2-amido-substituted aza-aromatic ring compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a 2-amido-substituted aza-aromatic ring compound as well as a pharmaceutical composition and application of the 2-amido-substituted aza-aromatic ring compound. The structure of the compound is shown as a formula (I), and the compound also comprises a stereoisomer, a tautomer, a deuterated compound, a pharmaceutically acceptable salt or a mixture thereof. The compounds can effectively inhibit the activity of HPK1 kinase in vitro and inhibit the growth of tumors in vivo, are obviously superior to existing HPK1 kinase small-molecule inhibitor positive control drugs, and have no obvious toxicity. The HPK1 kinase inhibitor has a wide application range, can be used for preparing medicines for treating and / or preventing HPK1 kinase-mediated related diseases, and can be combined with other related medicines, such as PD-1 antibody medicines, MCT1 antibody medicines and the like. A candidate drug with a prospect is provided for solving the drug resistance problem of existing drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a 2-amino-substituted nitrogen heterocyclic compound, its pharmaceutical composition and application, and particularly relates to a 2-amino-substituted nitrogen heterocyclic compound that can be prepared into a drug for treating and / or preventing hematopoietic progenitor kinase-mediated diseases, its pharmaceutical composition and application. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine protein kinase and belongs to the ste20-related protein kinase MAP4K family. The MAP4K family also includes glucokinase (GCK, MAP4K2), GPK-like kinase (GLK, MAP4K3), HPK1-GPK-like kinase (HGK, MAP4K4), SPS1 / STE20 homologous kinase (KHS, MAP4K5) and Nck-related kinase (MINK, MAP4K6). Studies have shown that MAP4K1 - / - T cells can relieve tumor-infiltrating T cell exhaustion and are resistant to prostaglandin E2 (PGE2)-mediated inhibition. At the same time, it is known that MAP4K1 - / - DC cells have better antigen presentation ability compared with WT DC.

[0003] HPK1 plays the role of MAP4K by activating MAP3K proteins (including MEKK1, MLK3 and TAK1) and activating MAPK-Jnk. There is sufficient evidence that HPK1 is involved in the signal transduction of the T cell receptor (TCR). After TCR stimulation, tyrosine kinases Lck and Zap70 induce tyrosine phosphorylation and activate HPK1. In addition, the adapter proteins LAT, GAD and SLP-76 bind to HPK1 in an inducible manner. There are also several other adapter proteins that interact with HPK1, including Nck, PLCy, VAV, Crk, Clnk, Grb2 and Grap. In addition, HPK1 inhibits the transcription of osteosarcoma oncogenes induced by prostaglandin E2 (PGE2). Since HPK1 phosphorylates SLP-76, the serine and threonine residues on the 14-3-3 signaling protein and SLP-76 can interact optimally at the level induced by TCR. Since the 14-3-3 protein is a negative regulator of TCR signaling and phosphorylated serine-binding proteins, these results indicate that HPK1 promotes the interaction of SLP-76-mediated 14-3-3 proteins by phosphorylating SLP-76 and ultimately terminates TCR signaling in T cells.

[0004] In recent years, although several new types of ATP-competitive and allosteric HPK1 inhibitors with novel structures have been developed and entered clinical trials. However, the development of highly efficient, safe, and highly selective HPK1 inhibitors, and the provision of HPK1 inhibitors that can have excellent activities intracellularly (inhibiting SLP-76 protein phosphorylation and inducing the release of cytokines such as IL-2) and in vivo have not been achieved yet. Summary of the Invention

[0005] Object of the Invention: The first object of the present invention is to provide a 2-amino-substituted heteroaromatic compound, the second object is to provide a pharmaceutical composition containing the compound, and the third object is to provide an application of the compound and its pharmaceutical composition or in combination with other related drugs in the preparation of drugs for treating and / or preventing hematopoietic progenitor kinase-mediated diseases.

[0006] Technical Solution: The 2-amino-substituted heteroaromatic compound described in the present invention has the structure of formula (I), and also includes its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, or mixtures thereof:

[0007]

[0008] Wherein:

[0009] L1 is selected from -NR 1a -, -OR 1a -, -SR 1a -, -OCR 1a R 1b -, -NR 1a CR 1b R 1c -, -CO-, -CONHR 1a -, -CONR 1a R 1b -;

[0010] L2 is a single bond, or is selected from -NHR 1a -, -NR 1a R 1b -, -O-, -S-, -SO-, -SO2-, -CO-, -CR 1a R 1b -;

[0011] R 1a 、R 1b 、R 1c are each independently selected from hydrogen, halogen, deuterium, -CN, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7Cycloalkyl, 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms;

[0012] X 1 , X 2 , X 3 are independently selected from N, C;

[0013] cy 1 is selected from C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms;

[0014] R 1 is selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -CN, -NO2, -OR 2a , -SO2R 2a , -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CONR 2b R 2c , -NR 2a CO2R 2b , -NR 2a SONR 2b R 2c , -NR 2a SO2NR 2b R 2c , -NR 2a SO2R 2b , 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 substituted by a carbocyclic group C 1-8 alkyl, 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms substituted C 1-8 alkyl;

[0015] R 2a , R 2b , R 2c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 Cycloalkyl-substituted C 1-8 Alkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms-substituted C 1-8 Alkyl;

[0016] R 2 Selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkyl ether, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 3a , -SO2R 3a , -COR 3a , -CO2R 3a , -CONR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b , -NHR 3a , CONR 3b R 3c , -NR 3a CO2R 3b , -NR 3a SONR[[ID=D61]] 3b R 3c , -NR 3a SO2NR 3b R 3c , -NR 3a SO2R 3b , wherein each of the C 1-8 Alkyl, C 1-8 Alkenyl, cycloalkyl is optionally substituted by halogen, hydroxyl, C 1-7 Alkyl, C 3-7 Cycloalkyl;

[0017] m is selected from 0, 1, 2 or 3;

[0018] R 3a , R 3b , R 3c Are each independently selected from hydrogen, halogen, C 1-8 Alkyl, C1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Alkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 A C- 1-8 alkyl substituted by a carbocyclic group, a C- 1-8 alkyl substituted by a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms;

[0019] R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-5 alkoxy, C 1-5 cycloalkyl;

[0020] R 4 is selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 2-8 alkyl ether, C 3-7 cycloalkyl, -NH2, -CN, -NO2, -OR 4a , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO2R 4b , -NR 4a COR 4b R 4c , -COR 4a , -CO2R 4a , -CONR 4a R 4b , -COR 4a a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, C 3-10 a C- 1-8 alkyl substituted by a carbocyclic group, the C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 2-8 alkyl ether, cycloalkyl, heterocyclic group, aryl, heteroaryl substituted by R 4d ;

[0021] n is selected from 0, 1, 2, 3 or 4;

[0022] R 4a , R4b , R 4c , R 4d are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7 cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaromatic ring containing 0 to 3 N, S, O ring heteroatoms, C 3-10 substituted by a carbocyclic group, C 1-8 alkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms substituted C 1-8 alkyl;

[0023] R 5 is selected from a saturated, partially unsaturated or fully unsaturated 3- to 7-membered monocyclic carbocyclic ring, 3- to 7-membered monocyclic heterocyclic ring or 7- to 14-membered bicyclic ring, wherein the 3- to 7-membered monocyclic heterocyclic ring has 0 to 5 ring heteroatoms selected from N, S, O; the 7- to 14-membered bicyclic ring is selected from a carbocyclic ring, nitrogen-containing or oxygen-containing heterocyclic ring fused by a single bond or chemically bonded, and contains 0 to 3 of the following substituents: halogen, CN, OH, =O, NO2, NR 5a R 5b , SO2R 5a , SR 5a , 0 to 3 OH and / or C 1-3 substituted by alkoxy, C 1-4 alkyl, 0 to 3 OH and / or C 1-3 substituted by alkoxy, C 3-6 cycloalkyl, 0 to 3 halogen-substituted C 1-3 alkyl, -O(C 1-3 alkoxy), -O(0 to 3 OH and / or C 1-3 substituted by alkoxy, C 3-6 cycloalkyl), -O(0 to 3 halogen-substituted C 1-3 alkyl), -O(0 to 3 OH and / or C<s 1-3 substituted by alkoxy, C 1-3 alkyl), NR 5a SO2R 5b , R 5a , C(O)R 5a , NR 5a C(O)R 5b , OR 5a , S(O)R 5a or CH2R 5a ;

[0024] R5a , R 5b are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-5 alkylamino, C 3-7 alkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 substituted by a carbocyclic group C 1-8 alkyl, C 1-8 alkyl substituted by a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms.

[0025] Preferably, in the structure:

[0026] L1 is selected from -C(O)NH-, -NHC(O)-, -CH2O-, -OCH2-, -OCF2-, -OCD2-, -C(HF)O-, -OC(HF)-, -O-, -NHCH2-, -OCH(CH3)-, -OC(CH3)2-, -CO-, -SCH2-;

[0027] The structure of L2 is selected from a single bond, -O-, -CO-, -CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CF2-;

[0028] X 1 、X 2 、X 3 are independently selected from N, C;

[0029] R 3 is selected from hydrogen, halogen, methyl, methoxy, ethyl, ethoxy;

[0030] cy 1 is selected from C 3-7 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrole, furan, thiophene, imidazole, pyrazole, triazole, indole, indolinone, benzothiophene, benzofuran, quinoline, isoquinoline, purine;

[0031] R 1 、R 2 are selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -OH, -OCH3-, -CN, -NO2, -OR 2a 、-SO2R 2a, -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CONR 2b R 2c , -NR 2a CO2R 2b , -NR 2a SONR 2b R 2c , -NR 2a SO2NR 2b R 2c , -NR 2a SO2R 2b ;

[0032] R 2a , R 2b , R 2c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 azacycloalkyl, C 3-10 carbocyclic group-substituted C 1-8 alkyl, 3- to 10-membered heterocyclic group-substituted C 1-8 alkyl containing 0 to 5 N, S, O ring heteroatoms.

[0033] Further preferably, in the structure:

[0034] L1 is selected from -C(O)NH-, -NHC(O)-, -CH2O-, -OCH2-, -OCF2-, -OCD2-, -C(HF)O-, -OC(HF)-, -O-, -NHCH2-, -OCH(CH3)-, -OC(CH3)2-, -CO-, -SCH2-;

[0035] The L2 structure is selected from a single bond, -O-, -CO-, -CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CF2-;

[0036] X 1 is selected from an N or C atom, X 2 , X 3 is selected from a C atom;

[0037] R 3is selected from hydrogen, halogen, methyl, methoxy, ethyl, ethoxy;

[0038] Cy1 is selected from any of the following structures:

[0039]

[0040] R 1 、R 2 Selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -OH, -OCH3-, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a SO2R 2b ;

[0041] R 2a 、R 2b 、R 2c are independently selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Azacycloalkyl, C containing 0 to 5 N, S, O ring heteroatoms 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms 1-8 alkyl.

[0042] Preferably, in the structure:

[0043] R 4 Selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8Alkenyl, C 1-8 Alkoxy, C 2-8 Alkyl ether, C 3-7 Cycloalkyl, C 3-7 Azacycloalkyl, C 3-7 Oxacycloalkyl, -NH2, -CN, -NO2, -OR 4a , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO2R 4b , -NR 4a COR 4b R 4c , -COR 4a , -CO2R 4a ,, -CONR 4a R 4b , -COR 4a ;

[0044] R 4a , R 4b , R 4c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 a carbocyclic group-substituted C 1-8 alkyl, a 3- to 10-membered heterocyclic group-substituted C 1-8 alkyl.

[0045] Preferably, in the structure:

[0046] R 5 is selected from cyclohexyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, piperidyl, piperazinyl, homopiperazinyl, C 1-8 alkyl-substituted oxetane, C 1-8 alkyl-substituted morpholine, C 1-8 alkyl-substituted piperidyl, C 1-8 alkyl-substituted piperazinyl, C 1-8 alkyl-substituted homopiperazinyl, cyclohexyl-substituted C 1-8 alkyl, and each R 5 is substituted by 1-4 R 5a .

[0047] R 5a selected from hydrogen, a halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 azacycloalkyl, C substituted with 0 to 5 N, S, O ring heteroatoms 3-10 carbocyclic group-substituted C 1-8 alkyl, C substituted with a 3- to 10-membered heteroaryl group containing 0 to 5 N, S, O ring heteroatoms 1-8 alkyl.

[0048] More preferably, R 5 is selected from any of the following structures:

[0049]

[0050] Preferably, the 2-amino-substituted nitrogen heteroaromatic compounds of the present invention are selected from any of the following compounds:

[0051]

[0052]

[0053]

[0054] The present invention has developed a new and effective class of HPK1 inhibitors by using skeleton jump, skeleton fusion strategies and rational SAR exploration, and has carried out in vitro / in vivo activity tests on the developed amino-substituted nitrogen heteroaryl HPK1 inhibitors. A new type of HPK1 inhibitor with strong activity, low toxicity, strong killing ability against tumor cells and high safety is obtained, and it is expected to achieve targeted treatment of tumors.

[0055] The compounds of the present invention can also be used as solvates.

[0056] The present invention includes various deuterated forms of the compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.

[0057] As used herein, "plurality" means two or more. "And / or" describes the relationship between associated objects and indicates that three relationships can exist. For example, A and / or B can mean: A exists alone, A and B exist simultaneously, and B exists alone. The character " / " generally indicates that the associated objects before and after are in an "or" relationship.

[0058] The term "halo" means one of the halogens in Group 17 of the periodic table. In particular, the term means fluorine, chlorine, bromine, and iodine. Preferably, the term means fluorine or chlorine.

[0059] The term "alkyl" refers to saturated aliphatic hydrocarbon groups including branched and straight-chain groups with a specific number of carbon atoms. For example, the definition of "C1-C8 alkyl" for "C1-C8" includes groups having 1, 2, 3, 4, 5, 7, or 8 carbon atoms arranged in a straight-chain or branched-chain configuration.

[0060] The term "alkoxy" refers to a group in which an alkyl group is directly connected to oxygen, i.e., a group having an -O-alkyl structure such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0061] The term "alkyl ether" refers to a straight-chain or branched-chain alkyl chain interrupted by a single oxygen atom to provide an ether. For example: "C 2-6 alkyl ether" refers to a straight-chain or branched-chain hydrocarbon chain containing 2, 3, 4, 5, or 6 carbon atoms and having a single oxygen atom within the chain, such as -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, or -(CH2)2O(CH2)2CH3.

