-3, [ka] Each of the substituents in the formula is as defined above.

[0066] The compounds of the present invention can form pharma- ceutically acceptable salts, such as organic or inorganic salts formed with the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronic acid, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may contain another molecule, such as an acetate ion, a succinate ion, or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged electron in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, the salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged electrons and / or one or more counter ions.

[0067] The compounds of the present invention can also form solvates (e.g., hydrates). The term "solvate" refers to a physical association of a compound with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. Under certain circumstances, a solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates and ethyl acetate solvates. Solvation methods are known in the art.

[0068] The compounds of the present invention can be metabolized in vivo. Therefore, the scope of protection of the present invention also includes "metabolites", i.e., products produced by metabolism of a particular compound or its salt in the body.

[0069] The compounds of the present invention can also be "prodrugs" or "prodrugs", i.e., prodrug compounds, which, when administered to a subject, undergo chemical conversion through metabolic or chemical processes to yield a compound of Formula I or a salt thereof. Prodrugs are well known in the art (see, e.g., Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0070] The compounds of the present invention can also form esters, and therefore esters are also within the scope of this application. Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates.

[0071] The compounds of the present application are intended to include all isotopes of atoms present in the compounds of the present application. For example, hydrogen isotopes include deuterium (D) and tritium (T). Carbon isotopes include 13C and 14C. Isotopically labeled compounds of the present application can be prepared by conventional techniques generally known to those skilled in the art, or by methods similar to those described in the present application, using suitable isotopically labeled reagents instead of non-labeled reagents used under other circumstances.

[0072] The term "derivative" refers to a compound formed by replacing an atom or group of atoms in a parent compound molecule with another atom or group of atoms.

[0073] Interferon-Related Disorders The interferon-associated disease as described herein refers to a disease that can be treated and / or prevented by increasing or restoring the expression or production of interferon in a subject by administering a compound of the present invention. In a specific embodiment, the interferon is IFN-β and / or IFN-γ, and thus the compound of the present invention can function as an enhancer of the IFN-β and / or IFN-γ signaling pathway, and the "interferon-associated disease" as described herein also includes all viral infections for which IFN-β / IFN-γ has a therapeutic and / or prophylactic effect.

[0074] In a specific embodiment, the interferon-associated disease is an infection caused by Hepatitis B virus, Measles virus, Sindbis virus, West Nile virus, Dengue virus, Herpes simplex virus, Human cytomegalovirus (HCMV), Ebola virus, Hepatitis C virus (HCV), Influenza A virus, Severe acute respiratory syndrome virus (SARS-CoV), Zika virus, Human immunodeficiency virus (HIV), Feline infectious peritonitis virus, Mouse hepatitis virus, Canine coronavirus, Feline calicivirus, Feline leukemia virus, Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus, Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea Virus, Porcine Hemagglutinating Encephalomyelitis Virus, Bovine Coronavirus, and the like, preferably Feline Infectious Peritonitis Virus, Mouse Hepatitis Virus,Virus, herpes simplex virus, severe acute respiratory syndrome virus, Zika virus, feline infectious peritonitis virus, canine coronavirus, feline calicivirus, avian infectious bronchitis virus, and porcine epidemic diarrhea virus.

[0075] Pharmaceutical Compositions In view of the fact that the compounds of the present invention can treat interferon-related diseases, the compounds of the present invention can be formulated into pharmaceutical compositions comprising the compounds of the present invention or a pharma- ceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite or derivative thereof, and any pharma- ceutically acceptable excipient.

[0076] The term "pharmacologically acceptable" means that the described compound, substance, composition and / or dosage form is, within the scope of reasonable medical judgment, suitable for contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0077] The term "excipient" or "carrier" refers to a carrier, excipient or stabilizer that is non-toxic to cells or mammals at the dosage and concentration used. Non-limiting examples include buffers such as phosphate, citrate and other organic acids; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates (glucose, mannose or dextrin); chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN™, polyethylene glycol (PEG) and PLURONICS™. In certain embodiments, the pharmaceutically acceptable carrier is a non-naturally occurring pharmaceutically acceptable carrier.

[0078] The compounds of the present invention can treat interferon-related diseases, especially viral infections. Therefore, in addition to the compounds of the present invention, the pharmaceutical composition of the present invention can also contain one or more other antiviral drugs to enhance the therapeutic effect of the pharmaceutical composition.

[0079] Advantages of this invention: 1. The present invention provides a new type of highly active and selective small molecule inhibitor of HPK1. 2. The present invention reveals for the first time a unique mechanistic link between HPK1 kinase and viral infection. 3. The HPK1 small molecule inhibitor of the present invention can exhibit antiviral effects as a monotherapy at the cell and animal model levels, thus laying a new material basis for drug development against interferon-related diseases, especially viral infections. 4. The HPK1 small molecule inhibitor of the present invention can be used as an adjuvant / combined drug to improve immunity to show antiviral effects at the cell and animal model levels, thereby laying a new material foundation for drug development of interferon-related diseases, especially viral infections.

[0080] The technical solutions of the present invention will be further described below in conjunction with specific examples, but the following examples do not constitute the limitation of the present invention, and all the various application methods adopted according to the principles and technical means of the present invention all belong to the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight. EXAMPLES

[0081] Example 1. Synthesis of compounds of the present invention 1. Synthesis of a series of compounds of formula I-1 and detection of HPK1 inhibitory activity 1.1. Synthesis of Compound DD02001H: 8-(((1s,4s)-4-aminocyclohexyl)oxo)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-2-amine The synthetic route of compound DD02001H is as shown in FIG.

[0082] 1.1.1. Synthesis of Compound 2 Under N2 protection, BH3 / THF (1.00M, 329mL, 2.20eq) is added dropwise to a solution of compound 1 (25.0g, 150mmol, 1.00eq) in THF (300mL) at 0°C. After the addition is complete, the mixture is stirred at 0°C for 30 minutes, then the mixture is heated to 50°C and stirred for 12 hours. TLC (petroleum ether:ethyl acetate=1:1, raw material R f =0.1, product R f =0.3) a new spot was formed, indicating the complete disappearance of raw materials. After the reaction was completed, the mixture was cooled to 0°C, MeOH (400mL) was added dropwise until no bubbles were formed, then 40.0mL of H2O was added and extracted with ethyl acetate (300mL x 2), the organic phase was washed with brine (100mL x 2), dried over anhydrous Na2SO4 and filtered, then concentrated under reduced pressure to obtain compound 2 (45.0g, 294mmol, 98.2% yield), which is a pale yellow oily substance with the structure: 1 Confirmed by H NMR. [ka] 1 H NMR (400MHz, CDCl3) δ 6.65-6.85 (m, 3H), 4.63 (s, 2H), 3.86 (s, 3H).

[0083] 1.1.2. Synthesis of Compound 3 [ka] To a solution of compound 2 (45.0 g, 294 mmol, 1.00 equiv.) in dichloromethane (DCM) (500 mL) was added MnO2 (128 g, 1.47 mmol, 5.00 equiv.), and the resulting mixture was stirred at 25° C. for 12 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, substance R f =0.45, product R f =0.8) indicates the formation of a new spot and the disappearance of the raw material spot. After the reaction is completed, the mixture is filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. It is separated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) to obtain compound 3 (25.0 g, 166 mmol, 56.3% yield), the structure of which is 1 Confirmed by H NMR. 1 H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),7.18(dd,J=8.0,1.2Hz,1H),7.02(dd,J=8.0,0.8Hz,1H),6.80(br s, 2H), 6.64 (t, J=8.0Hz, 1H), 3.77-3.87 (m, 3H).

[0084] 1.1.3. Synthesis of Compound 4 [ka] A mixture of compound 3 (23.0 g, 152 mmol, 1.00 eq), urea (101 g, 1.67 mmol, 89.7 mL, 11.0 eq) and NHOAc (586 mg, 7.61 mmol, 0.05 eq) is stirred at 160° C. for 0.5 h, and the mixture begins to precipitate out of the hot solution. NMP (100 mL) is added to dissolve the solid precipitate, and the reaction is stirred at 160° C. for 1 h. LC-MS shows that the target product 4 is detected by MS (RT=0.247 min) and the raw material disappears, and after the reaction is complete, the mixture is cooled to 25° C. and poured into 100 mL of H2O, stirred at 25° C. for 10 min, and filtered under reduced pressure. The crude product is dispersed in petroleum ether (60.0 mL) with shaking for 5 min at 25° C. and filtered under reduced pressure to give compound 4 (20.0 g, 114 mmol, 74.6% yield) as a grey solid. The structure is:1 Confirmed by H NMR. LCMS: Product RT=0.247 min, m / z=177.2(M+H) + . 1 H NMR(400MHz,DMSO)δ 8.36(s,1H),6.90(br d,J=4.0Hz,1H),6.87(d,J=8.0Hz,1H),6.79(dd,J=8.0,4.0Hz,1H),5.98(dd,J=8.0,4.0Hz,1H),3.79(s,3H).

[0085] 1.1.4. Synthesis of Compound 5 Compound 4 (19.0 g, 108 mmol, 1.00 eq) is added to POCl3 (248 g, 1.61 mmol, 150 mL, 15.0 eq) at 0 °C, the resulting mixture is stirred at 25 °C for 0.5 h, then heated to 140 °C and stirred for 2 h. LC-MS shows that the target product MS is detected (RT = 0.655 min). After the reaction is completed, the mixture is slowly poured into ice water (200 mL) at 0-10 °C and stirred, then extracted with ethyl acetate (300 mL x 4), washed the organic phase with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Dispersed in petroleum ether (60.0 mL) at 25 °C with shaking for 5 min, filtered to obtain yellow solid compound 5 (7.60 g, 39.1 mmol, 36.2% yield), the structure of which is: 1 Confirmed by H NMR. [ka] LCMS: Product RT=0.655 min, m / z=195.0(M+H) + 1 H NMR (400MHz, DMSO) δ 9.56 (s, 1H), 7.69-7.79 (m, 2H), 7.54 (br d, J = 4.0Hz, 1H), 3.99 (s, 3H).