[0062] The term "heterocycle" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O, or S. The "heterocycle" system can contain 1, 2, 3, or 4 heteroatoms. The "heterocycle" system can be a monocyclic or fused polycyclic system, such as a bicyclic or tricyclic system. The "heterocycle" moiety can contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocycle" encompasses heterocyclic alkyl moieties, heterocyclic alkenyl moieties, and heteroaromatic moieties. For example, a heterocyclic group can be ethylene oxide, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0063] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain in which at least one heteroatom selected from N, O, and S is located between any carbons in the chain or at the end of the chain. For example, the term "C 1-6 heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and having at least one heteroatom selected from N, O, and S located between any carbons in the chain or at the end of the chain.

[0064] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. The "cycloalkyl" group can be represented as "C" containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 3-10"Cycloalkyl". The ring system can be a monocyclic, bicyclic or tricyclic system. For example, "cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclohexyl, cycloheptyl and cyclooctyl.

[0065] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. "Cycloalkenyl" can be represented as "C 3-10 cycloalkenyl". "C 3-10 cycloalkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring can contain more than one double bond, provided that the ring system is not aromatic. The ring system can be a monocyclic, bicyclic or tricyclic system. For example, "cycloalkenyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl.

[0066] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system having at least one heteroatom selected from N, O and S within the ring. "Heterocycloalkyl" can be represented as "C 3-10 heterocycloalkyl". "C 3-10 heterocycloalkyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there can be 1, 2 or 3 heteroatoms, optionally 1 or 2. The ring system can be a monocyclic, bicyclic or tricyclic system. When the ring system is bicyclic, one of the rings can be an aromatic ring, such as in indane. "Heterocycloalkyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkyl" can have one or more, for example one or two, bonds to the rest of the molecule: these bonds can be through any atom in the ring. For example, "heterocycloalkyl" can be ethylene oxide, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran and indane.

[0067] The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic and has at least one heteroatom selected from N, O and S within the ring. "Heterocycloalkenyl" can be represented as "C 3-10 heterocycloalkenyl". "C 3-10 heterocycloalkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there can be 1, 2 or 3 heteroatoms, optionally 1 or 2. The ring system can be a monocyclic, bicyclic or tricyclic system. When the ring system is bicyclic, one of the rings can be an aromatic ring, such as in dihydroindole and dihydrobenzofuran. "Heterocycloalkenyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkenyl" can have one or more, for example one or two, bonds to the rest of the molecule: these bonds can be through any atom in the ring. For example, "C 3-8"Heterocyclic alkenyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene, and dihydroindole.

[0068] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n + 2 electrons in the conjugated π-system within the ring, where all atoms contributing to the conjugated π-system are in the same plane. The ring system can be a monocyclic, bicyclic, or tricyclic system. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted by other groups.

[0069] The pharmaceutically acceptable salts are salts formed by the compound with an acid selected from any of the following:

[0070] Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, acidic amino acids, ferulic acid.

[0071] "Pharmaceutically acceptable salts" refers to salts of a compound prepared from a compound having specific substituents with a relatively non-toxic acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates), sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; organic acid salts also include salts of amino acids (such as arginine, etc.), glucuronic acid, and other organic acids. When certain specific compounds contain both basic and acidic functional groups, they can thus be converted into either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated to regenerate the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0072] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, the preparation of such salts involves reacting these compounds in the form of free acids or bases with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0073] Preferably, the stereoisomer is R 5 , L 1 , R 1 , R 2 The isomers introduced by chiral C or N in

[0074] The compounds of general formula (I) of the present invention can be prepared by the following methods:

[0075]

[0076] The synthesis steps of Reaction Scheme 1 are as follows: Using ethyl R 1 -substituted 3-bromoarylformate (I-1) and R 2 NH2 as raw materials, a C-N coupling reaction occurs under the protection of CuI and N2 to obtain a C-N coupling product. Subsequently, the C-N coupling product is reduced with NaBH4 as a reducing agent and MeOH as a solvent to obtain compound I-2. Subsequently, using dibromo-substituted arylamine (I-3) in the presence of NaH and anhydrous THF as a solvent, a nucleophilic substitution reaction occurs with intermediate I-2 to obtain intermediate I-4. Compound I-4 undergoes a Suzuki-Miyaura reaction with bis(pinacolato)diboron and potassium acetate in the presence of 1,4-dioxane as a solvent under N2 protection to obtain intermediate I-5. Aryl halide I-6 and nitrogen-containing aliphatic heterocyclic compound I-7 undergo a C-N coupling reaction in the presence of CuI and DMF as a solvent to obtain intermediate I-8 (alternatively, aryl halide I-6 and nitrogen-containing aliphatic heterocyclic compound I-7 can undergo a nucleophilic substitution reaction in the presence of DIPEA and DMF as a solvent to obtain I-8). Subsequently, intermediate I-8 and the previously prepared intermediate I-5 undergo a Suzuki reaction in the presence of Pd(dppf)Cl2 as a catalyst, K2CO3 as a base, under N2 protection, with 1,4-dioxane:water = 4:1 as a solvent, to obtain compound I-9.

[0077]

[0078] The synthesis steps of Reaction Scheme 2 are as follows: Using ethyl R 1 -substituted 3-bromoarylformate (II-1) and R 2Using NH2 as the raw material, a C-N coupling reaction occurs under the protection of CuI and N2 to obtain a C-N coupling product. Subsequently, the C-N coupling product is subjected to a reduction reaction using NaBH4 as the reducing agent and MeOH as the solvent to obtain Compound II-2. Then, a dibromo-substituted aromatic amine (II-3) reacts with Intermediate II-2 in the presence of NaH and using anhydrous THF as the solvent to undergo a nucleophilic substitution reaction to obtain Intermediate II-4. An aryl halide II-5 and a nitrogen-containing aliphatic heterocyclic compound II-6 undergo a C-N coupling reaction in the presence of CuI and using DMF as the solvent to obtain Intermediate II-7 (alternatively, an aryl halide II-5 and a nitrogen-containing aliphatic heterocyclic compound II-6 can undergo a nucleophilic substitution reaction in the presence of DIPEA and using DMF as the solvent to obtain II-7). Compound II-7 undergoes a Suzuki-Miyaura reaction in the presence of bis(pinacolato)diboron and potassium acetate, using dioxane as the solvent and under the protection of N2 to obtain Intermediate II-8. Subsequently, Intermediate II-8 and the previously prepared Intermediate II-4 undergo a Suzuki reaction in the presence of Pd(dppf)Cl2 as the catalyst, K2CO3 as the base, under the protection of N2, and using dioxane:water = 4:1 as the solvent to obtain Compound II-9.

[0079] The corresponding acid is salted with the compound (I) prepared by the above method to obtain the pharmaceutically acceptable salt of the said compound.

[0080] The pharmaceutical composition of the present invention comprises the said 2-amino-substituted azarene compounds and a pharmaceutically acceptable carrier.

[0081] Preferably, the dosage form of the pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, patches. The carriers that can be arbitrarily mixed can be changed according to the dosage form, administration form, etc. Examples of carriers include excipients, binders, disintegrants, lubricants, flavoring agents, fragrances, colorants, or sweetening agents, etc.

[0082] "Pharmaceutically acceptable carrier" may be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. The described pharmaceutical excipients may be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The described pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesives, glidants, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweetening agents.

[0083] The pharmaceutical composition described in the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0084] The pharmaceutical composition described in the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be in a controlled-release or sustained-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, cachets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injection solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the described pharmaceutical composition include but are not limited to eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0085] The 2-amino-substituted azarene compound or its pharmaceutical composition described in the present invention is used in the preparation of a drug for preventing and / or treating a disease mediated by hematopoietic progenitor kinase (HPK1), specifically a drug for preventing and / or treating immune disorders or cancers. Among them, cancers include diseases related to abnormal functions of hematopoietic progenitor kinase (HPK1), including lung cancer, malignant hematological diseases, prostate cancer, breast cancer, ovarian cancer, glioblastoma, pancreatic cancer, hepatolithiasis-related liver cancer, papillary thyroid cancer, colon cancer, head and neck squamous cell carcinoma, melanoma, etc.

[0086] The described 2-amino-substituted heteroaromatic compounds or their pharmaceutical compositions can also be used in combination with other related drugs, such as PD-1 antibodies, MCT1 antibodies and other drugs.

[0087] Advantages: Compared with the prior art, the present invention has the following remarkable advantages:

[0088] These compounds all have excellent inhibitory activity against HPK1 kinase in vitro, and the IC 50 value reaches the nanomolar concentration level, even lower than 1.0 nM; it can significantly inhibit tumor growth in the Ba1b / c mouse model. The in vitro and in vivo activities are significantly better than the existing small molecule inhibitor drugs of HPK1 kinase, and there is no obvious toxicity. It has a wide range of applications and can be prepared into drugs for the treatment and / or prevention of diseases mediated by HPK1 kinase, providing a promising candidate drug for solving the drug resistance problem of existing drugs. Description of the Drawings

[0089] Figure 1 Shows the results of the effects of Compound 1 and Compound 66 on the tumor volume of transplanted tumors of mouse colon cancer CT-26 cells in Balb / c mice;

[0090] Figure 2 Shows the results of the effects of Compound 1 and Compound 66 on the body weight of animals with transplanted tumors of CT-26 cells in Balb / c mice;

[0091] Figure 3 Shows the results of the effects of Compound 1 and Compound 66 on the tumor weight of transplanted tumors of mouse colon cancer CT-26 cells in Balb / c mice. Detailed Embodiments

[0092] The technical solutions of the present invention will be further described below in conjunction with the embodiments.

[0093] The experimental methods without specific conditions in the following embodiments of the present invention are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers. All kinds of common chemical reagents used in the embodiments are commercially available products.

[0094] Example 1: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0095]

[0096] Step1: (2-Aminopyridin-4-yl)methanol

[0097] In a 20 mL Schlenk tube, dissolve (2-chloropyridin-4-yl)methanol in DMF. Then, successively add a dioxane solution of NH3 and CuI, and react overnight in an oil bath at 120 °C. After the reaction is completed, dilute with water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (DCM / MeOH = 30:1) to obtain (2-aminopyridin-4-yl)methanol with a yield of 78%, a colorless oily substance. ESI-MS m / z: 125.06 [M+H] +

[0098] Step2: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine

[0099] In a 100 mL round-bottom flask, dissolve (2-aminopyridin-4-yl)methanol in anhydrous THF, stir for 10 min under an ice bath condition, then add NaH and stir for 30 min under an ice bath condition. Under the ice bath condition, slowly add 3,5-dibromopyrazin-2-amine to the above reaction solution. Then transfer the round-bottom flask to an oil bath at 50 °C and react for 4 h. After the reaction is completed, dilute with water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (PE:EA = 1:1) to obtain 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine with a yield of 46.8%, a pale yellow solid. ESI-MS m / z: 296.01 [M+H] +

[0100] Step3: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0101] In a 100 mL round-bottom flask, dissolve 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine, 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine, K2CO3, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium in a solvent of dioxane:water = 4:1. React in an oil bath at 100 °C for 3 h under N₂ protection. After the reaction is completed, dilute with water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (DCM / MeOH =  20:1) to obtain  3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine with a yield of 76.5%, a light yellow solid.1 HNMR(400MHz,DMSO-d6)δ8.03(s,1H),7.89(d,J=5.2Hz,1H),7.72(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),6.62(d,J=5.3Hz,1H),6.53(s,1H),6.37(s,2H),5.94(s,2H),5.38(s,2H),3.16(t,J=4.9Hz,4H),2.48(s,4H),2.24(s,3H);HR-MS(ESI)m / z:calcdfor C 21 H 25 N7O[M+H] + 392.2121found392.2134.

[0102] Example2:3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(1,4-oxazepan-4-yl)phenyl]pyrazin-2-amine

[0103] ThesynthesismethodwasreferredtothesynthesisofExample1,theyieldwas74.8%,andyellowishsolids. 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.88(d,J=5.3Hz,1H),7.74(d,J=8.3Hz,2H),6.96(d,J=8.4Hz,2H),6.61(d,J=5.5Hz,1H),6.53(s,1H),6.34(s,2H),5.91(s,2H),5.38(s,2H),3.75(t,J=4.8Hz,4H),3.13(t,J=4.8Hz,4H);HR-MS(ESI)m / z:calcd for C 20 H 22 N6O2[M+H] + [[ID=?]]379.1804found379.1834.

[0104] Example3:3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]pyrazin-2-amine <>

[0105] <> <> <>

[0106] Step1:(2-Aminopyridin-4-yl)methanol

[0107] There seems to be a formatting error in the "379.1804found379.1834." line in the original text where the "found" is not properly separated. I've translated it as best as possible while maintaining the structure. If this is incorrect, please provide the correct text for a more accurate translation.In a 20 mL Schlenk tube, dissolve (2-chloropyridin-4-yl)methanol in DMF. Sequentially add a dioxane solution of NH3, CuI, and react overnight in an oil bath at 120 °C. After the reaction is complete, dilute with water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (DCM / MeOH = 30:1) to obtain (2-aminopyridin-4-yl)methanol, with a yield of 78%, a colorless oily substance. ESI-MS m / z: 125.06 [M+H] + .

[0108] Step 2: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine

[0109] In a 100 mL round-bottom flask, dissolve (2-aminopyridin-4-yl)methanol in anhydrous THF, stir for 10 min under ice bath conditions, then add NaH and stir for 30 min under ice bath conditions. Under ice bath conditions, slowly add 3,5-dibromopyrazin-2-amine to the above reaction solution. Transfer the round-bottom flask to an oil bath at 50 °C and react for 4 h. After the reaction is complete, dilute with water, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (PE:EA = 1:1) to obtain 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine, with a yield of 46.8%, a pale yellow solid. ESI-MS m / z: 296.01 [M+H] +

[0110] Step 3: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine

[0111] In a 100 mL round-bottom flask, dissolve 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-bromopyrazin-2-amine in anhydrous dioxane. Then, successively add Bis(pinacolato)diboron, AcOK, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. React under N2 protection in an oil bath at 120 °C for 2 h. After the reaction is completed, dilute with water and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Then, perform column chromatography (DCM / MeOH = 10:1) to obtain 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine, with a yield of 51.2%, as a brown solid. ESI-MS m / z: 344.19 [M+H] + .

[0112] Step4: 1-(5-Bromopyridin-2-yl)-4-methylpiperazine

[0113] In a 20 mL Schlenk tube, dissolve 2,5-dibromopyridine in DMF. Then, successively add N-methylpiperazine and Et3N. React at 90 °C overnight. After the reaction is completed, dilute with water and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with water (20 mL × 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Then, perform column chromatography (DCM / MeOH = 30:1) to obtain 1-(5-bromopyridin-2-yl)-4-methylpiperazine, with a yield of 89.9%, as a white solid. ESI-MS m / z: 256.04 [M+H] + .

[0114] Step5: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]pyrazin-2-amine

[0115] In a 100 mL round-bottom flask, 1-(5-bromopyridin-2-yl)-4-methylpiperazine, 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine, K2CO3, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium were dissolved in a solvent of dioxane:water = 4:1. The reaction was carried out in an oil bath at 100 °C for 3 h under N2 protection. After the reaction was completed, it was diluted with water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 20:1) to obtain 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]pyrazin-2-amine with a yield of 79.5%, as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.5Hz,1H),8.02(s,1H),7.97(dd,J=8.9,2.5Hz,1H),7.87(d,J=5.2Hz,1H),6.85(d,J=9.0Hz,1H),6.63-6.57(m,1H),6.50(s,1H),6.38(s,2H),5.89(s,2H),5.37(s,2H),3.49(d,J=4.9Hz,4H),2.40(d,J=4.8Hz,4H),2.21(s,4H).HR-MS(ESI)m / z:calcd for C 20 H 24 N8O[M+H] + 393.2073found 393.2058.

[0116] Example 4: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-{2-[4-(1,4-oxazepan-4-yl)piperidin-1-yl]pyridin-5-yl}pyrazin-2-amine

[0117] The synthesis method was referred to that of Example 3, with a yield of 69.5%, as a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 2.5 Hz, 1H), 8.04 (s, 1H), 7.97 (dd, J = 9.0, 2.4 Hz, 1H), 7.91 (d, J = 5.3 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.63 (d, J = 5.1 Hz, 1H), 6.54 (s, 1H), 6.39 (s, 2H), 5.92 (s, 2H), 5.79 (s, 1H), 5.40 (s, 2H), 4.35 (d, J = 13.0 Hz, 3H), 3.59 (t, J = 4.6 Hz, 6H), 2.84 (t, J = 12.3 Hz, 2H), 2.49 (d, J = 5.4 Hz, 6H), 1.86 (d, J = 12.3 Hz, 3H), 1.27 (d, J = 4.3 Hz, 2H); HR-MS (ESI) m / z: calcd for C 24 H 30 N8O2 [M + H] + 463.2492 found 463.2501.

[0118] Example 5: 3 - ({[2-(ethylamino)pyridin-4-yl]methyl}oxy)-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0119] The synthesis method was referred to the synthesis of Example 1, with a yield of 79.2%, and it was a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 6.34 (s, 2H), 5.41 (s, 2H), 3.31 - 3.23 (m, 1H), 3.20 (s, 5H), 2.26 (s, 4H), 1.14 (t, J = 7.1 Hz, 3H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M + H] + 420.2434 found 420.2430.

[0120] Example 6: 3 - {[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(pyridin-4-yl)phenyl]pyrazin-2-amine

[0121] The synthesis method was referred to the synthesis of Example 1, with a yield of 65.5%, and it was a light yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 2H), 8.26 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 5.2 Hz, 2H), 6.65 (d, J = 11.0 Hz, 3H), 6.56 (s, 1H), 5.93 (s, 2H), 5.43 (s, 2H); HR-MS (ESI) m / z: calcd for C 23 H 22 N6O [M+H] + 399.1855 found 399.1875.

[0122] Example 7: 3-{[(2-Amino-6-methylpyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0123] The synthesis method was referred to the synthesis of Example 1, with a yield of 69.7%, a pale yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 2H), 8.26 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 5.2 Hz, 2H), 6.65 (d, J = 11.0 Hz, 3H), 6.56 (s, 1H), 5.93 (s, 2H), 5.43 (s, 2H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M+H] + 406.2277 found 406.2279.

[0124] Example 8: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[2-(1,4-thiazepan-4-yl)pyridin-5-yl]pyrazin-2-amine

[0125] The synthesis method was referred to the synthesis of Example 3, with a yield of 59.2%, a pale yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.92 (dd, J = 8.9, 2.4 Hz, 1H), 7.83 (d, J = 5.3 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 2H), 5.84 (s, 2H), 5.32 (s, 2H), 3.87 (d, J = 5.8 Hz, 4H), 2.54 (s, 4H); HR-MS (ESI) m / z: calcd for C 20 H 22 N6OS [M+H] + 395.1576 found 395.1575.

[0126] Example 9: 1-{4-[5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)pyridin-2-yl]piperazin-1-yl}ethan-1-one

[0127] The synthesis method was referred to the synthesis of Example 3, with a yield of 67.3%, a pale yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 8.05 (dd, J = 8.9, 2.5 Hz, 1H), 7.93 (d, J = 5.3 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 5.1 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 2H), 5.94 (s, 2H), 5.42 (s, 2H), 3.60 (s, 8H), 2.10 (s, 3H); HR-MS (ESI) m / z: calcd for C 21 H 24 N8O2 [M+H] + 421.2022 found 421.2025.

[0128] Example 10: 3-{[(2-{[2-(Dimethylamino)ethyl]amino}pyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0129] The synthesis method was referred to the synthesis of Example 1, with a yield of 78.3%, a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.95 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 5.6 Hz, 2H), 6.35 (d, J = 6.2 Hz, 3H), 5.39 (s, 2H), 3.16 (d, J = 5.1 Hz, 4H), 2.23 (t, J = 2.4 Hz, 13H); HR-MS (ESI) m / z: calcd for C 25 H 34 N8O [M + H] + 463.2856 found 463.2825.

[0130] Example 11: 3-{[(2-Amino-6-chloropyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0131] The synthesis method was referred to the synthesis of Example 1, with a yield of 59.3%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.67 (s, 1H), 6.44 (s, 1H), 6.39 (s, 2H), 6.35 (s, 2H), 5.35 (s, 2H), 3.14 (t, J = 4.9 Hz, 4H), 2.43 (d, J = 5.3 Hz, 4H), 2.20 (s, 3H); HR-MS (ESI) m / z: calcd for C 21 H 24 ClN7O [M + H] + 425.1731 found 425.1725.

[0132] Example 12: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyrazin-2-amine

[0133] The synthesis method was referred to the synthesis of Example 1, with a yield of 79.8%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.88 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.32 (dd, J = 8.3, 2.6 Hz, 3H), 7.06 (s, 1H), 6.73 (s, 1H), 6.62 (d, J = 5.2 Hz, 1H), 6.53 (s, 3H), 5.93 (s, 2H), 5.39 (s, 2H), 2.46 (d, J = 5.7 Hz, 8H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M+H] + 406.2277 found 406.2275.

[0134] Example 13: [4-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)phenyl](4-methylpiperazin-1-yl)methanone

[0135] The synthesis method was referred to that of Example 1, with a yield of 83.2%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 6.68 (s, 2H), 6.63 (d, J = 5.2 Hz, 1H), 6.54 (s, 1H), 5.95 (s, 2H), 5.40 (s, 2H), 2.21 (s, 4H); HR-MS (ESI) m / z: calcd for C 22 H 25 N7O2 [M+H] + 420.2070 found 420.2075.

[0136] Example 14: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(1,4-oxazepan-4-yl)piperidin-1-yl]phenyl}pyrazin-2-amine

[0137] The synthesis method was referred to that of Example 3, with a yield of 45.2%, a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.94 - 7.84 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.54 (s, 1H), 6.34 (s, 2H), 5.91 (s, 2H), 5.36 (s, 2H), 3.75 (d, J = 12.3 Hz, 2H), 3.56 (t, J = 4.5 Hz, 4H), 2.66 (t, J = 12.0 Hz, 2H), 2.46 (s, 2H), 2.25 (d, J = 11.2 Hz, 1H), 1.84 (d, J = 12.2 Hz, 2H), 1.45 (h, J = 9.2, 8.8 Hz, 2H), 1.23 (d, J = 5.2 Hz, 1H); HR-MS (ESI) m / z: calcd for C 25 H31N7O2 [M + H] + 462.2539 found 462.2545.

[0138] Example 15: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(1,4-oxazepan-4-ylmethyl)phenyl]pyrazin-2-amine

[0139] The synthesis method refers to the synthesis of Example 3, with a yield of 82.2%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 6.41 (s, 3H), 5.80 (s, 2H), 5.27 (s, 2H), 3.45 (s, 4H), 3.34 (s, 2H), 2.23 (s, 4H); HR-MS (ESI) m / z: calcd for C 21 H 24 N6O2 [M + H] + 393.1961 found 393.1965.

[0140] Example 16: 1-{4-[4-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)phenyl]piperazin-1-yl}ethan-1-one

[0141] The synthesis method refers to the synthesis of Example 3, with a yield of 69.3%, a yellow solid. 11H NMR(300 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.92 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 5.2 Hz, 1H), 6.56 (s, 1H), 6.40 (s, 2H), 5.96 (s, 2H), 5.42 (s, 2H), 3.62 (s, 4H), 3.36 - 3.11 (m, 4H), 2.09 (s, 3H); HR-MS(ESI) m / z: calcd for C 22 H 25 N7O2[M + H] + 420.2070 found 420.2065.

[0142] Example 17: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(Methyldioxo-λ6-sulfanyl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0143] The synthesis method was referred to the synthesis of Example 3, with a yield of 49.6%, and it was a yellow solid. 1 1H NMR(500 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.33 (dt, J = 16.1, 5.2 Hz, 4H), 3.19 - 3.10 (m, 4H), 2.87 (s, 2H); HR-MS(ESI) m / z: calcd for C 21 H 25 N7O3S[M + H] + 456.1740 found 456.1765.

[0144] Example 18: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(Hexahydropyridin-1-yl)phenyl]pyrazin-2-amine

[0145] The synthesis method was referred to the synthesis of Example 1, with a yield of 69.3%, and it was a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.89 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 6.53 (s, 1H), 6.31 (s, 2H), 5.91 (s, 2H), 5.38 (s, 2H), 3.23 - 3.12 (m, 4H), 1.61 (t, J = 5.2 Hz, 4H), 1.54 (q, J = 7.2, 5.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H<000{}431>N6O [M+H] + 376.2012 found 376.2002.

[0146] Example 19: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(4-ethylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0147] The synthesis method was referred to the synthesis of Example 1, with a yield of 81.5%, yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 6.54 (s, 1H), 6.33 (s, 2H), 5.91 (s, 2H), 5.38 (s, 2H), 3.16 (t, J = 5.0 Hz, 4H), 2.38 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.1 Hz, 4H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M+H] + 406.2277 found 406.2279.

[0148] Example 20: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}pyrazin-2-amine

[0149] Note: In the translation of chemical-related content, it is important to ensure the accuracy of chemical terms and symbols. Here, the chemical shift values and mass spectrometry data are presented as they are in the original text, following the standard conventions in the field of chemistry. The chemical compound names are translated according to the common naming rules in organic chemistry. For the tags 21 , 24 , etc., they are preserved as they are because they might be specific identifiers in a particular context, perhaps related to a database or a specific numbering system within the patent document. The same applies to ,

[0146] , etc. The text within the [[ID=...]] tags is translated while keeping the tags intact to maintain the integrity of the original document's structure. The line breaks are preserved to match the original format, which is likely for better readability and organization of the different pieces of information in the patent description.The synthesis method was referred to the synthesis in Example 3, with a yield of 53.9%, and it was a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.88 (d, J = 5.2 Hz, 1H), 7.80 - 7.67 (m, 2H), 7.03 - 6.90 (m, 2H), 6.61 (dd, J = 5.2, 1.4 Hz, 1H), 6.53 (s, 1H), 6.32 (s, 2H), 5.91 (s, 2H), 5.38 (s, 2H), 3.75 (dt, J = 13.1, 3.7 Hz, 2H), 2.67 (td, J = 12.3, 2.5 Hz, 2H), 2.29 (dq, J = 12.6, 6.4, 5.0 Hz, 1H), 2.23 (s, 6H), 1.87 - 1.80 (m, 2H), 1.47 (qd, J = 12.0, 3.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M+H] + 420.2434 found 420.2456.

[0150] Example 21: Methyl {4-[4-(5-amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)phenyl]piperazin-1-yl}acetate

[0151] The synthesis method was referred to the synthesis in Example 3, with a yield of 37.8%, and it was a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.90 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 5.4 Hz, 1H), 6.54 (s, 2H), 6.32 (s, 2H), 5.89 (s, 3H), 5.38 (s, 2H), 3.64 (s, 3H), 3.30 (s, 2H), 3.17 (t, J = 4.9 Hz, 4H), 2.65 (t, J = 4.9 Hz, 4H); HR-MS (ESI) m / z: calcd for C 23 H 27 N7O3 [M+H] + 450.2175 found 450.2179.

[0152] Example 22: Methyl 4-{4-[4-(5-amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)phenyl]piperazin-1-yl}butanoate

[0153] The synthesis method was referred to the synthesis in Example 3, with a yield of 39.8%, and it was a yellow solid.1 1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 5.1 Hz, 1H), 6.55 (s, 1H), 6.32 (s, 2H), 5.90 (s, 2H), 5.39 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.16 (t, J = 4.8 Hz, 4H), 2.40 - 2.29 (m, 4H), 1.74 (p, J = 7.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). HR-MS (ESI) m / z: calcd for C 25 H 31 N7O3 [M + H] + 478.2488 found 478.2479.

[0154] Example 23: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[1-(4-methylpiperazin-1-yl)-2-nitrobenz-4-yl]pyrazin-2-amine

[0155] The synthesis method was referred to the synthesis of Example 3, with a yield of 66.7%, yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 5.1 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 10.7 Hz, 3H), 6.51 (s, 1H), 5.92 (s, 2H), 5.37 (s, 2H), 3.01 (t, J = 4.8 Hz, 4H), 2.26 (s, 4H); HR-MS (ESI) m / z: calcd for C 21 H 24 N8O3 [M + H] + 437.1971 found 437.1979.