[0086] 1.1.5. Synthesis of Compound 6 [ka] At 0°C, DIAD (26.3g, 130mmol, 25.3mL, 1.50eq) is added to a solution of compound 6-1 (10.0g, 86.8mmol, 10.1mL, 1.00eq), compound 6-1a (11.7g, 104mmol, 1.20eq) and triphenylphosphorane (34.2g, 130mmol, 1.50eq) in THF (300mL), and the resulting mixture is stirred at 25°C under N2 protection for 12 hours. LCMS shows that the raw materials are completely reacted and the product is formed. After the reaction is complete, the reaction mixture is adjusted to pH=4 with 1M HCl and extracted with ethyl acetate (300mL), the aqueous phase is adjusted to pH=8 with NaHCO3 (saturated) and extracted again with ethyl acetate (100mL x 2). The organic phase was washed with saturated brine (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 6-2 (8.00 g, 38.1 mmol, 43.8% yield), which is a yellow oil and has the structure: 1 Confirmed by H NMR. LCMS product RT=0.150 min, m / z=211.1(M+H) + 1 H NMR (400MHz, CDCl3) δ 8.15 (s, 1H), 8.04 (s, 1H), 4.08-4.14 (m, 1H), 2.95-2.98 (m, 2H), 2.31 (s, 3H), 2.09-2.15 (m, 6H).

[0087] Compound 6-2 (8.00 g, 38.1 mmol, 1.00 equiv.), Pd / C (2.00 g, 10% purity) are stirred in methanol (50.0 mL), and the mixture is stirred at 25° C. under H2 (15 psi) for 12 h. LCMS shows that compound 6-2 is completely consumed, and after the reaction is complete, the mixture is filtered and concentrated under reduced pressure to give yellow oily compound 6 (5.00 g, 27.7 mmol, 72.9% yield), the structure of which is: 1 Confirmed by H NMR. LCMS: Product RT=0.10 min, m / z=181.1(M+H) + 1H NMR (400MHz, CDCl3) δ 7.09(s,1H),7.01(s,1H),3.92-3.98(m,1H),2.88-2.91(m,4H),2.26(s,3H),1.85-2.26(m,6H).

[0088] 1.1.6. Synthesis of Compound 7 [ka] To a solution of compound 5 (400 mg, 2.06 mmol, 1.00 eq) and compound 6 (444 mg, 2.47 mmol, 1.20 eq) in IPA (10.0 mL), TFA (23.4 mg, 205 umol, 15.2 uL, 0.10 eq) is added, and the resulting mixture is stirred at 100° C. for 2 hours. LCMS shows that the mass of the target product is detected (RT=0.653 min). The mixture is diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (50.0 mL), the organic phase is washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a solid material, which is dispersed in petroleum ether (25.0 mL) with shaking to obtain compound 7 (570 mg, 1.68 mmol, 81.9% yield) as a yellow solid, and the structure is shown by LCMS and 1 Confirmed by H NMR. LCMS: Product RT=0.673 min, m / z=339.3(M+H) + 1 H NMR(400MHz,CDCl3)δ 9.05(s,1H),8.22(s,1H),7.60(s,1H),7.31-7.35(m,2H),7.21-7.25(m,1H),7.10-7.12( m,1H),4.12-4.14(m,1H),4.05(s,3H),2.98-3.01(m,2H),2.34(s,3H),2.14-2.23(m,6H).

[0089] 1.1.7. Synthesis of compound 8 [ka] To a solution of compound 7 (570 mg, 1.68 mmol, 1.00 eq) in DCM (15.0 mL), BBr3 (1.05 g, 4.21 mmol, 405.7 uL, 2.50 eq) is added dropwise. The mixture is stirred at 25° C. for 12 hours. LCMS (EW20001-101-P1A1) shows that the target product is detected (RT=0.622 min). After the reaction is complete, the mixture is diluted with DCM (100 mL) and washed with saturated NaHCO3 solution (50.0 mL), the organic phase is washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 8 (500 mg, crude product) as a yellow solid, which is used directly in the next reaction. LCMS: Product RT=0.847 min, m / z=325.2(M+H) +

[0090] 1.1.8. Synthesis of Compound 10 [ka] Cs2CO3 (502mg, 1.54mmol, 2.50eq) is added to a solution of compound 8 (200mg, 616umol, 1.00eq) and compound 9 (273mg, 740umol, 1.20eq) in DMF (3.00mL), and the resulting mixture is stirred at 80°C for 1 hour. LCMS shows that the target product is detected (RT=0.799min). After the reaction is complete, the mixture is quenched by adding water (50.0mL) and extracted with ethyl acetate (50.0mL×2), the organic phase is washed with brine (50.0mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 10 (320mg, 613umol, 99.5% yield) as a yellow oily material, which is used directly in the next reaction without further purification. LCMS product RT=0.799 min, m / z=522.3(M+H) + .

[0091] 1.1.9. Synthesis of compound DD02001H [ka] A mixture of compound 10 (320 mg, 613 umol, 1.00 eq) and HCl / dioxane (4M, 10.0 mL, 65.2 eq) is stirred at 25° C. for 1 h. LCMS shows that the target product is detected (RT=0.651 min). The mixture is concentrated to give a residue, which is purified by preparative HPLC. The mixture is adjusted to pH=8 with saturated NaHCO3 solution and extracted with DCM (50.0 mL×2), the organic phase is washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound DD02001H as a yellow solid (27.2 mg, 91.7 umol, 14.9% yield, 96.7% purity), and the structure of the compound is confirmed by LCMS, HPLC (EW20001-106-P1A2) and HPLC. 1 Confirmed by H-NMR. LCMS product RT=0.644 min, m / z=422.3(M+H) + 1 H NMR(400MHz,CDCl3)δ 8.94(s,1H),8.14(s,1H),7.68(s,1H),7.23-7.25(m,1H),7.12-7.13(m,2H),7.06(s,1H),4.67-4.68(m,1H) ,4.05-4.09(m,1H),2.89-2.92(m,2H),2.78-2.80(m,1H),2.26(s,3H),2.05-2.15(m,8H),1.62-1.74(m,8H).

[0092] 1.2. Synthesis of Compound DD02013H: 4-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)quinazolin-8-yl)oxo)cyclohexan-1-ol The synthetic route of compound DD02013H is as shown in FIG.

[0093] 1.2.1. Synthesis of Compound 11 [ka] At 0°C, a solution of BBr3 (1.42g, 5.65mmol, 545uL, 2.20eq) in DCM (5.00mL) is added dropwise to a solution of compound 5 (500mg, 2.57mmol, 1.00eq) in DCM (10.0mL). After the addition is complete, the mixture is stirred at 25°C for 12h. LCMS shows that the molecular weight of the target product is detected (RT=0.585min). After the reaction is complete, the mixture is quenched with water (50.0mL) and extracted with DCM (50.0mL). The organic phase is washed with brine (50.0mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 10 / 1, TLC (petroleum ether:ethyl acetate=3:1, R f =0.3) to give compound 11 (400 mg, 2.21 mmol, 86.2% yield) as a yellow solid, the structure of which was confirmed by LCMS and 1 Confirmed by H NMR. LCMS: Product RT=0.575 min, m / z=181.0(M+H) + 1 H NMR (400MHz, CDCl3) δ 9.30 (s, 1H), 7.59-7.64 (m, 1H), 7.49-7.52 (m, 1H), 7.42-7.45 (m, 2H).

[0094] 1.2.2. Synthesis of Compound 12 [ka] To a solution of compound 11 (200 mg, 1.11 mmol, 1.00 eq) and compound 11a (639 mg, 1.66 mmol, 1.50 eq) in DMF (5.00 mL), Cs2CO3 (721.6 mg, 2.21 mmol, 2.00 eq) is added, and the resulting mixture is stirred at 80 °C for 2 h. The target product molecular weight is detected by LCMS (RT = 1.229 min). After completion of the reaction, the reaction is quenched by adding water (50.0 mL), extracted with ethyl acetate (50.0 mL x 2), the organic phase is washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1, TLC (petroleum ether / ethyl acetate = 5:1, R f =0.4) to give compound 12 (100 mg, 254 umol, 22.9% yield) as a yellow solid, the structure of which is 1 Confirmed by H NMR. LCMS: Product RT=1.229 min, m / z=393.2(M+H) + 1 H NMR(400MHz,CDCl3)δ 9.25(s,1H),7.55-7.60(m,1H),7.49-7.51(m,1H),7.34-7.37(m,1H),4.53-4.57(m,1H),3.90- 3.92(m,1H),2.15-2.20(m,2H),1.86-1.89(m,4H),1.60-1.64(m,2H),0.93(s,9H),0.08(s,6H).

[0095] 1.2.3. Synthesis of compound 12a [ka] To a solution of compound 12-1 (2.00 g, 14.2 mmol, 1.50 mL, 1.00 eq) and compound 12-1a (1.59 g, 15.6 mmol, 2.03 mL, 1.10 eq) in dimethyl sulfoxide (10.0 mL), K2CO3 (3.92 g, 28.4 mmol, 2.00 eq) was added, and the resulting mixture was stirred at 40 °C for 2 h. Compound 12-1 (R f =0.6) was retained, and the formation of a new product was detected. After completion of the reaction, the reaction mixture was diluted with HO (100 mL) and extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 12-2 (3.20 g, crude oil), the structure of which is 1 After being confirmed by 1 H NMR, it is used in the next reaction without further purification. 1 H NMR(400MHz, CDCl3)δ 8.09-8.12(m,2H),6.59-6.62(m,2H),3.55(t,J=7.2Hz,2H),3.10(s,1H),2.50(t,J=7.2Hz,2H),2.30(s,6H).

[0096] To a solution of compound 12-2 (3.20 g, 14.3 mmol, 1.00 equiv.) in MeOH (30.0 mL) is added Pd / C (1.00 g, 10% purity, 1.00 equiv.). The suspension is degassed under vacuum and purged with hydrogen gas several times, and the resulting solution is then stirred for 2 h under an atmosphere of H2 (15 psi) at 25 °C. Compound 12-2 (R f =0.5) disappearance of the raw material spot, and the formation of a new compound is detected. After the reaction is completed, the mixture is filtered and concentrated to obtain compound 12a (2.30 g, 11.9 mmol, 83.0% yield). The product is a reddish brown oil, and the structure is shown in Table 1 without further purification. 1 Confirmed by H NMR. 1H NMR(400MHz,DMSO)δ 6.47-6.54(m,4H),4.34(br.s,2H),3.19(t,J=7.2Hz,2H),2.72(s,1H),2.30(t,J=7.2Hz,2H),2.14(s,6H).