[0156] Example 24: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(4-methylpiperazin-1-yl)benz-1-carbonitrile

[0157] The synthesis method was referred to the synthesis of Example 3, with a yield of 75.9%, yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.61 (m, 2H), 8.26 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 5.2 Hz, 2H), 6.65 (d, J = 11.0 Hz, 3H), 6.56 (s, 1H), 5.93 (s, 2H), 5.43 (s, 2H); HR-MS (ESI) m / z: calcd for C 22 H 24 N8O [M + H] + 417.2073 found 417.2079.

[0158] Example 25: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[1,3-dimethyl-2-(4-methylpiperazin-1-yl)phenyl-5-yl]pyrazin-2-amine

[0159] The synthesis method was referred to the synthesis of Example 3, with a yield of 45.1%, yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M + H] + 42,0.2434 found 420.2439.

[0160] Example 26: N-[5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(4-methylpiperazin-1-yl)phenyl]acetamide

[0161] The synthesis method was referred to the synthesis of Example 3, with a yield of 36.5%, yellow solid. 11H NMR(400MHz,DMSO-d6)δ8.69-8.61(m,2H),8.26(s,1H),8.03(d,J=8.1Hz,2H),7.90(d,J=5.3Hz,1H),7.85(d,J=8.1Hz,2H),7.75(d,J=5.2Hz,2H),6.65(d,J=11.0Hz,3H),6.56(s,1H),5.93(s,2H),5.43(s,2H);HR-MS(ESI)m / z:calcd for C 23 H 28 N8O2[M+H] + 449.2335found 449.2337.

[0162] Example 27: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[2-fluoro-1-(1,4-oxazepan-4-yl)phenyl]pyrazin-2-amine

[0163] The synthesis method was referred to the synthesis of Example 3, with a yield of 79.5%, a yellow solid. 1 1H NMR(300MHz,DMSO-d6)δ7.89(s,1H),7.66(d,J=5.3Hz,1H),7.43(s,1H),7.39(d,J=4.7Hz,1H),6.82(t,J=8.8Hz,1H),6.40(d,J=5.2Hz,1H),6.30(d,J=8.6Hz,3H),5.70(s,2H),5.17(s,2H),3.53(t,J=4.7Hz,4H),2.80(t,J=4.7Hz,4H);HR-MS(ESI)m / z:calcd for C 20 H 21 FN6O2[M+H] + 397.17I0found 397.1737.

[0164] Example 28: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(4-cyclopropylpiperazin-1-yl)phenyl]pyrazin-2-amineThe synthesis method was referred to the synthesis of Example 3, with a yield of 65.1%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.33 - 3.20 (m, 5H), 2.79 (dd, J = 6.1, 3.8 Hz, 2H), 2.61 (dd, J = 6.1, 3.8 Hz, 2H), 2.50 (p, J = 5.7 Hz, 1H), 0.76 - 0.52 (m, 4H); HR-MS (ESI) m / z: calcd for C 23 H 27 N7O [M+H] + 418.2277 found 418.2282.

[0165] Example 29: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(4-cyclopropylpiperazin-1-yl)benzene-1-carbonitrile

[0166] The synthesis method was referred to the synthesis of Example 3, with a yield of 36.5%, a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.13 (m, 2H), 8.07 (dd, J = 8.7, 2.3 Hz, 1H), 7.89 (d, J = 5.3 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 6.66 - 6.60 (m, 1H), 6.58 (s, 2H), 6.52 (s, 1H), 5.89 (s, 2H), 5.39 (s, 2H), 3.13 (t, J = 4.9 Hz, 4H), 2.73 (t, J = 4.8 Hz, 4H), 1.72 (dt, J = 6.4, 3.1 Hz, 1H), 0.45 (dt, J = 6.1, 2.9 Hz, 2H), 0.35 (q, J = 3.4, 2.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 24 H 26 N8O [M+H] + 443.2230 found 443.2237.

[0167] Example 30a, 30b: 3-{[1-(2-aminopyridin-4-yl)ethyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0168] The synthesis method refers to the synthesis in Example 1, with a yield of 66.3%, a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 5.4 Hz, 1H), 6.57 (s, 1H), 6.36 (s, 2H), 6.09 (q, J = 6.5 Hz, 1H), 5.95 (s, 2H), 3.26 (t, J = 5.1 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H), 1.65 (d, J = 6.5 Hz, 2H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M+H] + 406.2277 found 406.2267.

[0169] Example 31a, 31b: 3-{[1-(2-aminopyridin-4-yl)ethyl]oxy}-5-[4-(4-cyclopropylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0170] The synthesis method refers to the synthesis in Example 3, with a yield of 48.3%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.16 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.19 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 4.1, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 5.96 (s, 1H), 5.55 (q, J = 6.2 Hz, 1H), 4.91 (s, 1H), 3.33 - 3.20 (m, 4H), 2.79 (dd, J = 6.1, 3.8 Hz, 2H), 2.61 (dd, J = 6.1, 3.8 Hz, 2H), 2.50 (p, J = 5.7 Hz, 1H), 1.72 (s, 1H), 0.76 - 0.64 (m, 2H), 0.64 - 0.52 (m, 2H); HR-MS (ESI) m / z: calcd forC 24 H 29 N7O [M+H] + 432.2434 found 432.2432.

[0171] Example 32: 3-{[(2-Aminopyridin-4-yl)difluoromethyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0172] The synthesis method was referred to the synthesis of Example 1, with a yield of 64.1%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.23(d,J=3.7Hz,1H),7.91-7.85(m,2H),7.27(dd,J=3.7,1.9Hz,1H),7.20(d,J=1.9Hz,1H),6.95-6.89(m,2H),5.95(s,2H),5.76(s,2H),3.28-3.17(m,4H),2.80(ddd,J=12.3,5.5,3.9Hz,2H),2.57(ddd,J=12.4,5.5,3.9Hz,2H);HR-MS(ESI)m / z:calcdfor C 21 H 23 F2N7O[M+H] + 428.1932found 428.1932.

[0173] Example 33: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-(4-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}phenyl)pyrazin-2-amine

[0174] The synthesis method was referred to the synthesis of Example 3, with a yield of 46.9%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91-7.85(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,1H),5.27(s,1H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.25(td,J=5.7,3.1Hz,4H),2.65(ddd,J=17.6,6.0,3.3Hz,4H),2.58-2.49(m,4H);HR-MS(ESI)m / z:calcd for C 24 H 32 N8O[M+H] + 448.2699found 448.2658.

[0175] Examples 34a, 34b: 3-{[(2-Aminopyridin-4-yl)(fluoro)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0176] The synthesis method refers to the synthesis in Example 1, with a yield of 55.8%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.26(d,J=4.1Hz,1H),7.91-7.85(m,2H),7.22(dd,J=4.1,1.9Hz,1H),7.07(d,J=1.9Hz,1H),6.95-6.89(m,2H),5.97(s,2H),5.46(d,J=6.8Hz,1H),5.39(d,J=6.6Hz,1H),3.28-3.17(m,4H),2.80(ddd,J=12.3,5.5,3.9Hz,2H),2.57(ddd,J=12.4,5.5,3.9Hz,2H);HR-MS(ESI)m / z:calcd for C 21 H 24 FN7O[M+H] + 409.2026found 409.2058.

[0177] Examples 35a, 35b: 5-(5-Amino-6-{[1-(2-aminopyridin-4-yl)ethyl]oxy}pyrazin-2-yl)-2-(4-cyclopropylpiperazin-1-yl)benzene-1-carbonitrile

[0178] The synthesis method refers to the synthesis in Example 1, with a yield of 73.2%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.19-8.14(m,2H),7.92(dd,J=8.2,1.8Hz,1H),7.19(d,J=1.8Hz,1H),7.07(d,J=8.1Hz,1H),7.00(dd,J=4.1,1.9Hz,1H),5.96(s,1H),5.55(q,J=6.2Hz,1H),4.91(s,1H),3.25-3.13(m,4H),2.77(dd,J=5.9,3.8Hz,2H),2.65(dd,J=5.9,3.8Hz,2H),2.50(p,J=5.7Hz,1H),1.72(s,1H),0.76-0.64(m,2H),0.64-0.52(m,2H);HR-MS(ESI)m / z:calcd for C 25 H 28N8O[M+H] + 457.2386 found 457.2377.

[0179] Example 36: 3-{[(2-Aminopyridin-4-yl)dideuteromethyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0180] The synthesis method was referred to that of Example 1, with a yield of 72.1%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),8.07(d,J = 4.2Hz,1H),7.91-7.85(m,2H),7.05(dd,J = 4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J = 2.0Hz,1H),5.92(s,2H),4.93(s,2H),3.28-3.17(m,4H),2.80(ddd,J = 12.3,5.5,3.9Hz,2H),2.57(ddd,J = 12.4,5.5,3.9Hz,2H); HR-MS(ESI)m / z: calcd for C 21 H 23 D2N7O[M+H] + 394.2246 found 394.2232.

[0181] Example 37: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(methoxymethyl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0182] The synthesis method was referred to that of Example 3, with a yield of 64.5%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J = 4.2Hz,1H),7.91-7.85(m,2H),7.16(dd,J = 4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J = 1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J = 6.6Hz,1H),4.72(d,J = 6.6Hz,1H),3.98(s,2H),3.29(s,2H),3.21(dd,J = 4.9,4.0Hz,4H),2.85-2.74(m,4H); HR-MS(ESI)m / z: calcd for C 22 H 27 N7O2[M+H] +422.2226 found 422.2232.

[0183] Examples 38a, 38b: 3-{[(2-Aminopyridin-4-yl)(deuterio)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0184] The synthesis method was referred to the synthesis of Example 1, with a yield of 74.6%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.15 (d, J = 4.3 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.17 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.55 (d, J = 1.8 Hz, 1H), 5.94 (s, 2H), 5.07 - 5.00 (m, 2H), 4.85 (d, J = 6.6 Hz, 1H), 3.28 - 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.5, 3.9 Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H 24 DN7O[M + H] + 393.2183 found 393.2132.

[0185] Example 39: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0186] The synthesis method was referred to the synthesis of Example 3, with a yield of 69.7%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.31 - 3.20 (m, 4H), 2.75 (p, J = 6.7 Hz, 1H), 2.70 (dd, J = 5.6, 4.3 Hz, 2H), 2.62 (dd, J = 5.6, 4.3 Hz, 2H), 1.05 (d, J = 6.8 Hz, 6H); HR-MS (ESI) m / z: calcd for C23 H 29 N7O[M+H] + 420.2434found 420.2432.

[0187] Example 40: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(3,4,5,6-Tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0188] The synthesis method was referred to the synthesis of Example 3, with a yield of 59.8%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91-7.85(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.58(qdd,J=12.5,6.2,3.9Hz,4H),3.33-3.20(m,4H),2.73(dd,J=6.0,3.8Hz,2H),2.64(d,J=3.7Hz,1H),2.65-2.57(m,2H),1.82(dtd,J=12.4,6.2,4.0Hz,2H),1.65(dtd,J=12.4,6.2,4.0Hz,2H); HR-MS(ESI)m / z:calcd for C 25 H 31 N7O2[M+H] + 462.2539found 462.2532.

[0189] Example 41: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(Hexahydropyridin-4-yl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0190] The synthesis method was referred to the synthesis of Example 3, with a yield of 49.8%, and it was a yellow solid. 11H NMR(400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.33 - 3.20 (m, 4H), 2.92 (dddd, J = 12.4, 5.9, 4.2, 3.0 Hz, 2H), 2.84 - 2.75 (m, 2H), 2.72 (dd, J = 6.0, 3.8 Hz, 2H), 2.63 (dd, J = 6.1, 3.7 Hz, 2H), 2.56 (p, J = 4.2 Hz, 1H), 2.45 (p, J = 6.0 Hz, 1H), 1.78 (dtd, J = 12.4, 5.9, 3.1 Hz, 2H), 1.57 (ddt, J = 12.4, 6.0, 3.0 Hz, 2H); HR-MS(ESI) m / z: calcd for C 25 H 32 N8O [M+H] + 461.2699 found 461.2702.

[0191] Example 42: 3-{[(Pyridin-amine-4-yl)methyl]oxy}-5-{4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}pyrazine-2-amine

[0192] The synthesis method was referred to the synthesis of Example 3, with a yield of 69.2%, and it was a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.33 - 3.20 (m, 4H), 2.75 - 2.61 (m, 6H), 2.44 (ddd, J = 12.4, 8.1, 5.4 Hz, 2H), 2.37 (p, J = 5.4 Hz, 1H), 1.77 (ddt, J = 12.3, 8.1, 5.3 Hz, 2H), 1.58 (ddt, J = 12.4, 8.2, 5.5 Hz, 2H); HR-MS (ESI) m / z: calcd for C 26 H 34 N8O [M+H] + 475.2856 found 475.2850.

[0193] Example 43: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]pyrazin-2-amine

[0194] The synthesis method refers to the synthesis of Example 3, with a yield of 54.7%, a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.37 - 3.26 (m, 4H), 2.63 - 2.52 (m, 4H), 2.31 (s, 2H), 1.80 (ddt, J = 14.0, 13.2, 6.6 Hz, 2H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M+H] + 406.2277 found 406.2287.

[0195] Examples 44a, 44b: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[3-(dimethylamino)tetrahydro-1H-pyrrol-1-yl]phenyl}pyrazin-2-amine

[0196] The synthesis method was referred to the synthesis of Example 3, with a yield of 49.5%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.70 - 3.54 (m, 3H), 3.36 (ddd, J = 12.4, 6.4, 4.6 Hz, 1H), 3.14 - 3.07 (m, 1H), 2.28 (d, J = 1.4 Hz, 6H), 1.90 (ddt, J = 11.3, 6.6, 4.9 Hz, 1H), 1.71 (ddt, J = 12.5, 6.6, 4.6 Hz, 1H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M + H] + 406.2277 found 406.2277.

[0197] Example 45: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(trifluoromethyl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0198] The synthesis method was referred to the synthesis of Example 3, with a yield of 66.3%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.41 - 3.29 (m, 4H), 3.12 - 2.97 (m, 4H); HR-MS (ESI) m / z: calcd for C 21 H 25 F3N7O [M + H]+ 446.1838found 446.1850.

[0199] Example 46: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl]pyrazin-2-amine

[0200] The synthesis method refers to that of Example 3, with a yield of 61.9% and a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 8.17 (d, J = 4.2Hz, 1H), 7.91-7.85 (m, 2H), 7.16 (dd, J = 4. 3,1.9Hz,1H),6.88-6.82(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(d,J=1.6Hz,2H),4 .82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.59(dd,J=12.4,3.7Hz,2H),3.43(dd,J=12.5,3 .7Hz,2H),3.32-3.24(m,2H),2.45(t,J=1.6Hz,3H),1.93-1.77(m,4H); HR-MS(ESI)m / z:calcd for C 23 H 23 N7O[M+H] + 418.2277found 418.2282.