[0097] 1.2.4. Synthesis of compound 13 [ka] Compound 12 (100mg, 254umol, 1.00eq) and compound 12a (59.0mg, 305umol, 1.20eq) are added to a solution of IPA (3.00mL) with TFA (29.0mg, 255umol, 18.8uL, 1.00eq). The resulting mixture is stirred at 100°C for 1 hour. LCMS shows that the molecular weight of the target product is detected (RT=0.913min). After the reaction is complete, it is extracted with ethyl acetate (100mL), and the organic phase is washed successively with saturated NaHCO3 solution (50.0mL) and brine (50.0mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13 (130mg, crude product) as a yellow solid, which is used directly in the next reaction without purification.

[0098] 1.2.5. Synthesis of compound DD02013H [ka] TFA (0.50 mL) is added to a solution of compound 13 (130 mg, 236 umol, 1.00 equiv.) in DCM (5.00 mL), and the resulting mixture is stirred at 25° C. for 1 h. LCMS shows that the molecular weight of the target product is detected (RT=0.701 min). After the reaction is completed, the mixture is concentrated to obtain a residual solid, which is purified by preparative high performance liquid chromatography, and the resulting solid is adjusted to pH=8 with saturated NaHCO3 solution, extracted with DCM (50.0 mL×2), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound DD02013H (47.6 mg, 130.7 umol, 55.3% yield, 94.9% purity) as a yellow solid, and the structure is shown by LCMS, HPLC and HPLC.1 Confirmed by H-NMR. LCMS product RT=0.997 min, m / z=436.3(M+H) + HPLC product RT=2.951 min, purity: 95.6% 1 H NMR(400MHz,CDCl3)δ 9.00(s,1H),7.83-7.85(m,2H),7.29-7.31(m,1H),7.17-7.19(m,3H),6.85-6.87(m,2H),4.78-4.79(m,1H),3.76-3.81(m,1H),3.49(t,J =7.2Hz,2H),2.95(s,3H),2.54(t,J=7.2Hz,2H),2.33(s,6H),2.16-2.21(m,2H),2.03-2.06(m,2H),1.80-1.83(m,2H),1.69-1.73(m,2H).

[0099] 1.3. Synthesis of Compound DD02014H: 4-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinazolin-8-yl)oxo)cyclohexan-1-ol The synthetic route to compound DD02014H is shown in FIG. To a solution of compound 8 (400 mg, 1.23 mmol, 1.00 eq) and compound 11a (569.1 mg, 1.48 mmol, 1.20 eq) in DMF (10.0 mL), Cs2CO3 (1.00 g, 3.08 mmol, 2.50 eq) is added and the resulting mixture is stirred at 80° C. for 1 h. LCMS shows that the molecular weight of the target product is detected (RT=0.958 min). After completion of the reaction, ethyl acetate (100 mL) was added, and the organic phase was washed successively with saturated NaHCO3 solution (50.0 mL) and brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was dispersed in petroleum ether:ethyl acetate (3:1, 20.0 mL) with shaking, filtered and dried to obtain compound 14 (300 mg, 559 umol, 45.3% yield) as a yellow solid, the structure of which was characterized by LCMS. LCMS product RT=0.912 min, m / z=537.3(M+H) + . A mixture of compound 14 (300 mg, 559 umol, 1.00 eq) and HCl / MeOH (4M, 10.0 mL, 71.6 eq) was stirred at 25°C for 1 hour, and the disappearance of the product was detected by LCMS (EW20001-117-P1A1), indicating the appearance of the molecular weight of the target product (RT=0.729 min). After the reaction was completed, the mixture was concentrated and the resulting solid was purified by preparative HPLC, then the mixture was adjusted to pH=8 with saturated NaHCO3 solution, extracted with DCM (50.0 mL x 2), the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound DD02014H (35.5 mg, 138 umol, 24.6% yield, 96.9% purity) as a yellow solid, and the structure was confirmed by LCMS, HPLC and HPLC. 1 Confirmed by H NMR. LCMS product RT=0.730 min, m / z=423.2(M+H) + HPLC product RT=1.192 min, purity: 98.0% 1 H NMR(400MHz,CDCl3)δ 9.01(s,1H),8.61(s,1H),7.49(s,1H),7.28-7.30(m,1H),7.17-7.22(m,3H),4.66-4.68(m,1H),4.23-4.30(m,1H),3.85- 3.89(m,1H),2.99-3.03(m,2H),2.33(s,3H),2.25-2.29(m,4H),2.15-2.17(m,4H),1.95-2.06(m,2H),1.84-1.88(m,4H).

[0100] 1.4. Synthesis of Compound DD02006H: 4-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxo)cyclohexan-1-ol The synthetic route to compound DD02006H is shown in FIG.

[0101] 1.4.1. Synthesis of Compound 16 At 25°C, TFA (586mg, 5.14mmol, 380uL, 1.00eq) was added to a solution of compound 5 (1.00g, 5.14mmol, 1.00eq) and compound 16a (1.08g, 5.65mmol, 1.10eq) in IPA (20.0mL), and after uniform mixing, the reaction mixture was heated to 100°C and stirred for 3 hours. [ka] LCMS shows that the molecular weight of the target product is detected (RT=0.691 min). After the reaction is completed, the mixture is poured into 30.0mL of H2O, then extracted with ethyl acetate (60.0mL×4), the organic phase is washed with brine (60.0mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 16 (1.50g, crude product) as a yellow solid. The product is used directly in the next reaction without purification. LCMS: Product RT=0.691 min, m / z=350.2(M+H) +

[0102] 1.4.2. Synthesis of Compound 17 [ka] At 0°C, BBr3 (2.80g, 11.2mmol, 1.08mL, 3.00eq) dissolved in DCM (10.0mL) is added dropwise to a solution of compound 16 (1.30g, 3.72mmol, 1.00eq) in DCM (20.0mL), and after the addition is complete, the mixture is stirred at 0°C for 30 minutes, and then the mixture is heated to 25°C and stirred for 12 hours. LCMS shows that the molecular weight of the target product is detected (RT=0.677 minutes). After the reaction is complete, the mixture is poured into ice water (30.0mL), extracted with ethyl acetate (60.0mL x 3), the organic phase (30.0mL x 2) is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 17 (1.20g, crude product) as a grey solid. The product is used directly in the next reaction without purification. LCMS: Product RT=0.677 min, m / z=336.2(M+H) +

[0103] 1.4.3. Synthesis of Compound 18 [ka] Compound 17 (150 mg, 447 umol, 1.00 eq), compound 11a (276 mg, 894 umol, 2.00 eq) and Cs2CO3 (364 mg, 1.12 mmol, 2.50 eq) are dissolved in DMF (10.0 mL), and then the mixture is heated to 80 °C and reacted for 12 hours. LCMS shows that the molecular weight of the target product is detected (RT = 0.934 min). After the reaction is completed, the mixture is poured into 30.0 mL of H2O, and then extracted with ethyl acetate (30.0 mL x 4), and the organic phase is washed with brine (30.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 18 (200 mg, crude product) as a yellow solid. The product is used directly in the next reaction without purification. LCMS product: RT=0.934 min, m / z=548.4(M+H) +

[0104] 1.4.4. Synthesis of compound DD02006H [ka] HCl / 1,4-dioxane (4M, 2.00mL, 21.9eq) is added dropwise to a solution of compound 18 (200mg, 365umol, 1.00eq) in DCM (6.00mL) at 25°C, and the resulting mixture is stirred for 2h. LCMS shows that the molecular weight of the target product is detected (RT=0.746min). Thin layer chromatography (DCM:MeOH=8:1, substance R f =0.5, product R f=0.2) indicates the formation of a new spot, indicating no residual material. The mixture is poured into 30.0 mL of H2O, the pH value is adjusted to about 8 with saturated NaHCO3, then extracted with ethyl acetate (30.0 mL x 4), the organic phase is washed with brine (30.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product is subjected to pre-HPLC and concentrated under reduced pressure to give the target product (68.6 mg, 157 umol, 43.1% yield, 99.4% purity) as a yellow solid, the structure of which is 1 Confirmed by 1 H NMR, LCMS and HPLC. LCMS product: RT=0.734 min, m / z=434.3(M+H) + ; HPLC product RT=1.373 min, 99.4% purity; 1 H NMR(400MHz,DMSO)δ 9.57-9.71(m,1H),9.12-9.27(m,1H),7.90-8.06(m,2H),7.40-7.47(m ,1H),7.28-7.34(m,1H),7.18-7.26(m,1H),6.86-6.99(m,2H),4.75(br s,1H),4.52-4.64(m,1H),3.63(br s,1H),3.07(br d,J=4.0Hz,4H),2.24(s,3H),1.91-2.05(m,2H),1.74-1.87(m,2H),1.56-1.72(m,4H).

[0105] 1.5. Synthesis of Compound DD02008H: 8-(2-Methoxyethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine FIG. 13 shows the synthetic route for compound DD02008H. Compound 17 (150 mg, 447 umol, 1.00 eq), compound 17a (68.4 mg, 492 umol, 46.2 uL, 1.10 eq) and Cs2CO3 (437 mg, 1.34 mmol, 3.00 eq) were dissolved in DMF (10.0 mL), and the mixture was then heated to 80° C. and stirred for 12 hours, showing that the molecular weight of the target product was detected by LCMS (RT=0.703 min). Thin layer chromatography (DCM:MeOH=10:1, substance R f =0.1, product R f =0.3) indicates the formation of a new spot, indicating the absence of starting material. After the reaction is completed, the mixture is poured into 30.0 mL of H2O, then extracted with ethyl acetate (30.0 mL x 4), washed the organic phase with brine (30.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 5 / 1) gave the target compound DD02008H (71.94 mg, 183 umol, 40.9% yield, 98.6% purity) as a yellow solid, the structure of which is: 1 Confirmed by 1 H NMR, LCMS and HPLC. LCMS product: RT=0.710 min, m / z=416.2(M+H+Na)+ HPLC product: RT=1.267 min, 98.7% purity 1 H NMR(400MHz,CDCl3)δ 9.04(s,1H),7.72(br d,J=8.0Hz,2H),7.33(dd,J=8.0,4.0Hz,1H),7.15-7.24(m,2H),6.97(d,J=8.0Hz,2H),4.33-4 .41(m,2H),3.91-3.99(m,2H),3.56(s,3H),3.13-3.25(m,4H),2.58-2.65(m,4H),2.38(s,3H).

[0106] 1.6. Synthesis of Compound DD02015H: 3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxo)cyclopentan-1-ol FIG. 14 shows the synthetic route for compound DD02015H. Compound 17 (150 mg, 447 umol, 1.00 eq), compound 18a (331 mg, 894 umol, 2.00 eq) and Cs2CO3 (364 mg, 1.12 mmol, 2.50 eq) are dissolved in DMF (10.0 mL), and then the mixture is heated to 80° C. and stirred for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT=0.893 min), and TLC (DCM:MeOH=10:1, substance R f =0.1, product R f =0.25) indicates the formation of a new spot, indicating the absence of starting material. After the reaction is complete, the resulting mixture is poured into 30 mL of water, then extracted with ethyl acetate (30.0 mL x 4), washed with brine (30.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure, and the resulting residual solid is purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 5 / 1) to give compound 19 (200 mg, 375 umol, 83.8% yield) as a yellow solid. LCMS product: RT=0.893 min, m / z=534.4(M+H) +

[0107] Compound 19 (200 mg, 375 umol, 1.00 eq) was dissolved in DCM (6.00 mL), and HCl / 1,4-dioxane (4 M, 4.00 mL, 42.7 eq) was added dropwise at 25° C. After the addition was completed, the reaction was stirred for 2 hours. LCMS showed that the molecular weight of the target product was detected (RT=0.721 min), and HPLC showed that the reaction of the starting material was complete. After the reaction was completed, the mixture was poured into 30.0 mL of H2O, and the pH value was adjusted to about 8 with saturated NaHCO3, then extracted with ethyl acetate (30.0 mL x 4), the organic phase was washed with brine (30.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography to obtain the target compound DD02015H (110 mg, 262 umol, 70.0% yield, 100% purity) as a yellow solid, the structure of which is: 1 Confirmed by 1 H NMR, LCMS and HPLC. LCMS product: RT=0.716 min, m / z=420.3(M+H) + HPLC product: RT=1.286 min, 100% purity. 1 H NMR(400MHz,CDCl3)δ 9.04(s,1 H),7.60(br d,J=8.0Hz,2 H),7.32-7.38(m,1 H),7.21-7.24(m,2 H),6.93-7.01(m,2 H),5.15(t,J=4.0Hz,1 H),4.41(br t,J=4.0Hz,1 H),3.17-3.26(m,4 H),2.62(m,4 H),2.38(s,3 H),1.94-2.20(m,6 H).

[0108] 1.7. Synthesis of Compound DD02021H: 4-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)quinazolin-8-yl)oxo)cyclohexan-1-ol FIG. 15 shows the synthetic route for compound DD02021H.

[0109] 1.7.1. Synthesis of Compound 20 [ka] At 25°C, compound 5 (500mg, 2.57mmol, 1.00eq), compound 19a (988mg, 5.14mmol, 2.00eq), Pd2(dba)3 (353mg, 386umol, 0.15eq) and BINAP (184mg, 295umol, 1.15e-1eq) are dissolved in 1,4-dioxane (30.0mL), and Cs2CO3 (1.67g, 5.14mmol, 2.00eq) is added to the resulting mixture, and then the reaction mixture is heated to 100°C and stirred for 10 hours. LCMS shows that the molecular weight of the target product is detected (RT=0.643min). After the reaction is complete, the mixture is poured into 30.0 mL of H2O, then extracted with DCM (50.0 mL x 3), the organic phase is washed with brine (30.0 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound 20 (600 mg, crude product) as a yellow solid. The product is used directly in the next reaction without purification.

[0110] 1.7.2. Synthesis of Compound 21 [ka] Compound 20 (600 mg, 1.71 mmol, 1.00 eq) is dissolved in DCM (10.0 mL), and the resulting solution is added dropwise with BBr3 (429 mg, 1.71 mmol, 165 uL, 1.00 eq) dissolved in DCM (5.00 mL), and after the addition is complete, the system is stirred and reacted at 25 °C for 12 hours. LCMS shows that the molecular weight of the target product is detected (RT = 0.321 min). After the reaction is complete, the mixture is poured into ice water (40.0 mL), the pH is adjusted to about 8 with saturated NaHCO3, and then extracted with DCM (50.0 mL x 3), and the organic phase is washed with brine (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 21 (600 mg, crude product) as a yellow solid. The product is used directly in the next reaction without purification. LCMS product RT=0.324 min, m / z=337.2(M+H) +

[0111] 1.7.3. Synthesis of Compound 22 [ka] Compound 21 (600 mg, 1.78 mmol, 1.00 eq), compound 11a (1.37 g, 3.57 mmol, 2.00 eq) and Cs2CO3 (1.45 g, 4.46 mmol, 2.50 eq) are dissolved in DMF (10.0 mL), and the resulting mixture is heated to 80 °C and reacted for 12 h. LCMS shows that the molecular weight of the target product is detected (RT = 0.830 min), and thin layer chromatography (DCM:MeOH = 10:1, substance R f =0.1, product R f =0.3) indicates the formation of a new spot, indicating the absence of starting material. After the reaction is completed, the mixture is poured into 30.0 mL of H2O, then extracted with ethyl acetate (60.0 mL x 3), the organic phase is washed with brine (40.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the resulting material is purified by column chromatography (SiO2, DCM / MeOH = 40 / 1 to 5 / 1) to give compound 22 (700 mg, 1.08 mmol, 60.5% yield, 84.6% purity) as a yellow solid. LCMS product RT=0.830 min, m / z=549.4(M+H) + HPLC product RT=2.563 min, 84.6% purity.

[0112] 1.7.4. Synthesis of Compound DD02021H [ka] Compound 22 (600 mg, 925 umol, 1.00 eq.), HCl / 1,4-dioxane (4 M, 6.00 mL, 25.9 eq.) are dissolved in DCM (10.0 mL), and the resulting mixture is stirred and reacted at 25° C. for 1 h. LCMS showed that the molecular weight of the target product was detected (RT=0.680 min), and thin layer chromatography (DCM:MeOH=10:1, substance R f =0.3, product R f=0.15) indicates the absence of starting material. After the reaction is completed, the mixture is slowly poured into 40.0 mL of H2O with stirring, then extracted with ethyl acetate (80.0 mL x 3), the organic phase is washed with brine (50.0 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained solid is purified by preparative high performance liquid chromatography, the obtained material is adjusted to pH about 8 with saturated NaHCO3, then extracted with DCM (40.0 mL x 4), the organic phase is washed with brine (40.0 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the target product DD02021H (148 mg, 329 umol, 35.6% yield, 96.7% purity) as a yellow solid, the structure of which is: 1 Confirmed by 1 H NMR, LCMS and HPLC. LCMS product RT=0.717 min, m / z=435.3(M+H) + HPLC product RT=1.232 min, 96.7% purity 1 H NMR(400MHz,DMSO)δ 9.74(s,1H),9.26(s,1H),8.86(d,J=8.0Hz,1H),8.02(d,J=4.0Hz,1H),7.43-7.57(m,2H),7.24-7.40(m,2H),4.78(br s,1H),4.62-4.73(m,1H),3.54-3.69(m,1H),3.08-3.16(m,4H),2.47(m,3 H),2.23(s,3H),1.93-2.04(m,2H),1.74-1.88(m,2H),1.58-1.72(m,4H).

[0113] 1.8. Synthesis of Compound DD02018H: 4-((8-((4-hydroxycyclohexyl)oxo)quinazolin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benamide FIG. 16 shows the synthetic route for compound DD02018H. At 25°C, compound 11 (400mg, 2.21mmol, 1.00eq), compound 11a (1.28g, 3.32mmol, 1.50eq) and Cs2CO3 (1.44g, 4.43mmol, 2.00eq) are dissolved in DMF (10.0mL), the resulting mixture is heated to 80°C and stirred for 2 hours. LCMS shows that the molecular weight of the target product is detected (RT=1.218min). After the reaction is completed, the mixture is slowly poured into 40.0mL of H2O, then extracted with DCM (80.0mL x 3), the organic phase is washed with brine (50.0mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 15 (310mg, crude product) as a grey solid. The product is used directly in the next reaction without purification.

[0114] Compound 15 (260 mg, 661 umol, 1.00 eq), compound 15a (231.53 mg, 992.38 umol, 1.50 eq) and TFA (75.4 mg, 661 umol, 49.0 uL, 1.00 eq) are dissolved in IPA (10.0 mL), and then the resulting mixture is heated to 80 ° C and stirred for 2 hours, and the mixture is heated to 100 ° C and stirred for 2 hours. LCMS shows that the molecular weight of the target product is detected (RT = 0.762 min), and high performance liquid chromatography shows that the purity is 59.7% (RT = 1.535 min). After the reaction was completed, the mixture was slowly poured into 40.0mL of H2O under stirring, the pH was adjusted to about 8 with saturated NaHCO3, then extracted with DCM (80.0mL x 3), the organic phase was washed with brine (50.0mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained crude product was purified by preparative high performance liquid chromatography, the pH was adjusted to about 8 with saturated NaHCO3, extracted with DCM (40.0mL x 4), the organic phase was washed with brine (40.0mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to obtain the target product DD02018H (17.1mg, 35.13umol, 5.31% yield, 97.7% purity) as a pale yellow solid, the structure of which is: 1 Confirmed by 1 H NMR, LCMS and HPLC. LCMS product RT=0.771 min, m / z=476.2(M+H) + HPLC product RT=1.535 min, 97.3% purity 1 H NMR(400MHz,DMSO-d6)δ 10.15(br s,1H),9.30(br s,1H),8.23(br d,J=8.0Hz,2H),8.13(br s,1H),7.83(br d,J=8.0Hz,2H),7.49(br s,1H),7.27-7.42(m,2H),4.73(br s,1H),4.60(br s,1H),3.87(br s,1H),3.07(br s,2H),2.62-2.67(m,2H),2.33(br s, 3H), 1.84-2.08 (m, 3H), 1.73 (m, 9H).

[0115] 1.9. Synthesis of Compound DD02002H: 4-((8-((3-hydroxycyclopentyl)oxo)quinazolin-2-yl)amino)benzenesulfonamide FIG. 17 shows the synthetic route for compound DD02002H.