[0201] Example 47: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-{4-[4-(trideuteriomethyl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0202] The synthesis method refers to that of Example 3, with a yield of 68.4% and a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91-7.85(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J=1.9Hz,1H ),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.27(dd,J=5.0,4.4Hz,4H),2.81-2.70(m,4H); HR-MS(ESI)m / z:calcdfor C21 H 22 D3N7O[M+H] + 395.2309found 395.2311.

[0203] Example 48: 4-[4-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)phenyl]-1-methylpiperazin-2-one

[0204] The synthesis method was referred to the synthesis of Example 3, with a yield of 63.1%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91-7.85(m,2H),7.18-7.13(m,1H),6.97-6.91(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),4.25(s,1H),4.18(s,1H),3.80(dd,J=5.8,3.9Hz,1H),3.72(dd,J=5.9,3.6Hz,1H),3.66-3.54(m,2H),2.97(s,2H); HR-MS(ESI)m / z:calcd for C 21 H 23 N7O2[M+H] + 406.1913found 406.1918.

[0205] Example 49a, 49b: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(3,4-dimethylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0206] The synthesis method was referred to the synthesis of Example 3, with a yield of 51.6%, and it was a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 4.44 (dd, J = 12.4, 4.5 Hz, 1H), 3.56 (dd, J = 12.5, 4.6 Hz, 1H), 3.42 (ddd, J = 12.4, 6.0, 3.7 Hz, 1H), 3.33 (ddd, J = 12.5, 6.0, 3.8 Hz, 1H), 3.19 - 3.09 (m, 1H), 3.02 - 2.88 (m, 2H), 2.29 (d, J = 1.4 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M + H] + 406.2277 found 406.2218.

[0207] Example 50a, 50b: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(3,4,5-trimethylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0208] The synthesis method was referred to the synthesis of Example 3, with a yield of 49.7%, and it was a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.88 - 6.82 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 4.44 (dd, J = 12.5, 4.4 Hz, 2H), 3.49 (dd, J = 12.3, 4.4 Hz, 2H), 3.26 - 3.16 (m, 2H), 2.32 (d, J = 3.1 Hz, 2H), 1.14 (d, J = 6.8 Hz, 6H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M + H] +420.2434 found 420.2430.

[0209] Example 51: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(2-methyl-2,5-diazabicyclo[2.2.1]hept-5-yl)phenyl]pyrazin-2-amine

[0210] The synthesis method was referred to the synthesis of Example 3, with a yield of 32.9%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.90-7.84(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.90-6.84(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(d,J=1.6Hz,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),4.06(dd,J=12.5,2.2Hz,1H),4.00(tt,J=3.1,2.1Hz,1H),3.72(dd,J=12.4,2.3Hz,1H),3.31-3.25(m,1H),2.89(dd,J=12.3,2.2Hz,1H),2.83(dd,J=12.3,2.1Hz,1H),2.32(d,J=1.4Hz,3H),2.18-2.10(m,1H),1.84-1.77(m,1H); HR-MS(ESI)m / z: calcd for C 22 H 25 N7O[M+H] + 404.2121 found 404.2130.

[0211] Example 52a, 52b: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(3-ethyl-4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0212] The synthesis method was referred to the synthesis of Example 3, with a yield of 25.9%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.56 (dd, J = 12.4, 5.2 Hz, 1H), 3.35 (dd, J = 12.4, 5.2 Hz, 1H), 3.35 - 3.22 (m, 2H), 2.96 (ddd, J = 12.4, 5.9, 3.7 Hz, 1H), 2.88 - 2.73 (m, 2H), 2.29 (d, J = 1.4 Hz, 3H), 1.69 - 1.52 (m, 2H), 0.90 (td, J = 7.3, 1.5 Hz, 3H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M+H] + 420.2434 found 420.2432.

[0213] Example 53: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(3,3,4-trimethylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0214] The synthesis method was referred to the synthesis of Example 3, with a yield of 41.1%, and it was a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.59 (s, 2H), 3.40 (dd, J = 5.0, 4.1 Hz, 2H), 2.89 - 2.82 (m, 1H), 2.85 - 2.78 (m, 1H), 1.20 (s, 5H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M+H] + 420.2434 found 420.2442.

[0215] Examples 54a, 54b: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-{4-[3-ethyl-4-(propan-2-yl)piperazin-1-yl]phenyl}pyrazin-2-amine

[0216] The synthesis method was referred to that of Example 3, with a yield of 39.2%, and it was a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91 - 7.85(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.96 - 6.90(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(d,J=1.6Hz,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.54(dd,J=12.4,4.5Hz,1H),3.39(dd,J=12.5,4.4Hz,1H),3.32 - 3.23(m,2H),3.04 - 2.92(m,2H),2.89(hept,J=6.9Hz,1H),2.82 - 2.74(m,1H),1.68 - 1.51(m,2H),1.09(dd,J=6.8,1.1Hz,6H),0.91(td,J=7.5,1.5Hz,3H); HR-MS(ESI)m / z: calcd for C 25 H 33 N7O[M + H] + 448.2747 found 448.2745.

[0217] Example 55: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]pyrazin-2-amine

[0218] The synthesis method was referred to that of Example 1, with a yield of 61.4%, and it was a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.90 - 6.84 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.93 - 3.87 (m, 2H), 2.92 (dd, J = 12.3, 3.5 Hz, 2H), 2.73 (dd, J = 12.5, 3.5 Hz, 2H), 1.95 - 1.81 (m, 4H); HR-MS (ESI) m / z: calcd for C 23 H 27 N7O [M + H] + 418.2277 found 418.2281.

[0219] Example 56: 4-{[(2-Aminopyridin-4-yl)methyl]oxy}-6-[4-(4-methylpiperazin-1-yl)phenyl]-1,2-diazacyclohexen-3-amine

[0220] The synthesis method was referred to the synthesis of Example 1, with a yield of 34.2%, and it was a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 4.2 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.34 (s, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.93 - 6.87 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.28 (d, J = 11.7 Hz, 1H), 5.10 (d, J = 11.7 Hz, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.28 - 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.5, 3.9 Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H 25 N7O [M + H] + 392.2121 found 392.2118.

[0221] Example 57: 3-{[(2-Aminopyridin-4-yl)methyl]thio}-5-[2-(4-methylpiperazin-1-yl)pyrazin-5-yl]pyrazin-2-amine

[0222] The synthesis method refers to the synthesis in Example 1, with a yield of 48.1%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.14 (d, J = 4.1 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.15 (dd, J = 4.2, 1.8 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.75 (d, J = 1.8 Hz, 1H), 6.34 (s, 2H), 4.77 (d, J = 6.6 Hz, 1H), 4.64 (d, J = 6.6 Hz, 1H), 4.44 (s, 2H), 3.28 - 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.5, 3.9 Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H 25 N7S [M + H] + 408.1892 found 408.1895.

[0223] Example 58: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-6-methyl-5-[2-(4-methylpiperazin-1-yl)pyrazin-5-yl]pyrazin-2-amine

[0224] The synthesis method refers to the synthesis in Example 1, with a yield of 65.1%, a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 4.2 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.90 - 6.84 (m, 2H), 6.64 (d, J = 1.9 Hz, 1H), 5.77 (s, 1H), 5.28 (s, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.28 - 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.5, 3.9 Hz, 2H), 2.57 (ddd, J = 12.5, 5.5, 3.9 Hz, 2H), 2.53 (s, 2H); HR-MS (ESI) m / z: calcd for C 22 H 27 N7O [M + H] + 406.2277 found 406.2284.

[0225] Example 59: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[2-(4-methylpiperazin-1-yl)pyrazin-5-yl]-6-(trifluoromethyl)pyrazin-2-amine

[0226] The synthesis method was referred to the synthesis of Example 1, with a yield of 37.9%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.17(d,J=4.2Hz,1H),7.84-7.78(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.92-6.86(m,2H),6.64(d,J=1.9Hz,1H),5.91(d,J=9.5Hz,1H),5.84(d,J=9.5Hz,1H),5.28(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.28-3.17(m,4H),2.80(ddd,J=12.3,5.5,3.9Hz,2H),2.57(ddd,J=12.4,5.5,3.9Hz,2H);HR-MS(ESI)m / z:calcd for C 22 H 24 F3N7O[M+H] + 460.1994found 460.1992.

[0227] Example 60: 6-Amino-5-{[(2-aminopyridin-4-yl)methyl]oxy}-3-[2-(4-methylpiperazin-1-yl)pyrazin-5-yl]pyrazine-2-carbonitrile

[0228] The synthesis method was referred to the synthesis of Example 1, with a yield of 63.8%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.17(d,J=4.2Hz,1H),7.86-7.80(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J=1.9Hz,1H),5.63(d,J=9.5Hz,1H),5.49(d,J=9.5Hz,1H),5.28(s,1H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.28-3.17(m,4H),2.80(ddd,J=12.3,5.5,3.9Hz,2H),2.57(ddd,J=12.4,5.5,3.9Hz,2H);HR-MS(ESI)m / z:calcd for C 22 H 24N8O[M+H] + 417.2073 found 417.2078.

[0229] Example 61: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-6-chloro-5-[2-(4-methylpiperazin-1-yl)pyrazin-5-yl]pyrazin-2-amine

[0230] The synthesis method refers to the synthesis of Example 1, with a yield of 55.3%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.17(d,J = 4.2Hz,1H),7.87-7.81(m,2H),7.16(dd,J = 4.3,1.9Hz,1H),6.94-6.88(m,2H),6.64(d,J = 1.9Hz,1H),5.90(d,J = 9.5Hz,1H),5.76(d,J = 9.5Hz,1H),5.27(s,1H),4.82(d,J = 6.6Hz,1H),4.72(d,J = 6.6Hz,1H),3.28-3.17(m,4H),2.80(ddd,J = 12.3,5.5,3.9Hz,2H),2.57(ddd,J = 12.4,5.5,3.9Hz,2H); HR-MS(ESI)m / z: calcd for C 21 H 24 ClN7O[M+H] + 426.1731 found 426.1737.

[0231] Example 62: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-{3-[(dimethylamino)methyl]phenyl}pyrazin-2-amine

[0232] The synthesis method refers to the synthesis of Example 1, with a yield of 67.4%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.92(s,1H),7.91-7.85(m,2H),7.67-7.57(m,1H),7.44(t,J = 7.7Hz,1H),7.34(d,J = 7.6Hz,1H),6.79(s,1H),6.64(d,J = 5.6Hz,1H),6.61(s,2H),6.55(s,1H),5.96(s,2H),5.41(s,2H),2.54(s,6H); HR-MS(ESI)m / z: calcd for C 19 H 22 N6O[M+H] +351.1855 found 351.1846.

[0233] Example 63: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(1-methylpiperidin-4-yl)phenyl]pyrazin-2-amine

[0234] The synthesis method was referred to the synthesis of Example 1, with a yield of 55.7%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.87(d,J=5.3Hz,1H),7.77(d,J=8.2Hz,2H),7.25(d,J=8.1Hz,2H),6.61(d,J=5.3Hz,1H),6.52(s,1H),6.47(s,2H),5.90(s,2H),5.38(s,2H),2.88(dt,J=11.5,3.1Hz,3H),2.21(s,4H),2.00(td,J=11.5,2.8Hz,3H),1.71(d,J=3.7Hz,2H);HR-MS(ESI)m / z:calcd for C 22 H 26 N6O[M+H] + 391.2168 found 391.2159.

[0235] Example 64: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[4-(piperidin-4-yl)phenyl]pyrazin-2-amine

[0236] The synthesis method was referred to the synthesis of Example 1, with a yield of 73.2%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.17(d,J=4.2Hz,1H),7.92 - 7.86(m,2H),7.32 - 7.26(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),2.99(p,J=3.8Hz,1H),2.96 - 2.90(m,2H),2.83(dddd,J=12.1,5.3,3.8,2.7Hz,2H),2.69 - 2.61(m,1H),2.00 - 1.91(m,2H),1.89 - 1.82(m,2H);HR-MS(ESI)m / z:calcd for C 21 H 24N6O[M+H] + 377.2012 found 377.2059.

[0237] Example 65: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(piperazin-1-yl)benzene-1-carbonitrile

[0238] The synthesis method refers to the synthesis in Example 3, with a yield of 79.3%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.19-8.15(m,2H),7.92(dd,J=8.2,1.8Hz,1H),7.16(dd,J=4.3,1.9Hz,1H),7.07(d,J=8.1Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.20(td,J=4.2,1.5Hz,4H),3.06-2.95(m,4H),1.93(q,J=3.3Hz,1H);HR-MS(ESI)m / z:calcd for C 21 H 22 N8O[M+H] + 403.1917 found 403.2009.

[0239] Example 66: 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(piperazin-1-yl)phenyl]pyrazin-2-amine

[0240] The synthesis method refers to the synthesis in Example 1, with a yield of 71.6%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.17(d,J=4.2Hz,1H),7.91-7.85(m,2H),7.16(dd,J=4.3,1.9Hz,1H),6.95-6.89(m,2H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.35-3.24(m,4H),3.10-2.99(m,4H),1.95(q,J=3.3Hz,1H);HR-MS(ESI)m / z:calcd for C 20 H 23 N7O[M+H] +378.1964 found 378.1991.

[0241] Example 67: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)benzene-1-carbonitrile

[0242] The synthesis method was referred to the synthesis of Example 3, with a yield of 69.2%, and it was a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.15 (m, 2H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.72 (s, 2H), 3.67 (s, 2H), 2.86 (s, 2H), 2.73 (s, 2H); HR-MS (ESI) m / z: calcd for C 23 H 24 N8O [M + H] + 429.2073 found 429.2061.

[0243] Example 68: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(2,6-diazaspiro[3.3]hept-2-yl)benzene-1-carbonitrile

[0244] The synthesis method was referred to the synthesis of Example 3, with a yield of 65.8%, and it was a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.15 (m, 2H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.74 (s, 2H), 3.67 (s, 2H), 3.41 (d, J = 3.5 Hz, 2H), 3.05 (d, J = 3.5 Hz, 2H), 2.23 - 2.17 (m, 1H); HR-MS (ESI) m / z: calcd for C 22 H22 N8O[M+H] + 415.1917 found 415.2061.