[0116] 1.9.1. Synthesis of Compound 23 Under nitrogen gas protection, compound 11 (200 mg, 1.11 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triphenylphosphorane (581 mg, 2.22 mmol) and DIAD (449 mg, 2.22 mmol) were added in sequence, stirred for 15 minutes, and finally 1,3-cyclopentanediol (i.e., compound 22, 340.1 mg, 3.33 mmol) was added, and the reaction solution was stirred at room temperature overnight, and TLC (PE / EA=3:1) analysis showed that the raw material was completely consumed and a new product spot was generated. After the reaction was completed, the resulting mixture was concentrated to remove the solvent, and the crude product was separated by silica gel column to obtain compound 23 (210 mg) as a pale yellow solid, with a yield of 71.5%. LCMS product RT=2.76 min, m / z=265.1(M+H) +

[0117] 1.9.2. Synthesis of Compound DD02002H Under nitrogen gas protection, compound 23 (200 mg, 0.76 mmol) was dissolved in isopropanol (5 mL), p-aminobenzenesulfonamide (260.2 mg, 1.51 mmol) was added, and the reaction was heated to 90 ° C. and reacted overnight. Thin layer chromatography analysis showed that some raw materials remained and a new product spot was generated, and the molecular weight of the target product was detected by LCMS. After the reaction was completed, it was concentrated and the resulting crude product was separated by a silica gel column to obtain the target molecule DD02002H (104 mg) as a white solid, the yield was 34%, and the structure was 1 Confirmed by 1 H NMR and LCMS. LCMS product RT=3.46 min, m / z=401.1(M+H) + 1 H NMR(400MHz,MeOD)δ 9.21(s,1H),8.23-8.25(m,2H),7.87-7.89(m,2H),7.48(d,J=7.6Hz,1H),7.33-7.37(m,2H),4.36(m,1H),4.20(m,1H),1.76-2.10(m,6H).

[0118] 1.10. Synthesis of Compound DD02019H: 3-((8-((4-hydroxycyclohexyl)oxo)quinazolin-2-yl)amino)benzenesulfonamide FIG. 18 shows the synthetic route for compound DD02019H.

[0119] 1.10.1. Synthesis of Compound 26 Under nitrogen gas protection, compound 11 (200 mg, 1.11 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triphenylphosphorane (581 mg, 2.22 mmol) and DIAD (449 mg, 2.22 mmol) were added in sequence, the resulting mixture was stirred for 15 minutes, and finally 1,4-cyclohexanediol (387 mg, 3.33 mmol) was added, and the resulting reaction solution was stirred at room temperature overnight, TLC (PE / EA=3:1) analysis showed that the raw material was completely consumed and a new product spot was generated, and the target product molecular weight was detected by LCMS (RT=4.03 min), the reaction solution was concentrated, and the resulting crude product was separated by silica gel column to obtain compound 26 (197 mg) as a pale yellow solid, the yield was 70.7%. LCMS product RT=4.03 min, m / z=279.1(M+H) +

[0120] 1.10.2. Synthesis of compound DD02019H Under nitrogen gas protection, compound 26 (150 mg, 0.54 mmol) was dissolved in isopropanol (5 mL), m-aminobenzenesulfonamide (185.4 mg, 1.1 mmol) was added, and the reaction was heated to 90 ° C. and reacted overnight. TLC analysis showed that the raw material remained and a new product spot was formed at the same time. The target product molecular weight was detected by LC-MS. The reaction solution was concentrated, and the obtained crude product was separated by a silica gel column to obtain the target molecule DD02019H (27 mg) as a white solid. The yield was 12.1%. The structure was as follows: 1 Confirmed by H NMR. LCMS product RT=3.54 min, m / z=415.2(M+H) + 1 H NMR (400MHz, MeOD) δ 9.19 (s, 1H), 8.51 (m, 2H), 7.34-7.55 (m, 5H), 4.62 (m, 1H), 3.73 (m, 1H), 1.57-1.94 (m, 8H).

[0121] 1.11. In Vitro Inhibition Test of HPK1 Kinase Activity by a Series of Compounds of Formula I-1 [Table 1] The starting concentration of all compounds tested is 10 μM, with 3-fold gradient dilutions for a total of 10 concentration spots, with each concentration repeated once.

[0122] 1.11.1. In Vitro Testing of Compounds That Inhibit HPK1 Kinase Activity Before starting the experiment, prepare 50 μM DTT and enzyme reaction buffer. Pipette compound dilution into 384-well plate, add 384-well plate, seal and centrifuge at 1000g for 1 min; Prepare 2x HPK1 solution in kinase buffer, add 2.5μL of 2x HPK1 solution to 384-well, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 10 minutes; Prepare 2x MBP and ATP mixture in kinase buffer, add 2.5μL of 2x MBP and ATP mixture to the above reaction system to start reaction, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 1 hour; Add 5μL ADP-Glo ​​reagent to reaction system, incubate at room temperature for 40 minutes; Add 10μL kinase detection reagent, incubate at room temperature for 40 minutes, and then read luminescence signal with Envision2104 plate reader, calculate inhibition rate according to the following formula: Inhibition% = 100-(Signal cmpd -signal Ave_PC ) / (signal Ave_VC -signal Ave_PC ) x 100 In the above formula, cmpd refers to the test compound, PC refers to the positive control, and VC refers to the negative control. The positive control used in the HPK1 experiment is sunitinib.

[0123] [Table 2]

[0124] 2. Synthesis of a series of compounds of formula I-2 and detection of HPK1 inhibitory activity 2.1. Synthesis of the compound (1S,2S)-N-(8-amino-7-fluoro-6-(1-methyl-1H-pyrrol-2-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide (i.e., DD02001A_cis) and the compound (1S,2R)-N-(8-amino-7-fluoro-6-(1-methyl-1H-pyrrol-2-yl)isoquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide (i.e., DD02001A_trans)

[0125] 2.1.1. Synthesis of Compound 2 [ka] A solution of compound 1 (345 g, 2.67 mmL, 371 mL, 1.00 eq) in MeOH (2.00 L) was added with MeONa (14.4 g, 267 mmol, 0.10 eq), purged with N2 three times, and then stirred at 20 °C for 16 h. Compound 1 (R f =0.70) disappeared, and a new spot (R f =0.45) was detected. The pH value of the resulting mixture was adjusted to about 9 with dry ice, and then concentrated under vacuum to obtain a yellow mixture. The mixture was poured into water (1.00 L) and then extracted with ethyl acetate (1.00 L x 2). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 2 (400 g, 2.48 mmL, 92.9% yield) as a pale yellow oily substance, the structure of which is 1 Confirmed by H NMR. 1 H NMR (400MHz, CDCl3) δ 7.89 (s, 1H), 4.80 (s, 1H), 3.81 (s, 3H), 3.61-3.53 (m, 4H), 1.24 (t, J = 7.2Hz, 6H).

[0126] 2.1.2. Synthesis of Compound 3 [ka] Compound 2 (41.3 g, 256 mmol, 1.50 eq) is added to a solution of compound b (80.0 g, 171 mmol, 61.0% purity, 1.00 eq) in MeOH (500 mL) at 25° C., then stirred at 25° C. for 2 h. LCMS shows that compound b disappears and the desired mass is detected. After the reaction is completed, the resulting liquid mixture is concentrated under reduced pressure at 45° C. The residue is dissolved in ethyl acetate (1.00 L) and washed with brine (200 mL×2). The organic phase is dried over Na2SO4, filtered and concentrated to obtain a residue. The residue is triturated with petroleum ether / ethyl acetate (5 / 1, 150 ml) at 20° C. and filtered to obtain a filter cake, which gives compound 3 (53.0 g, 121 mmol, 71.0% yield, 95.0% purity) as a pale yellow solid, and the structure is shown by LC-MS and NMR (Hz) δ 1.01-1.03 (Hz), ... 1 Confirmed by H NMR. LCMS: m / z=415.0 (M+H) + 1 H NMR:(400MHz,DMSO-d6)δ 7.76(dd,J=6.2,8.2Hz,1H),7.13(d,J=8.0Hz,1H),6.62-6.19(m,1H),4.76(s,1H),4.23(s,2H),3.66-3.42(m,4H),1.15(t,J=7.0Hz,6H).

[0127] 2.1.3. Synthesis of Compound 4 [ka] Compound 3 (94.0 g, 212 mmol, 93.5% purity, 1.00 equiv.) was added to H2SO4 (920 g, 9.38 mmL, 500 mL, 44.2 equiv.) at 10°C, then heated to 60°C and reacted for 16 hours. LCMS showed that compound 3 was completely consumed and the target product molecular weight was detected. After the reaction was completed, the reaction solution was cooled to 25°C, cooled with ice (5.00 L), and the pH value was adjusted to about 13 with NaOH solid, and the temperature was kept below 20°C. A large amount of solid appeared, filtered, the filter cake was dried under vacuum, and the filter cake was polished with ethyl acetate (300 mL) at 25°C to obtain compound 4 (60.0 g, 186 mmol, 87.7% yield) as a yellow solid, and the structure was confirmed by LC-MS and HPLC. 1 Confirmed by H NMR. LCMS: m / z=322.9 (M+H) + 1 H NMR: (400MHz, DMSO-d6) δ 8.96 (s, 1H), 8.21 (d, J=5.8Hz, 1H), 6.62 (s, 1H), 6.31 (s, 2H).

[0128] 2.1.4. Synthesis of Compound 5 [ka] At 25°C, compound 4 (41.0g, 121mmol, 95.6% purity, 1.00 eq) and compound c (30.2g, 146mmol, 1.20eq) are dissolved in dioxane (410mL) and H2O (41.0mL), K3PO4 (51.6g, 243mmol, 2.00eq) and Pd(dppf)Cl2 (8.89g, 12.1mmol, 0.10eq) are added to the resulting solution, the resulting suspension is degassed under vacuum and purged with N2 several times, and then the reaction is stirred at 100°C for 7 hours. LCMS shows that compound 4 is completely consumed and the target product molecular weight is detected. After completion of the reaction, the resulting mixture was quenched with ice water (1000 mL), then extracted with dichloromethane (1000 mL×2), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum, and the resulting solid was triturated with petroleum ether / ethyl acetate (2 / 1, 200 mL) at 25° C. to give compound 5 (33.0 g, 103 mmol, 85.3% yield, 86.7% purity) as a yellow solid, the structure of which was confirmed by LC-MS and NMR (Hz) NMR (Hz) δ 1.0 (3.5), 1.5 (4.0), 1.0 (2.5), 1.5 (1.0 ... 1 Confirmed by H NMR. LCMS: m / z=276.1 (M+H) + 1 H NMR(400MHz,CDCl3)δ 9.20(s,1H),7.41(d,J=6.6Hz,1H),6.92-6.79(m,1H),6.71(s,1H),6.36(ddd,J=0. 8,1.6,3.6Hz,1H),6.27(dd,J=2.8,3.6Hz,1H),4.57(s,2H),3.64(d,J=1.6Hz,3H).

[0129] 2.1.5. Synthesis of Compound 6 [ka] Compound 5 (33.0 g, 104 mmol, 86.7% purity, 1.00 eq), compound d (13.0 g, 124 mmol, 1.20 eq) and pyridine Py (82.1 g, 1.04 mmol, 83.8 mL, 10.0 eq) are dissolved in DCM (500 mL) at 0° C., POCl3 (19.3 g, 126 mmol, 11.7 mL, 1.22 eq) is added to the resulting solution, and the reaction mixture is stirred at 15° C. for 1.5 h. Compound 5 (R f = 0.40) was completely consumed, and the target product spot (R f After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then purified by silica gel chromatography (petroleum ether / ethyl acetate=8 / 1 to 5 / 1, R f =0.47, 0.75) to give compound 6_cis (7.00 g, 19.3 mmoL, 18.6% yield, 100% purity) as a pale yellow solid and compound 6_trans (5.00 g, 13.7 mmoL, 13.2% yield, 99.1%) as a pale yellow solid. LCMS: RT=0.959 min, m / z=362.1(M+H) + LCMS: RT=0.986 min, m / z=362.1(M+H) + Compound 6_cis: 1 H NMR:(400MHz,CDCl3)δ 9.31(s,1H),8.61(s,2H),7.66(d,J=6.6Hz,1H),6.94-6.80(m,1H),6.43(td,J=1.6,3.4Hz,1H),6.29( dd,J=2.8,3.6Hz,1H),5.00-4.73(m,1H),3.66(d,J=1.4Hz,3H),2.08-1.87(m,2H),1.34-1.24(m,1H). Compound 6_trans: 1H NMR:(400MHz,CDCl3)δ 9.33(s,1H),8.59(s,1H),8.49(s,1H),7.66(d,J=6.6Hz,1H),6.93-6.80(m,1H),6.42(td,J=1.6,3.4Hz,1H) ,6.29(dd,J=2.8,3.6Hz,1H),5.10-4.81(m,1H),3.66(d,J=1.4Hz,3H),2.21-2.08(m,1H),1.60-1.50(m,2H).

[0130] 2.1.6. Synthesis of compound 7_cis [ka] Compound 6_Cis (10.0 g, 27.6 mmol, 1.00 eq), BocNH2 (62.8 g, 536 mmol, 19.4 eq), BrettPhos Pd G3 (2.51 g, 2.76 mmol, 0.10 eq) and K3PO4 (17.6 g, 82.9 mmol, 3.00 eq) are dissolved in 2-methyl-2-butanol (1.00 L), the resulting solution is degassed and purged with N2 three times, and then reacted at 100 °C under N2 atmosphere with stirring for 16 hours. LCMS shows that compound 6_Cis is completely consumed and the target product molecular weight is detected. After the reaction is completed, it is filtered, and the obtained filtrate is concentrated under vacuum, and the residue is purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1, R f =0.40) to give compound 7_cis (3.90 g, 8.31 mmol, yield 30.1%, purity 94.3%) as a pale yellow solid. The structure was confirmed by LC-MS and 1 Confirmed by H NMR. LCMS: m / z=443.3 (M+H) + HPLC: 94.3% purity or less 220nm. 1H NMR:(400MHz,DMSO-d6)δ 10.99(s,1H),9.33(s,1H),9.09(s,1H),8.51(s,1H),7.84(d,J=6.6Hz,1H),7.00(d,J=1.8Hz,1H),6.52-6.29(m,1H),6 .23-6.13(m,1H),5.15-4.81(m,1H),3.63(s,3H),2.30-2.15(m,1H),1.77-1.60(m,1H),1.47(s,9H),1.25-1.02(m,1H).

[0131] 2.1.7. Synthesis of compound 7_trans [ka] Compound 6_trans (10.0 g, 27.6 mmol, 1.00 eq), BocNH2 (62.8 g, 536 mmol, 19.4 eq), BrettPhos Pd G3 (2.51 g, 2.76 mmol, 0.10 eq) and K3PO4 (17.6 g, 82.9 mmol, 3.00 eq) are dissolved in 2-methyl-2-butanol (1.00 L), the resulting solution is degassed and purged with N2 three times, and then reacted at 100 °C under N2 atmosphere with stirring for 16 hours. LCMS shows that compound 6_trans is consumed and the target product molecular weight is detected. After the reaction is completed, it is filtered, the filtrate is concentrated under reduced pressure, and the resulting solid is purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1, R f =0.50) to give compound 7_trans (5.50 g, 10.8 mmol, yield 39.3%, purity 87.4%) as a pale yellow solid. The structure was confirmed by LC-MS and 1 Confirmed by H NMR. LCMS: m / z=443.3 (M+H) + HPLC: 87.4% purity or less 220nm. 1H NMR:(400MHz,DMSO-d6)δ 11.11(s,1H),9.33(s,1H),9.09(s,1H),8.45(s,1H),7.82(d,J=6.6Hz,1H),7.04-6.93(m,1H),6.45-6.31(m,1H),6.17(d d,J=2.6,3.6Hz,1H),5.11-4.77(m,1H),3.62(s,3H),2.74-2.57(m,1H),1.67-1.42(m,10H),1.27(dt,J=6.6,13.0Hz,1H).

[0132] 2.1.8. Synthesis of compound DD02001A_cis [ka] Compound 7_Cis (3.90g, 8.31mmol, 94.3% purity, 1.00eq) is dissolved in ethyl acetate (40.0mL), and HCl / ethyl acetate (4M, 39.4mL, 18.9eq) is added to the above solution at 25°C, and the reaction is stirred at 25°C for 16 hours. LCMS shows that compound 7_Cis is completely consumed and the target product molecular weight is detected. After the reaction is completed, the resulting solution is concentrated under reduced pressure to obtain a solid, and the pH value is adjusted to about 8 with saturated NaHCO3 aqueous solution, and then the residue is extracted with dichloromethane / methanol=10 / 1 (100mL), and the obtained organic phase is dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain DD02001A_Cis (3.07g, 8.17mmol, yield 98.3%, purity 93.2%) as a yellow solid, and the structure is shown by LCMS, 1 This is confirmed by 1 H NMR as well as F NMR. LCMS: m / z=343.2 (M+H) + HPLC: 93.2% purity or less 220nm. 1H NMR:(400MHz,DMSO-d6)δ 10.80(s,1H),9.36(s,1H),8.28(s,1H),7.06-6.88(m,2H),6.31-6.10(m,4H),5.08 -4.78(m,1H),3.60(s,3H),2.30-2.17(m,1H),1.74-1.60(m,1H),1.18-1.09(m,1H). FNMR: (400MHz, DMSO-d6)δ-141.11,-221.11.

[0133] 2.1.9. Synthesis of compound DD02001A_trans [ka] Compound 7_trans (5.50g, 10.8mmol, 87.0% purity, 1.00 equivalent) is dissolved in ethyl acetate (40.0mL), HCl / ethyl acetate (4M, 51.3mL, 19.0eq) is added to the above solution at 25°C, and the resulting mixture is reacted with stirring at 25°C for 16 hours. LCMS shows that compound 7_trans is completely consumed and the target product molecular weight is detected. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a solid, and the pH value was adjusted to about 8 with saturated aqueous NaHCO3, then extracted with dichloromethane / methanol=10 / 1 (100 mL). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, slurried with petroleum ether / ethyl acetate=2 / 1 (30 mL) at 25°C, filtered, and the filter cake was dried under vacuum to obtain a yellow solid DD02001A_trans (3.30 g, 9.20 mmol, 85.0% yield, 95.4% purity), the structure of which was confirmed by LCMS: 1 This is confirmed by 1 H NMR as well as F NMR. LCMS: m / z=343.2 (M+H) + HPLC: 220nm below 95.4% purity. 1H NMR:(400MHz,DMSO-d6)δ 10.94(s,1H),9.38(s,1H),8.24(s,1H),7.03-6.91(m,2H),6.25-6.22(m,3H),6.14-6.12(m, 3H),5.07-4.79(m,1H),3.60(s,3H),2.67-2.54(m,1H),1.62-1.44(m,1H),1.35-1.19(m,1H) FNMR:(400MHz,DMSO-d6)δ-140.94,-206.78.

[0134] 2.2. Testing the in vitro inhibitory kinase activity of a series of compounds of formula I-2 [Table 3] The starting concentration of all compounds tested is 10 μM, with 3-fold gradient dilutions for a total of 10 concentration spots, with each concentration repeated once.

[0135] 2.2.1. In Vitro Testing of Compounds That Inhibit HPK1 Kinase Activity Before starting the experiment, prepare 50 μM DTT and enzyme reaction buffer. Pipette compound dilution into 384-well plate, add 384-well plate, seal and centrifuge at 1000g for 1 min; Prepare 2x HPK1 solution in kinase buffer, add 2.5μL of 2x HPK1 solution to 384-well, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 10 minutes; Prepare 2x MBP and ATP mixture in kinase buffer, add 2.5μL of 2x MBP and ATP mixture to the above reaction system to start reaction, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 1 hour; Add 5μL ADP-Glo ​​reagent to reaction system, incubate at room temperature for 40 minutes; Add 10μL kinase detection reagent, incubate at room temperature for 40 minutes, and then read luminescence signal with Envision2104 plate reader, calculate inhibition rate according to the following formula: Inhibition% = 100-(Signalcmpd -signal Ave_PC ) / (signal Ave_VC -signal Ave_PC ) x 100 In the above formula, cmpd refers to the test compound, PC refers to the positive control, and VC refers to the negative control.

[0136] 2.2.2. In Vitro Testing of Compounds That Inhibit GCK, TNIK, and PDK1 Kinase Activity The experimental process was completely consistent with the HPK1 kinase activity inhibition test experiment, with the difference being that the positive control used in the HPK1 experiment was sunitinib, and the positive control used in the GCK, TNIK and PDK1 experiments was staurosporine (staurosporine). [Table 4] As shown in Table 4, DD02001A_trans has an effective inhibitory effect on HPK1 kinase activity.