[0245] Example 69: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(6-aza-2-oxaspiro[3.3]hept-6-yl)benzene-1-carbonitrile

[0246] The synthesis method was referred to the synthesis of Example 3, with a yield of 58.2%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.19-8.15(m,2H),7.92(dd,J=8.2,1.8Hz,1H),7.16(dd,J=4.3,1.9Hz,1H),7.09(d,J=8.2Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.82(s,4H),3.70(s,4H);HR-MS(ESI)m / z:calcd forC 22 H 21 N7O2[M+H] + 416.1757 found 416.1761.

[0247] Example 70: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)benzene-1-carbonitrile

[0248] The synthesis method was referred to the synthesis of Example 3, with a yield of 69.2%, and it was a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.15 (m, 2H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.67 (d, J = 0.7 Hz, 4H), 2.73 - 2.67 (m, 1H), 2.59 - 2.53 (m, 2H), 2.49 (ddd, J = 12.2, 3.9, 2.2 Hz, 1H), 1.83 (dd, J = 3.9, 2.0 Hz, 1H), 1.73 (dd, J = 4.0, 2.1 Hz, 1H); HR-MS (ESI) m / z: calcd for C 24 H 26 N8O [M + H] + 443.2230 found 443.2231.

[0249] Example 71: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(7-methyl-2,7-diazaspiro[3.5]non-2-yl)benzene-1-carbonitrile

[0250] The synthesis method was referred to the synthesis of Example 3, with a yield of 68.7%, and it was a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.15 (m, 2H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.67 (s, 2H), 3.61 (s, 2H), 2.57 (dd, J = 5.4, 2.7 Hz, 2H), 2.46 (dd, J = 5.4, 2.7 Hz, 2H), 1.82 (dd, J = 5.4, 2.7 Hz, 2H), 1.76 (dd, J = 5.4, 2.7 Hz, 2H); HR-MS (ESI) m / z: calcd for C 25 H 28 N8O [M + H] + 457.2386 found 457.2388.

[0251] Example 72: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-[4-(trideuteriomethyl)piperazin-1-yl]benzene-1-carbonitrile

[0252] The synthesis method was referred to the synthesis of Example 3, with a yield of 65.8%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.19-8.15(m,2H),7.92(dd,J=8.2,1.8Hz,1H),7.16(dd,J=4.3,1.9Hz,1H),7.07(d,J=8.1Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(s,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),3.23(ddd,J=5.0,4.2,0.8Hz,4H),2.84-2.73(m,4H);HR-MS(ESI)m / z:calcd for C 22 H 21 D3N8O[M+H] + 420.2261found 420.2288.

[0253] Example 73: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)benzene-1-carbonitrile

[0254] The synthesis method was referred to the synthesis of Example 3, with a yield of 55.9%, and it was a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.21-8.15(m,2H),8.00(dd,J=8.7,1.9Hz,1H),7.16(dd,J=4.3,1.9Hz,1H),7.09(d,J=8.7Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(d,J=1.6Hz,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),4.02-3.95(m,2H),3.03(dd,J=12.5,3.5Hz,2H),2.74(dd,J=12.4,3.4Hz,2H),1.97-1.78(m,4H);HR-MS(ESI)m / z:calcd for C 24 H26 N8O[M+H] + 443.2230 found 443.2238.

[0255] Example 74: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)benzene-1-carbonitrile

[0256] The synthesis method refers to the synthesis in Example 3, with a yield of 45.2%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.22-8.15(m,2H),7.92(dd,J=8.5,1.9Hz,1H),7.16(dd,J=4.3,1.9Hz,1H),7.09(d,J=8.5Hz,1H),6.64(d,J=1.9Hz,1H),5.92(s,2H),5.27(d,J=1.6Hz,2H),4.82(d,J=6.6Hz,1H),4.72(d,J=6.6Hz,1H),4.08(dd,J=12.5,2.1Hz,1H),4.04(ddd,J=5.1,3.1,2.0Hz,1H),3.75(dd,J=12.4,2.4Hz,1H),3.32(dqd,J=3.2,2.1,1.0Hz,1H),2.91(dd,J=12.2,2.0Hz,1H),2.84(dd,J=12.5,2.0Hz,1H),2.32(d,J=1.4Hz,3H),2.21-2.13(m,1H),1.88-1.81(m,1H);HR-MS(ESI)m / z:calcd for C 23 H 24 N8O[M+H] + 429.2073 found 429.2078.

[0257] Example 75: 5-(5-Amino-6-{[(2-aminopyridin-4-yl)methyl]oxy}pyrazin-2-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)benzene-1-carbonitrile

[0258] The synthesis method refers to the synthesis in Example 3, with a yield of 33.8%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.15 (m, 2H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (d, J = 1.6 Hz, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.61 (dd, J = 12.5, 3.7 Hz, 2H), 3.48 (dd, J = 12.5, 3.7 Hz, 2H), 3.27 - 3.19 (m, 2H), 2.45 (t, J = 1.6 Hz, 3H), 1.93 - 1.77 (m, 4H); HR-MS (ESI) m / z: calcd for C 24 H 26 N8O [M + H] + 443.2230 found 443.2229.

[0259] Example 76: N-{4-[({3-Amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}oxy)methyl]pyridin-2-yl}acetamide

[0260] The synthesis method was referred to the synthesis of Example 1, with a yield of 59.3%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 23 H 27 N7O2 [M + H] + 434.2226 found 434.2225.

[0261] Example 77: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{[(2-methylpyridin-4-yl)methyl]oxy}pyrazin-2-amine

[0262] The synthesis method was referred to the synthesis of Example 1, with a yield of 69.3%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 5.1 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.34 (d, J = 5.1 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.41 (s, 2H), 5.50 (s, 2H), 3.17 (t, J = 4.9 Hz, 4H), 2.48 (s, 3H), 2.46 (d, J = 7.0 Hz, 6H), 2.23 (s, 3H); HR-MS (ESI) m / z: calcd for C 22 H 26 N6O [M+H] + 391.2168 found 391.2160.

[0263] Example 78: 3-({[2-(Dimethylamino)pyridin-4-yl]methyl}oxy)-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0264] The synthesis method was referred to the synthesis of Example 1, with a yield of 55.2%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.78 (s, 1H), 6.72 (d, J = 5.1 Hz, 1H), 6.36 (s, 2H), 5.43 (s, 2H), 3.18 (s, 3H), 3.02 (s, 6H), 2.26 (s, 4H); HR-MS (ESI) m / z: calcd for C 23 H 29 N7O [M+H] + 420.2434 found 420.2429.

[0265] Example 79: 3-{[(2-Methoxypyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0266] The synthesis method was referred to the synthesis of Example 1, with a yield of 55.6%, a white solid. 11H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 7.7 Hz, 2H), 6.83 (s, 1H), 5.49 (s, 2H), 4.80 (s, 2H), 3.95 (s, 3H), 3.27 (t, J = 5.1 Hz, 4H), 2.60 (t, J = 5.1 Hz, 5H), 2.37 (s, 3H); HR-MS (ESI) m / z: calcd for C 22 H 26 N6O2 [M + H] + 407.2117 found 407.2110.

[0267] Example 80: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-({[2-(trifluoromethyl)pyridin-4-yl]methyl}oxy)pyrazin-2-amine

[0268] The synthesis method was referred to that of Example 1, with a yield of 71.8%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 5.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 2H), 5.60 (d, J = 4.5 Hz, 2H), 4.86 (s, 2H), 3.26 (d, J = 5.8 Hz, 4H), 2.59 (d, J = 5.5 Hz, 4H), 2.36 (d, J = 3.7 Hz, 3H); HR-MS (ESI) m / z: calcd for C 22 H 23 F3N6O [M + H] + 445.1885 found 445.1888.

[0269] Example 81: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-({[2-(1,4-oxazepan-4-yl)pyridin-4-yl]methyl}oxy)pyrazin-2-amine

[0270] The synthesis method was referred to that of Example 1, with a yield of 55.9%, a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.10 (s, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 5.1 Hz, 1H), 6.46 (s, 2H), 5.54 (s, 2H), 3.82 - 3.70 (m, 4H), 3.54 (t, J = 4.8 Hz, 4H), 3.26 (t, J = 4.9 Hz, 4H), 2.56 (d, J = 5.6 Hz, 4H), 2.33 (s, 3H); HR-MS (ESI) m / z: calcd for C 25 H 31 N7O2 [M+H] + 462.2539 found 462.2533.

[0271] Example 82a, 82b: 3-{[(1-(2-chloropyridin-4-yl)ethyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0272] The synthesis method was referred to that of Example 1, with a yield of 59.3%, and it was a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.40 (s, 1H), 7.28 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.19 (q, J = 6.7 Hz, 1H), 4.85 (s, 2H), 3.27 (t, J = 5.0 Hz, 4H), 2.61 (t, J = 5.0 Hz, 4H), 1.71 (d, J = 6.7 Hz, 3H); HR-MS (ESI) m / z: calcd for C 22 H 25 ClN6O [M+H] + 425.1778 found 425.1777.

[0273] Example 83: 3-{[(1-methylindazol-5-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0274] The synthesis method was referred to that of Example 1, with a yield of 53.8%, and it was a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.68 (s, 1H), 7.63 (s, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.68 (s, 1H), 6.65 (s, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.94 (s, 2H), 5.28 (s, 2H), 3.72 (s, 3H), 3.68 (s, 2H), 2.86 (s, 7H), 1.91 (d, J = 6.8 Hz, 6H); HR-MS (ESI) m / z: calcd for C 24 H 27 N7O [M + H] + 430.2277 found 430.2281.

[0275] Example 84: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-[(pyrimidin-5-ylmethyl)oxy]pyrazin-2-amine

[0276] The synthesis method was referred to the synthesis of Example 1, with a yield of 82.1%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 9.04 (s, 2H), 8.04 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.40 (s, 2H), 5.55 (s, 2H), 3.18 (s, 4H), 2.23 (s, 3H); HR-MS (ESI) m / z: calcd for C 20 H 23 N7O [M + H] + 378.1964 found 378.1959.

[0277] Example 85: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-[(pyrazin-2-ylmethyl)oxy]pyrazin-2-amine

[0278] The synthesis method was referred to the synthesis of Example 1, with a yield of 81.5%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.64 (d, J = 14.1 Hz, 2H), 8.03 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.43 (s, 2H), 5.62 (s, 2H), 3.16 (s, 4H), 2.23 (s, 4H); HR-MS (ESI) m / z: calcd forC 20H 23 N7O[M + H] + 378.1964 found 378.1960.

[0279] Example 86: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0280] The synthesis method refers to the synthesis in Example 1, with a yield of 69.5%, a yellow solid. 1 H NMR(300MHz, DMSO-d6) δ8.63 - 8.53(m, 2H), 8.03(s, 1H), 7.72(d, J = 8.6Hz, 2H), 7.57(d, J = 5.2Hz, 2H), 6.95(d, J = 8.6Hz, 2H), 6.45(s, 2H), 5.54(s, 2H), 3.16(t, J = 5.1Hz, 4H), 2.45(t, J = 5.1Hz, 4H), 2.22(s, 3H); HR-MS(ESI) m / z: calcd for C 21 H 24 N6O[M + H] + 377.2012 found 377.2019.

[0281] Example 87: 5-{4-[(Dimethylamino)methyl]phenyl}-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0282] The synthesis method refers to the synthesis in Example 1, with a yield of 76.4%, a yellow solid. 1 H NMR(300MHz, DMSO-d6) δ8.59(d, J = 5.0Hz, 2H), 8.15(s, 1H), 7.83(d, J = 7.8Hz, 2H), 7.59(d, J = 5.2Hz, 2H), 7.31(d, J = 7.9Hz, 2H), 6.65(s, 2H), 5.57(s, 2H), 2.15(s, 6H); HR-MS(ESI) m / z: calcd forC 19 H 21 N5O[M + H] + 336.1746 found 336.1744.

[0283] Example 88: 5-{3-[(Dimethylamino)methyl]phenyl}-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0284] The synthesis method refers to the synthesis in Example 1, with a yield of 78.5%, a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 5.0 Hz, 2H), 8.14 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 5.0 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.66 (s, 2H), 5.56 (s, 2H), 3.45 (s, 2H), 2.18 (s, 6H); HR-MS (ESI) m / z: calcd for C 19 H 21 N5O [M+H] + 336.1746 found 336.1735.

[0285] Example 89: 3-{5-Amino-6-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N,N-dimethylbenzamide

[0286] The synthesis method was referred to that of Example 1, with a yield of 82.1%, a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 2H), 8.22 (s, 1H), 7.95 (dt, J = 7.9, 1.4 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 3.8 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.28 (dt, J = 7.6, 1.4 Hz, 1H), 6.73 (s, 2H), 5.57 (s, 2H), 2.96 (d, J = 33.2 Hz, 6H); HR-MS (ESI) m / z: calcd for C 19 H 19 N5O2 [M+H] + 350.1539 found 350.1541.

[0287] Example 90: 5-[4-(Methoxymethyl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0288] The synthesis method was referred to that of Example 1, with a yield of 81.2%, a white solid. 11H NMR(300 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.13 (d, J = 28.0 Hz, 1H), 7.83 (dd, J = 28.2, 7.8 Hz, 2H), 7.63 (s, 2H), 7.31 (dd, J = 18.4, 7.7 Hz, 2H), 6.68 (s, 2H), 5.57 (s, 2H), 4.42 (s, 2H), 3.29 (s, 3H); HR-MS(ESI) m / z: calcd for C 18 H 18 N4O2 [M + H] + 323.1430 found 323.1434.

[0289] Example 91: 5-[4-(1,4-Oxazepan-4-yl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0290] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.1%, and it was a yellow solid. 1 1H NMR(300 MHz, DMSO-d6) δ 8.56 (d, J = 5.0 Hz, 2H), 8.03 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 5.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.42 (s, 2H), 5.54 (s, 2H), 3.73 (t, J = 4.6 Hz, 4H), 3.12 (d, J = 5.1 Hz, 4H); HR-MS(ESI) m / z: calcd for C 20 H 21 N5O2 [M + H] + 364.1695 found 364.1689.

[0291] Example 92: 5-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0292] The synthesis method was referred to the synthesis of Example 1, with a yield of 52.4%, and it was a yellow solid. 11H NMR(300 MHz, DMSO-d6) δ 8.67 - 8.54 (m, 2H), 8.12 (s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 5.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 6.61 (s, 2H), 5.55 (s, 2H), 3.45 (s, 5H), 2.50 (d, J = 1.9 Hz, 4H), 2.18 (s, 3H); HR-MS(ESI) m / z: calcd for C 22 H 26 N6O [M + H] + 391.2168 found 391.2171.

[0293] Example 93: 3 - [(Pyridin-4-ylmethyl)oxy]-5-[4-(pyridin-4-yl)phenyl]pyrazin-2-amine

[0294] The synthesis method was referred to the synthesis of Example 1, with a yield of 81.2%, and it was a yellow solid. 1 1H NMR(300 MHz, DMSO-d6) δ 9.05 (s, 4H), 8.62 (s, 1H), 8.38 (d, J = 8.1 Hz, 2H), 8.24 - 8.13 (m, 3H), 8.01 - 7.83 (m, 6H), 7.10 (s, 2H), 5.93 (s, 2H); HR-MS(ESI) m / z: calcd for C 21 H 17 N5O [M + H] + 356.1433 found 356.1431.

[0295] Example 94: 5 - [2-(4-Methylpiperazin-1-yl)pyridin-5-yl]-3 - [(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0296] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.8%, and it was a yellow solid. 1 1H NMR(400 MHz, DMSO-d6) δ 8.63 (d, J = 2.4 Hz, 1H), 8.59 - 8.56 (m, 2H), 8.04 (s, 1H), 7.98 (dd, J = 8.9, 2.5 Hz, 1H), 7.60 - 7.48 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.47 (s, 2H), 5.55 (s, 2H), 3.55 - 3.48 (m, 4H), 2.41 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H); HR-MS(ESI) m / z: calcd for C 20 H23 N7O[M+H] + 378.1964 found 378.1966.

[0297] Example 95: 5-[3-(Methoxymethyl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0298] The synthesis method was referred to the synthesis of Example 1, with a yield of 55.2%, a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.62(s,2H),8.18(s,1H),7.84-7.79(m,2H),7.61(d,J=4.9Hz,2H),7.50-7.33(m,1H),7.24(d,J=7.6Hz,1H),6.69(s,2H),5.58(s,2H),4.46(s,2H),3.40(s,1H),3.33(s,3H);HR-MS(ESI)m / z:calcd for C 18 H 18 N4O2[M+H] + 323.1430 found 323.1433.

[0299] Example 96: 5-[2-(4-Methylpiperazin-1-yl)pyrimidin-5-yl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0300] The synthesis method was referred to the synthesis of Example 1, with a yield of 59.2%, a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.83(s,2H),8.63-8.58(m,2H),8.07(s,1H),7.65-7.52(m,2H),6.56(s,2H),5.55(s,2H),3.76(t,J=5.0Hz,4H),2.38(t,J=5.0Hz,4H),2.23(s,3H);HR-MS(ESI)m / z:calcd forC 19 H 22 N8O[M+H] + 379.1917 found 379.1916.

[0301] Example 97: 4-(4-{5-Amino-6-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}phenyl)piperazine-1-carboxylic acid 2-methylpropan-2-yl ester

[0302] The synthesis method was referred to the synthesis of Example 1, with a yield of 81.3%, a white solid. 11H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 25 H 30 N6O3 [M + H] + 463.2379 found 463.2381.

[0303] Example 98: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-[(pyridin-3-ylmethyl)oxy]pyrazin-2-amine

[0304] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.6%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 21 H 24 N6O [M + H] + 377.2012 found 377.2023.

[0305] Example 99: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-[(pyridin-2-ylmethyl)oxy]pyrazin-2-amine

[0306] The synthesis method was referred to the synthesis of Example 1, with a yield of 73.5%, a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 21 H 24N6O[M+H] + 377.2012 found 377.2025.

[0307] Example 100: 5-[4-(Piperazin-1-yl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0308] The synthesis method refers to the synthesis in Example 1, with a yield of 69.8%, a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ9.39(s,2H),8.97(d,J=6.0Hz,2H),8.31(d,J=5.9Hz,2H),8.09(s,1H),7.79(d,J=8.6Hz,2H),7.03(d,J=8.5Hz,2H),5.88(s,2H),3.44(t,J=5.2Hz,4H),3.21(s,4H);HR-MS(ESI)m / z:calcd for C 20 H 22 N6O[M+H] + 363.1855 found 363.1852.

[0309] Example 101: (4-{5-Amino-6-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}phenyl)methanol

[0310] The synthesis method refers to the synthesis in Example 1, with a yield of 72.1%, a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ8.62-8.54(m,2H),8.14(s,1H),7.84(d,J=8.1Hz,2H), ,7.63-7.55(m,2H),7.33(d,J=8.0Hz,2H),6.62(s,2H),5.57(s,2H),4.51(s,1H);HR-MS(ESI)m / z:calcd for C 17 H 16 N4O2[M+H] + 309.1273 found 309.1269.

[0311] Example 102: 5-[4-(1-Methylhexahydropyridin-4-yl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0312] The synthesis method refers to the synthesis in Example 1, with a yield of 67.4%, a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.54 (m, 2H), 8.11 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.61 - 7.52 (m, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.56 (s, 2H), 5.56 (s, 2H), 2.91 (td, J = 8.1, 7.5, 4.1 Hz, 2H), 2.25 (s, 3H), 2.12 - 2.02 (m, 2H), 1.82 - 1.61 (m, 4H), 1.31 - 1.21 (m, 1H); HR-MS (ESI) m / z: calcd for C 22 H 25 N5O [M+H] + 376.2059 found 376.2055.

[0313] Example 103: 3-[(3-Methoxyphenyl)oxy]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0314] The synthesis method was referred to the synthesis of Example 1, with a yield of 56.3%, and it was a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 8.2 Hz, 1H), 7.05 - 6.98 (m, 3H), 6.96 (dd, J = 7.9, 2.1 Hz, 1H), 6.91 (dd, J = 8.3, 2.4 Hz, 1H), 3.88 (d, J = 12.2 Hz, 2H), 3.44 (d, J = 11.1 Hz, 2H), 3.14 (dt, J = 24.2, 11.5 Hz, 4H), 2.76 (d, J = 4.6 Hz, 3H); HR-MS (ESI) m / z: calcdfor C 22 H 25 N5O2 [M+H] + 391.2008 found 391.2012.

[0315] Example 104: 3-Amino-6-[4-(4-methylpiperazin-1-yl)phenyl]-N-(pyridin-4-yl)pyrazine-2-carboxamide

[0316] The synthesis method was referred to the synthesis of Example 1, with a yield of 59.4%, and it was a white solid. 11H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 20.2 Hz, 1H), 3.22 (d, J = 68.6 Hz, 4H), 2.62 (s, 4H), 2.39 (s, 3H); HR-MS (ESI) m / z: calcd for C 21 H 23 N7O [M+H] + 390.1964 found 390.1965.

[0317] Example 105: 5-(1H-Indazol-6-yl)-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0318] The synthesis method was referred to the synthesis of Example 1, with a yield of 72.3%, a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.77 (dd, J = 9.3, 1.9 Hz, 1H), 7.51 (dd, J = 8.0, 1.9 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.98 (dd, J = 9.3, 5.1 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.27 - 3.20 (m, 4H), 3.00 - 2.88 (m, 5H), 1.91 (q, J = 3.3 Hz, 1H).; HR-MS (ESI) m / z: calcd for C 20 H 22 FN7O [M+H] + 396.1870 found 396.1869.

[0319] Example 106: 3-{[(2-Aminopyridin-4-yl)methyl]oxy}-5-[2-fluoro-1-(4-methylpiperazin-1-yl)benz-4-yl]pyrazin-2-amine

[0320] The synthesis method was referred to the synthesis of Example 1, with a yield of 88.2%, an earth-yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.17 (d, J = 4.2 Hz, 1H), 7.77 (dd, J = 9.2, 1.9 Hz, 1H), 7.51 (dd, J = 8.0, 1.9 Hz, 1H), 7.16 (dd, J = 4.3, 1.9 Hz, 1H), 6.98 (dd, J = 9.3, 5.1 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 5.92 (s, 2H), 5.27 (s, 2H), 4.82 (d, J = 6.6 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 3.25 - 3.14 (m, 4H), 3.08 (ddd, J = 12.5, 5.6, 3.9 Hz, 2H), 2.69 (ddd, J = 12.4, 5.7, 3.8 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H 24 FN7O [M + H] + 410.2026 found 410.2022.

[0321] Example 107: 5-[3-(1,4-Oxazacyclohexan-4-yl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0322] The synthesis method was referred to the synthesis of Example 1, with a yield of 89.3%, and it was a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.63 - 8.53 (m, 2H), 8.14 (s, 1H), 7.60 - 7.50 (m, 2H), 7.34 - 7.29 (m, 2H), 7.23 (t, J = 8.1 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.61 (s, 2H), 5.56 (s, 2H), 3.76 (dd, J = 6.1, 3.4 Hz, 4H), 3.14 - 3.06 (m, 4H); HR-MS (ESI) m / z: calcd for C 20 H 21 N5O2 [M + H] + 364.1695 found 364.1699.

[0323] Example 108: 5-[3-(1,4-Oxazacyclohexan-4-ylmethyl)phenyl]-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-amine

[0324] The synthesis method was referred to the synthesis of Example 1, with a yield of 62.3%, and it was a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 8.69 - 8.57 (m, 2H), 8.14 (s, 1H), 7.76 (dt, J = 5.1, 1.4 Hz, 2H), 7.58 (d, J = 5.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.22 (dt, J = 7.6, 1.4 Hz, 1H), 6.64 (s, 2H), 5.56 (s, 2H), 3.58 (t, J = 4.5 Hz, 4H), 3.49 (s, 2H), 2.39 - 2.34 (m, 4H); HR-MS (ESI) m / z: calcd for C 21 H 23 N5O2 [M + H] + 378.1852 found 378.1859.

[0325] Example 109: 3 - [(2 - Methoxyethyl)oxy] - 5 - [4 - (4 - methylpiperazin - 1 - yl)phenyl]pyrazin - 2 - amine

[0326] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.2%, a white solid. 1 1H NMR (400 MHz, Chloroform - d) δ 7.96 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.63 (t, J = 4.6 Hz, 2H), 3.81 (t, J = 4.6 Hz, 2H), 3.44 (s, 3H), 3.27 (t, J = 5.0 Hz, 4H), 2.60 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H); HR-MS (ESI) m / z: calcd for C 18 H 25 N5O2 [M + H] + 344.2008 found 344.2015.

[0327] Example 110: 3 - {[(3 - Methoxyphenyl)methyl]oxy} - 5 - [4 - (4 - methylpiperazin - 1 - yl)phenyl]pyrazin - 2 - amine

[0328] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.2%, a white solid. 11H NMR(300MHz,DMSO-d6)δ8.02(s,1H),7.87(d,J=5.2Hz,1H),7.43(s,2H),6.61(d,J=5.3Hz,1H),6.51(s,1H),6.44(s,2H),5.91(s,2H),5.35(s,2H),3.02(t,J=4.6Hz,4H),2.29(s,6H);HR-MS(ESI)m / z:calcd for C 23 H 27 N5O2[M+H] + 406.2165found 406.2159.

[0329] Example 111: 5-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{[(3,4,5-trimethoxyphenyl)methyl]oxy}pyrazin-2-amine

[0330] The synthesis method was referred to the synthesis of Example 1, with a yield of 88.2%, and it was a white solid. 1 1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.82(d,J=8.3Hz,2H),6.98(d,J=8.3Hz,2H),6.74(d,J=3.1Hz,2H),5.44(s,2H),4.86(s,2H),3.86(s,8H),3.83(s,3H),3.27(t,J=4.9Hz,4H),2.60(t,J=5.0Hz,4H),2.37(s,3H);HR-MS(ESI)m / z:calcd for C 25 H 31 N5O4[M+H] + 466.2376found 466.2370.

[0331] Example 112: 6-({3-Amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}oxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

[0332] The synthesis method was referred to the synthesis of Example 1, with a yield of 37.8%, and it was a white solid. 11H NMR (500 MHz, Chloroform-d) δ 8.50 (s, 1H), 7.91 - 7.85 (m, 2H), 6.95 - 6.89 (m, 2H), 5.98 (s, 2H), 5.17 (dt, J=4.6, 3.7 Hz, 1H), 4.60 - 4.53 (m, 1H), 4.18 - 4.13 (m, 1H), 4.09 - 3.97 (m, 4H), 3.83 - 3.75 (m, 1H), 3.72 - 3.64 (m, 1H), 3.28 - 3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9 Hz, 2H), 2.57 (ddd, J=12.5, 5.5, 3.9 Hz, 2H); HR-MS (ESI) m / z: calcd for C 21 H 27 N5O4 [M + H] + 414.2063 found 414.2062.

[0333] Example 113: 3-{[(2-Chloropyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0334] The synthesis method was referred to the synthesis of Example 1, with a yield of 78.8%, and it was a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.87 (d, J=5.2 Hz, 1H), 7.43 (s, 2H), 6.61 (d, J=5.3 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 5.91 (s, 2H), 5.35 (s, 2H), 3.02 (t, J=4.6 Hz, 4H), 2.29 (s, 6H); HR-MS (ESI) m / z: calcd for C 21 H 23 ClN6O [M + H] + 411.1622 found 411.1625.

[0335] Example 114: 3-{[(3-Fluoropyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0336] The synthesis method was referred to the synthesis of Example 1, with a yield of 77.5%, and it was a khaki solid. 11H NMR(300MHz,DMSO-d6)δ8.02(s,1H),7.87(d,J=5.2Hz,1H),7.43(s,2H),6.61(d,J=5.3Hz,1H),6.51(s,1H),6.44(s,2H),5.91(s,2H),5.35(s,2H),3.02(t,J=4.6Hz,4H),2.29(s,6H);HR-MS(ESI)m / z:calcd for C 21 H 23 FN6O[M+H] + 395.1917found 395.1911.

[0337] Example 115: 3-(Benzyloxy)-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine

[0338] The synthesis method was referred to the synthesis of Example 1, with a yield of 59.8%, and it was a light yellow solid. 1 1H NMR(300MHz,DMSO-d6)δ8.02(s,1H),7.87(d,J=5.2Hz,1H),7.43(s,2H),6.61(d,J=5.3Hz,1H),6.51(s,1H),6.44(s,2H),5.91(s,2H),5.35(s,2H),3.02(t,J=4.6Hz,4H),2.29(s,6H);HR-MS(ESI)m / z:calcd for C 22 H 25 N5O[M+H] + 376.2059found 376.2048.