[0137] 2.2.3. In Vitro Testing of Compounds that Inhibit the Activity of Other Protein Kinases [Table 5]

[0138] Using the same experimental process as the above HPK1 kinase activity inhibition test experiment, the inhibition rate of compound DD02001A_trans against 48 kinases including HPK1 is tested at a concentration of 10 μM (duplicate wells). [Table 6] At a concentration of 10 μM, DD02001A_trans exhibited obvious inhibitory effects (inhibition rate <40%) against most kinases such as AKT1, HER2, EGFR, ERK1 / 2, ZAP70, IGF1R, ATR, MNK1 / 2, ROS1, CDK4, CDK7, CDK12, p38-alpha, IKK-beta, CK1gamma1, etc., but exhibited highly selective inhibition against the immune-related protein kinases shown in Table 6, indicating that compound DD02001A_trans has excellent kinase inhibition selectivity.

[0139] 2.2.4. Measurement of pharmacokinetic parameters of compounds The test compound is intravenously injected (2 mg / kg) and intragastrically administered (10 mg / kg) to every three male SD rats, and the blood drug concentration of the test compound in plasma is quantitatively measured using liquid chromatography tandem mass spectrometry, and pharmacokinetic parameters are calculated to examine the pharmacokinetic characteristics of the test compound in SD male rats. For test compounds, after oral administration, blood is collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours, respectively, after intravenous administration, blood is collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours, respectively, then 50μL of plasma sample is transferred to 96-well plate, 250μL of ACN (containing 260ng / ml of tosylbutamide as internal standard) is added to precipitate protein, centrifuged at 4℃, 4000rpm for 20 minutes, 150μL of supernatant is transferred to a new 96-well plate and mixed with 150μL of 0.1% FA / water, then 5μL of the obtained solution is taken and used for LC-MS / MS analysis. [Table 7]

[0140] 2.2.5.DD02001A_trans Acute Toxicity Experiment DD02001A_trans (2000, 1500, 1000, 500 mg / kg) will be intragastrically administered to mice at one time, and the reaction of the mice after administration and the death status within 2 weeks will be recorded.

[0141] 2.2.5.1. Animals: 10 Kunming mice (purchased from Guangdong Provincial Experimental Animal Center, license number: SCXK (Guangdong) 2018-0002), half female and half male. Body weight: 18-22g. After purchasing the mice, they were kept for 3 days to adapt to the environment. The mice were kept in an indoor cage at a room temperature of 23±1℃ and a relative humidity of 40%-60%, and food and drink were available ad libitum.

[0142] 2.5.1.2. Method: Mice were deprived of food and water for 10 hours before the experiment. Each mouse was intragastrically administered with various concentrations of the test drug (0.1ml / 10g) at one time, and observed continuously for 14 days. The animals' toxic symptoms after administration, the time of onset and duration of toxicosis, and the death status of the animals were recorded in detail; the dead animals were dissected in a timely manner, and the lesion status was recorded. If obvious changes were observed with the naked eye, pathological biopsy should be performed. According to the results of acute toxicity experiments, the maximum tolerated dose of DD02001A_trans administered intragastrically to mice is in the range of 1000-1500 mg / kg.

[0143] Example 2. Detection of HPK1 that inhibits the IFN-β signaling pathway Interferon-β (IFN-β) is a protein encoded by the IFNB1 gene. Natural or recombinant IFN-β protein has antiviral, antibacterial, and anticancer activities. To investigate the unique relationship between HPK1 and the IFN-β signaling pathway, we overexpress HPK1 and IFN-β luciferase reporter plasmid in HEK293 cells, stimulate the cells with Sendai virus (SeV) 24 hours after transfection, and collect the cells 12 hours later to examine the IFN-β luciferase activity. The results show that overexpression of the HPK1 (1-274) kinase structural region can significantly inhibit IFN-β transcription induced by SeV (Figure 1). Furthermore, expressing different amounts of HPK1 plasmid can inhibit IFN-β transcription induced by SeV in a dose-dependent manner (Figure 2).

[0144] ISRE (IFN-stimulated response elements) can bind to phosphorylated IRF3, thereby mediating IFN-β transcription, which is another important indicator of the antiviral pathway. We overexpress different doses of HPK1 and ISRE luciferase reporter plasmid in HEK293 cells, stimulate the cells with Sendai virus (SeV) 24 hours after transfection, and collect the cells 12 hours later to examine ISRE luciferase activity. The results show that HPK1 can inhibit ISRE transcription induced by SeV in a dose-dependent manner (Figure 3).

[0145] Example 3. Detection of in vitro enzyme activity of compounds of the present invention The present inventors detect the inhibitory activity of the compounds of the present invention (C1 to C6) against HPK1 kinase using the ADP-Glo™ method. [ka]

[0146] ADP-Glo™ Kinase Detection is a luminescent ADP detection method that provides a general, homogenous, high-throughput screening method to measure kinase activity by quantifying the amount of ADP generated during the kinase reaction. Detection is performed in two steps: after the kinase reaction, an equal volume of ADP-Glo™ Reagent is added to stop the kinase reaction and consume the remaining ATP. Next, the kinase detection reagent is added, which simultaneously converts ADP to ATP and allows the measurement of newly synthesized ATP using a luciferase / luciferin reaction. A photometer is used to measure the light produced. Using the ATP to ADP conversion curve, the luminescence can be related to the ADP concentration. All six small molecule inhibitors evaluated in this study showed good inhibitory activity against recombinant HPK1 kinase in vitro, with IC 50 is less than 0.1 μM (Table 1). At the same time, it shows excellent selectivity against kinases with closer homology, such as GCK / TNIK / PDK1. These properties ensure that the compound can specifically inhibit HPK1 enzyme activity in cell or animal experiments.

[0147] [Table 1-2]

[0148] Example 4. Compounds of the invention restore IFN-β expression inhibited by HPK1 Considering the research results that HPK1 inhibits the antiviral IFN-β signaling pathway, we consider whether HPK1 small molecule inhibitors can restore IFN-β expression inhibited by HPK1. Similar to the above experimental process, HPK1 and IFN-β luciferase reporter plasmid are overexpressed in HEK293 cells, 0.5 μM of compound is added 18 hours after transfection, cells are stimulated with SeV 24 hours later, and cells are collected 12 hours later to test IFN-β luciferase activity. The results show that compounds C2\C3\C4 have good activity, followed by compounds C1 and C6 (Figure 4). Furthermore, compound C2 shows a dose-dependent recovery of IFN-β expression inhibited by HPK1 (Figure 5).

[0149] Example 5. Maximum Tolerated Dose of Compounds of the Invention Administered Orally The present inventors test the maximum tolerated dose of representative compounds in mice by oral administration.The test results show that the maximum tolerated dose of compound C1 by single oral administration is 337.5mg / kg (Table 2), and the maximum tolerated dose of compound C3 by single oral administration is 225mg / kg (Table 3).

[0150] [Table 2-2]

[0151] [Table 3-2]

[0152] Example 6. Compounds of the invention effectively treat a murine MHV model To evaluate the antiviral therapeutic effect of HPK1 small molecule inhibitors in animal models, we use a C57 mouse model infected with Mouse Hepatitis Virus (MHV). MHV is a murine coronavirus that easily infects the liver and nervous system. For 8-week-old female C57 mice (3 mice per group), 4 × 10 4pfu of virus is injected. After inoculation of the virus, the mice are orally administered and treated (10 mg / kg, BID). Three days after virus infection, qPCR is used to detect the virus content in the liver tissue. Here, compound C1 exhibits remarkable antiviral therapeutic effects and can effectively reduce the virus titer in mouse liver (Figure 6). In a C57 mouse model infected with the same virus, orally administered different doses of C1 (5 mg / kg, 20 mg / kg) twice a day has a dose-dependent inhibitory effect on the virus titer in the mouse liver (Figure 7) and alanine aminotransferase in serum (Figure 8).

[0153] Example 7. Compounds of the invention effectively treat feline infectious peritonitis Feline infectious peritonitis (FIP), also known as feline peritonitis, is a fatal abnormal immune response in cats caused by a mutation of the feline coronavirus that cats carry. FIP remains a terminal disease, and although the time from onset to death is unknown, cats rarely survive for more than a year. Although the disease is called "peritonitis," FIP is actually a multisystem inflammatory disease, and not all affected cats necessarily show symptoms of peritonitis. The symptoms of affected cats are usually classified into two categories, wet FIP ​​and dry FIP, where wet FIP ​​accounts for about 70% of all cases and is characterized by the appearance of exudates and abnormal swelling in the abdominal and thoracic cavities, and the symptoms of cats with dry FIP vary depending on the type of organ affected by the virus. As of 2011, FIP ranks first among fatal infectious diseases of pet cats in developed countries.

[0154] Previous studies (Ishida et al., Journal of Feline Medicine and Surgery, 2004) have shown that recombinant feline interferon (rFeIFN) has a therapeutic effect against feline infectious peritonitis. Combined with our findings, HPK1 inhibitors can activate the IFN-β signaling pathway. Therefore, we hypothesize that HPK1 inhibitors may have a therapeutic effect against feline infectious peritonitis. To verify this hypothesis, we will conduct an animal clinical trial. All three animals involved in the experiment were infected with feline infectious peritonitis, aged 5-12 months, one female and two males (Table 4).

[0155] [Table 4-2]

[0156] After 20 days of treatment with injections of compound C1 solution (twice a day at a dose of 1.5 mg / kg), the physiological indices of the experimental animals were generally improved (Table 5): (1) increased appetite leading to weight gain, (2) improved mental state, going from lethargic to active, (3) disappearance of ascites, (4) increased white cell ratio, and (5) significant decrease in feline serum amyloid A.

[0157] [Table 5-2]

[0158] From this, we conclude that HPK1 small molecule inhibitors can effectively treat coronavirus-induced feline infectious peritonitis.

[0159] conclusion We have found that HPK1 can significantly inhibit the IFN-β signaling pathway. According to previous studies, we have found that HPK1 can also significantly inhibit the IFN-γ signaling pathway. The use of HPK1 inhibitors can provide anti-infectious disease treatment in two dimensions: antiviral action mediated by IFN-β and T cell activation mediated by IFN-γ.Thus, HPK1 inhibitors have therapeutic effects against all human or animal diseases caused by viruses with IFN-β / IFN-γ effects, including Hepatitis B virus, Measles virus, Sindbis virus, West Nile virus, Dengue virus, Herpes simplex virus, Human cytomegalovirus (HCMV), Ebola virus, Hepatitis C virus (HCV), Influenza A virus, Severe acute respiratory syndrome virus (SARS-CoV), Zika virus, Human immunodeficiency virus (HIV), Feline infectious peritonitis virus, Mouse hepatitis virus, Canine coronavirus, Feline calicivirus, and others. Calicivirus, Feline Leukemia Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus, Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea Virus, Porcine Hemagglutinating Encephalomyelitis Virus, Bovine Coronavirus, etc., are included, but are not limited to. HPK1 inhibitors are expected to be used as a new type of broad-spectrum antiviral therapy for the treatment of diseases caused by the above viruses.

[0160] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. Use of an HPK1 inhibitor in the preparation of a drug for treating or preventing an interferon-related disease or for enhancing immunity.

2. The interferon-associated disease is a viral infection.

2. The use according to claim 1.

3. HPK1 inhibitors have the formula I: 【Chemistry 1】 In the formula, Z １ is N or C-RR １ is selected from Z ２ and Z ３ are N or C-RR, respectively. ２ wherein Z is selected from ２ and Z ３ is different, R.R. １ is hydrogen, halogen, cyano group, hydroxyl group, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl groups, substituted or unsubstituted C １－６ selected from an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group; R.R. ２ is selected from a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted sulfhydryl group; R.R. ３ is H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ Cycloalkyl groups, substituted or unsubstituted C １－６ selected from an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group; R.R. ４ , R.R. ５ , R.R. ６ , R.R. ７ are each independently H, a hydroxyl group, a halogen atom, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ Cycloalkyl groups, substituted or unsubstituted C １－６ an alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted amide group, a substituted or unsubstituted C ５－１０ Heteroaryl group or RR ８ -Z ４ - is selected from, R.R. ８ is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or a substituted or unsubstituted hydroxyl group; Z ４ is -O-, -NH-, -S-, -SO-, -SO ２ -, a carbonyl group, a carbonylamino group or an aminocarbonyl group; or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite or derivative thereof, 2. The use according to claim 1.

4. The compound represented by formula I has the following formula I-1: 【Chemistry 2】 In the formula, R ａ , R ｂ , R ｃ , R ｄ Any one of the following is R １’ -X ’ -, and the remainder are each independently H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ a cycloalkyl group or a substituted or unsubstituted C １－６ alkoxy groups, R ｅ is H, a hydroxyl group, a halogen, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ a cycloalkyl group or a substituted or unsubstituted C １－６ alkoxy groups, X ’ is -O-, -NH-, -S-, -SO-, -SO ２ -, a carbonyl group, a carbonylamino group or an aminocarbonyl group; R １’ is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or R １４’ -O-(CH ２ ) ｍ－ where m is 0, 1, 2, 3, 4 or 5; R １４’ is a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein said heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R ２’ is selected from the following substituents: 【Transformation 3】 Here, Y ’ is C or N, and R ７’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ８’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ９ ’ and R １０ ’ are independently H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １１’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １２’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group; The compound is characterized in that it is represented by 4. The use according to claim 3.

5. The compound represented by formula I-1 has the formula I-1-1: 【Chemistry 4】 In the formula, R ｂ , R ｃ , R ｄ , R ｅ are each independently H, a hydroxyl group, a halogen atom, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ a cycloalkyl group or a substituted or unsubstituted C １－６ alkoxy groups, X ’ is -O-, -NH-, -S-, -SO-, -SO ２ -, a carbonyl group, a carbonylamino group or an aminocarbonyl group; R １’ is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, or R １４’ -O-(CH ２ ) ｍ－ where m is 0, 1, 2, 3, 4 or 5; R １４’ is a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein said heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R ２’ is selected from the following substituents: 【Transformation 5】 Here, Y ’ is C or N, and R ７’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ８’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ９ ’ and R １０ ’ are independently H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １１’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １２’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group; The compound is characterized in that it is represented by 5. The use according to claim 4.

6. The compound represented by formula I-1 is represented by formula I-1-1-1 or formula I-1-1-2: 【Transformation 6】 In the formula, R ｂ , R ｃ , R ｄ , R ｅ are each independently H, a hydroxyl group, a halogen atom, a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－８ a cycloalkyl group or a substituted or unsubstituted C １－６ alkoxy groups, X is -O-, -NH-, -S-, -SO-, -SO ２ -, a carbonyl group, a carbonylamino group or an aminocarbonyl group; n is 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; R １４’ is a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, A ’ the ring is a substituted or unsubstituted aryl group (preferably substituted or unsubstituted phenyl) or a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein said heteroaryl group has 1 to 4 heteroatoms selected from O, S or N; R ２’ is selected from the following substituents: 【Transformation 7】 Here, Y ’ is C or N, and R ７’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ８’ is H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R ９ ’ and R １０ ’ are independently H, substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １１’ is H, a substituted or unsubstituted amino group, a substituted or unsubstituted C １－６ alkyl group or substituted or unsubstituted C ３－８ is a cycloalkyl group, and R １２’ is a substituted or unsubstituted 4- to 6-membered heterocyclyl group; The compound is characterized in that it is represented by 6. The use according to claim 5.

7. The compound is: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 characterized in that it is selected from the group consisting of 4. The use according to claim 3.

8. The compound represented by formula I has the following formula I-2: 【Chemistry 9】 In the formula: R １ , R ２ , R ３ , R ４ and R ５ are each independently hydrogen, halogen, a cyano group, a hydroxyl group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl groups, substituted or unsubstituted C １－６ is selected from an alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted amido group, and R １ and R ２ is not hydrogen, R ６ teeth, 【Chemistry 10】 and X is O, NH, or S, Y is O, NH, or S, and the A ring is a substituted or unsubstituted C ３－６ a cycloalkyl group or a substituted or unsubstituted C ６－１０ an aryl group or a substituted or unsubstituted C ５－１０ a heteroaryl group, which refers to an aryl group containing one or more N, O, or S heteroatoms; R ７ is a halogen, a cyano group, a hydroxyl group, an amino group, an amide group, a branched or linear C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Heterocyclyl group, C ６－１０ Aryl group, C ５－１０ Heteroaryl groups or single or multiple substitutions on various rings, including —C(O)R′, where R′ is C ３－６ Heterocyclyl group, C ６－１０ Aryl group or C ５－１０ is a heteroaryl group, １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Heterocyclyl group, C ６－１０ Aryl groups and C ５－１０ The heteroaryl group may be hydrogen, a hydroxyl group, a halogen, a cyano group, an amino group, or —CHF ２ , -CF ３ , -CH ３ , -CH ２ CH ２ OH or -CONH ２ or R ７ and ring A together form a substituted or unsubstituted fused ring group, bridged ring group, heterobridged ring group, spiro ring group or heterospiro ring group; R ８ , R ９ and R １０ are each independently i. Hydrogen, hydroxyl group, halogen, cyano group, amino group, di(C １－６ alkyl)amino group, mono(C １－６ alkyl)amino group or C １－６ alkoxy groups, ii. Hydrogen, hydroxyl group, halogen, cyano group, amino group, -CHF ２ , -CF ３ , Ji (C １－６ alkyl)amino group, mono(C １－６ alkyl)amino group, C ３－６ Cycloalkyl group or C １－６ Branched or straight chain C further containing various single or multiple substitutions, including alkoxy groups. １－６ Alkyl group, C ２－６ Alkenyl group or C ２－６ alkynyl groups, iii. Hydrogen, C １－６ Alkyl group, hydroxyl group, halogen, cyano group, amino group, -CHF ２ or -CF ３ C containing various single or multiple substitutions, including ３－６ Cycloalkyl group, C ３－６ Heterocyclyl group, C ６－１０ Aryl group or C ５－１０ heteroaryl groups, The compound is characterized in that it is represented by 4. The use according to claim 3.

9. The compound represented by formula I-2 has the formula I-2-1: 【Chemistry 11】 In the formula, R １ , R ２ , R ６ , R ８ , R ９ and R １０ are each as defined in claim 8. The compound is characterized in that it is represented by 9. The use according to claim 8.

10. The compound represented by formula I-2 has the formula I-2-2: 【Chemistry 12】 In the formula, R １ , R ２ , R ６ and R ８ are each as defined in claim 8. The compound is characterized in that it is represented by 9. The use according to claim 8.

11. The compound represented by formula I-2 can be represented by formula I-2-3: 【Chemistry 13】 In the formula, R １ , R ２ , R ８ and ring A are each as defined in claim 8. The compound is characterized in that it is represented by 9. The use according to claim 8.

12. The compound is selected from the following:

9. The use according to claim 8. Table A-1 Table A-2 Table A-3 Table A-4 Table A-5 Table A-6 13. The compound comprising: 【Chemistry 14】 2. The use according to claim 1, characterized in that it is selected from:

14. The virus is selected from the group consisting of hepatitis B virus, measles virus, Sindbis virus, West Nile virus, dengue virus, herpes simplex virus, human cytomegalovirus (HCMV), Ebola virus, hepatitis C virus (HCV), influenza virus, severe acute respiratory syndrome virus (SARS-CoV), and Zika virus. Virus), Human Immunodeficiency Virus (HIV), Feline Infectious Peritonitis Virus, Mouse Hepatitis Virus, Canine Coronavirus, Feline Calicivirus, Feline Leukemia Virus, Feline Immunodeficiency Virus, Feline Panleukopenia Virus, Avian Infectious Bronchitis Virus Virus), Transmissible Gastroenteritis Virus, Porcine Epidemic Diarrhea Virus, Porcine Hemagglutinating Encephalomyelitis Virus, Bovine Coronavirus, etc., preferably Feline Infectious Peritonitis Virus, Mouse Hepatitis Virus, etc.

14. The use according to any one of claims 2 to 13, characterized in that the virus is selected from the group consisting of: herpes simplex virus, severe acute respiratory syndrome virus, Zika virus, canine coronavirus, feline calicivirus, avian infectious bronchitis virus, and porcine epidemic diarrhea virus.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, metabolite or derivative thereof, and one or more other antiviral agents, and any pharmaceutically acceptable excipients.

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