[0339] Example 116: Inhibitory Activity Assay of the Compound against HPK1 Kinase and SLP-76 Protein Phosphorylation

[0340] 1. Experimental Materials and Instruments

[0341]

[0342] 2. Experimental Method

[0343] (1) Detection of HPK1 In Vitro Kinase Inhibitory Activity

[0344] Dilute the 5X enzymatic buffer to 1X and add 10 mM MgCl2, 1 mM DTT, and 0.005% Tween 20. Prepare a working solution of 1.67 ng / μL (final concentration 1 ng / μL) of HPK1 (Life technology) from a 100 ng / μL stock solution using the enzymatic buffer at a dilution of 1.67X, and seed 6 μL per well (384-well plate). Add different compounds dissolved in DMSO to the wells to a final compound concentration of 1000 - 0.244 nM, in a 4-fold gradient, with a total of 7 concentrations. Also set up blank control wells (without enzyme) and negative control wells (with enzyme, added with solvent DMSO), with 2 replicates. After incubating the enzyme and compounds at room temperature for 1 h, mix 5X 0.5 mM ATP (final concentration 0.1 mM) and 5X 2.5 μM substrate (Cisbio, STK Substrate 1-biotin, final concentration 500 nM) diluted with the enzymatic buffer in equal volumes, add 4 μL per well, seal the plate with a sealing film, and incubate at room temperature for 2 h. Mix the antibody STK Antibody-cryptate (Cisbio) and 4X 500 nM Streptavidin-XL665 (Cisbio, final concentration 125 nM) in equal volumes to prepare the detection antibody, add 10 μL per well, and incubate at room temperature for 1 h. Use a PE Envision multimode plate reader to detect the signal value (excitation 665 nm, emission 620 nm), and use GraphPad to fit and calculate the IC 50 。

[0345] (2) Detection of P-SLP76 phosphorylation inhibition activity

[0346] Use Jurkat cells, which are stored in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (ThermoFisher), 50 units / mL penicillin and streptomycin (Thermo Fisher), and stored at 37 °C in a humidified atmosphere of 5% CO2 in air. Recover the cells from cryopreservation within 30 passages of the purchased original cells. After starving the cells for 18 h in the experimental buffer (RPMI 1640 supplemented with 0.1% heat-inactivated fetal bovine serum), seed the cells into a 96-well plate at a density of 150,000 cells per well. Treat the cells with a series of diluted test compounds. After mixing and treating with a final compound concentration of 0 - 2 μM for 2 h, stimulate the cells with 0.05 μg / mL anti-human CD3 (OKT3, Bioxcell) at 37 °C for 30 min. Then lyse the cells and quantify the pSLP-76 protein.

[0347] 3. Experimental results

[0348] Table 1. Inhibitory activities of the compounds in each example

[0349]

[0350]

[0351]

[0352] IC 50 : A ≤ 100 nM, 100 nM < B ≤ 500 nM, 1000 nM < C; ND: no detection.

[0353] As can be seen from Table 1, the compounds designed in the present invention have high inhibitory activities against both HPK1 kinase and SLP-76 protein phosphorylation, and the inhibitory activities are significantly better than those of the HPK1 inhibitor crizotinib, a positive drug reported in the literature.

[0354] Example 117: Efficacy experiment on transplanted tumor of mouse colon cancer CT-26 cells in Balb / c mice

[0355] 1. Experimental method

[0356] (1) Preparation of the model

[0357] Collect the cultured mouse colon cancer CT-26 cell suspension at a concentration of 1×10 7 cells / mL and inoculate 0.1 mL per mouse subcutaneously in the right axilla of the mouse.

[0358] (2) Grouping and administration

[0359] Measure the diameter of the transplanted tumor of the mouse with a vernier caliper. When the tumor grows to 100 mm 3 randomly divide the animals into groups. At the same time, start administering drugs to each group of mice, and the administration plan is shown in the group and administration plan. After the experiment, immediately sacrifice the mice and surgically remove the tumor mass for weighing.

[0360] (3) Observation indexes

[0361] 1) Body weight

[0362] Record the body weight of the animals once on days 0, 3, 7, 9, 14, and 17;

[0363] 2) Tumor volume

[0364] Record the tumor volume once on days 0, 3, 7, 9, 14, and 17;

[0365] The calculation formula for the tumor volume (TV) is:

[0366] TV = 1 / 2 × a × b 2, where a and b represent the length and width respectively.

[0367] Calculate the relative tumor volume (RTV) according to the measurement results. The calculation formula is:

[0368] RTV = V t / V0, where V0 is the tumor volume measured at the time of separate-cage administration (i.e., d0); V t is the tumor volume at each measurement.

[0369] Evaluation index of anti-tumor activity: relative tumor proliferation rate T / C (%), and the calculation formula is as follows:

[0370] T / C (%) = T RTV / C RTV ×100, T RTV : RTV of the treatment group; C RTV : RTV of the model group.

[0371] Evaluation index of anti-tumor activity: tumor growth inhibition rate (%), and the calculation formula is as follows:

[0372]

[0373] (4) Statistical processing

[0374] The mean value is expressed as X ± SD, and the inter-group analysis is performed by t-test for statistical processing. The results are statistically analyzed using SPSS (Statistical Package for the Social Science) 17.0.

[0375] 2. Experimental results

[0376] It can be Figures 1 to 3 seen that Example 1 and Example 66 of the HPK1 inhibitor in the present invention can significantly inhibit the growth of tumors in the CT-26 tumor model of Balb / c mice. Under the condition of the same administration dose, the in vivo tumor inhibitory effects of Example 1 and Example 66 are significantly better than those of the clinical compound BGB-15025. It can be seen from the experimental data that the drug combination of Example 1 and the PD-1 antibody in the present invention is significantly superior to the single drug use of Example 1, Example 66, and BGB-15025. More advantageously, Example 1 and Example 66 in the present invention do not have a significant impact on the body weight of mice at the drug administration concentration that significantly inhibits tumor growth, showing good safety of the compound.

[0377] In summary, the compounds designed in the present invention exhibit excellent HPK1 and pSLP-76 inhibitory activities in vitro and can significantly inhibit tumor growth in vivo. Based on the excellent properties exhibited by the compounds in the examples of the present invention, the compounds discovered in the present invention and the combination with PD-1 antibody can be used as clinical candidate drugs to provide support for further new drug research and development.

Claims

1. A 2-amino-substituted nitrogen heterocyclic aromatic compound, characterized in that, Having the structure of formula (I), and also including its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts or mixtures thereof: Wherein: L1 is selected from -NR 1a -、-OR 1a -、-SR 1a -、-OCR 1a R 1b -、-NR 1a CR 1b R 1c -、-CO-、-CONHR 1a -、-CONR 1a R 1b -; L2 is a single bond or is selected from -NHR 1a -, -NR 1a R 1b -, -O-, -S-, -SO-, -SO2-, -CO-, -CR 1a R 1b -; R 1a 、R 1b 、R 1c are each independently selected from hydrogen, halogen, deuterium, -CN, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7 cycloalkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms; X 1 、 X 2 、 X 3 are independently selected from N, C; cy 1 selected from C 3-7 cycloalkyl, 5- to 10-membered heteroaryl containing 0 to 3 N, S, O ring heteroatoms; R 1 Selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a SO2R 2b 、a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, a C 3-10 carbocyclic group-substituted C 1-8 alkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms-substituted C 1-8 alkyl; R 2a 、R 2b 、R 2c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7 cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 substituted by a carbocyclic group C 1-8 alkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms substituted C 1-8 alkyl; R 2 Selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 2-8 alkyl ether, C 3-7 cycloalkyl, -NH2, -CN, -NO2, -OR 3a 、-SO2R 3a 、-COR 3a 、-CO2R 3a 、-CONR 3a R 3b 、-NR 3a R 3b 、-NR 3a COR 3b 、-NHR 3a 、CONR 3b R 3c 、-NR 3a CO2R 3b 、-NR 3a SONR 3b R 3c 、-NR 3a SO2NR 3b R 3c 、-NR 3a SO2R 3b , wherein each of said C 1-8 alkyl, C 1-8 alkenyl, cycloalkyl is optionally substituted by halogen, hydroxy, C 1-7 alkyl, C 3-7 cycloalkyl; m is selected from 0, 1, 2 or 3; R 3a 、R 3b 、R 3c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7 alkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 a C 1-8 alkyl substituted with a carbocyclic group, a C 1-8 alkyl substituted with a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms; R 3 selected from hydrogen, halogen, C 1-4 alkyl, C 1-5 alkoxy, C 1-5 cycloalkyl; R 4 selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 2-8 alkyl ether, C 3-7 cycloalkyl, -NH2, -CN, -NO2, -OR 4a 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CO2R 4b 、-NR 4a COR 4b R 4c 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-COR 4a a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, C 3-10 a C 1-8 carbocyclic group-substituted C 1-8 alkyl, wherein the C 1-8 alkyl, C 1-8 alkenyl, C 2-8 alkoxy, C 4d alkyl ether, cycloalkyl, heterocyclic group, aryl, heteroaryl are substituted by R n is selected from 0, 1, 2, 3 or 4; R 4a 、R 4b 、R 4c 、R 4d are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-8 alkylamino, C 3-7 cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 substituted by a carbocyclic group, C 1-8 alkyl, C 1-8 alkyl substituted by a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms; R 5 Selected from saturated, partially unsaturated or fully unsaturated 3- to 7-membered monocyclic carbocycles, 3- to 7-membered monocyclic heterocycles or 7- to 14-membered bicyclic rings, wherein the 3- to 7-membered monocyclic heterocycle has 0 to 5 ring heteroatoms selected from N, S, O; the 7- to 14-membered bicyclic ring is selected from carbocycles, nitrogen-containing or oxygen-containing heterocycles fused by single bonds or connected by chemical bonds, and contains 0 to 3 substituents as follows: halogen, CN, OH, =O, NO2, NR 5a R 5b 、SO2R 5a 、SR 5a 、0 to 3 OH and / or C 1-3 alkoxy-substituted C 1-4 alkyl, 0 to 3 OH and / or C 1-3 alkoxy-substituted C 3-6 cycloalkyl, 0 to 3 halogen-substituted C 1-3 alkyl, -O(C 1-3 alkoxy), -O(0 to 3 OH and / or C 1-3 alkoxy-substituted C 3-6 cycloalkyl), -O(0 to 3 halogen-substituted C 1-3 alkyl), -O(0 to 3 OH and / or C 1-3 alkoxy-substituted C 1-3 alkyl), NR 5a SO2R 5b 、R 5a 、C(O)R 5a 、NR 5a C(O)R 5b 、OR 5a 、S(O)R 5a or CH2R 5a ; R 5a and R 5b are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 1-5 alkylamino, C 3-7 alkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 alkyl substituted with a carbocyclic group, C 1-8 alkyl substituted with a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms 1-8 alkyl.

2. The 2-amino-substituted nitrogen heterocyclic aromatic compound according to claim 1, wherein In the said structure: L1 is selected from -C(O)NH-, -NHC(O)-, -CH2O-, -OCH2-, -OCF2-, -OCD2-, -C(HF)O-, -OC(HF)-, -O-, -NHCH2-, -OCH(CH3)-, -OC(CH3)2-, -CO-, -SCH2-; The structure of L2 is selected from a single bond, -O-, -CO-, -CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CF2-; X 1 、X 2 、X 3 are independently selected from N, C; R 3 selected from hydrogen, halogen, methyl, methoxy, ethyl, ethoxy; cy 1 Selected from C 3-7 cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrole, furan, thiophene, imidazole, pyrazole, triazole, indole, indolinone, benzothiophene, benzofuran, quinoline, isoquinoline, purine; R 1 and R 2 are selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -OH, -OCH3-, -CN, -NO2, -OR 2a -SO2R 2a -COR 2a -CO2R 2a -CONR 2a R 2b -NR 2a R 2b -NR 2a COR 2b -NR 2a CONR 2b R 2c -NR 2a CO2R 2b -NR 2a SONR 2b R 2c -NR 2a SO2NR 2b R 2c -NR 2a SO2R 2b ; R 2a 、R 2b 、R 2c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 azacycloalkyl, C substituted with a C-cycloalkyl having 0 to 5 N, S, O ring heteroatoms 3-10 alkyl, C substituted with a 3- to 10-membered heterocyclic group having 0 to 5 N, S, O ring heteroatoms 1-8 alkyl. 1-8 ​ 3. The 2-amino-substituted nitrogen heterocyclic aromatic compound according to claim 2, wherein In the said structure: L1 is selected from -C(O)NH-, -NHC(O)-, -CH2O-, -OCH2-, -OCF2-, -OCD2-, -C(HF)O-, -OC(HF)-, -O-, -NHCH2-, -OCH(CH3)-, -OC(CH3)2-, -CO-, -SCH2-; The structure of L2 is selected from a single bond, -O-, -CO-, -CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CF2-; X 1 selected from N or C atoms, X 2 and X 3 is selected from C atoms; R 3 selected from hydrogen, halogen, methyl, methoxy, ethyl, ethoxy; cy1 is selected from any of the following structures: R 1 and R 2 are selected from hydrogen, a halogen, a C 1-8 alkyl group, a C 1-8 alkenyl group, a C 1-8 alkoxy group, a C 3-7 cycloalkyl group, -NH2, -OH, -OCH3-, -CN, -NO2, -OR 2a and -SO2R 2a and -COR 2a and -CO2R 2a and -CONR 2a R 2b and -NR 2a R 2b and -NR 2a COR 2b and -NR 2a CONR 2b R 2c and -NR 2a CO2R 2b and -NR 2a SONR 2b R 2c and -NR 2a SO2NR 2b R 2c and -NR 2a SO2R 2b ; R 2a 、R 2b 、R 2c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 azacycloalkyl, C 3-10 substituted with a carbocyclic group having from 0 to 5 N, S, O ring heteroatoms, C 1-8 alkyl, C 1-8 alkyl substituted with a 3- to 10-membered heterocyclic group having from 0 to 5 N, S, O ring heteroatoms.

4. The 2-amino-substituted azaromatic compound according to claim 1, wherein In the said structure: R 4 selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 2-8 alkyl ether, C 3-7 cycloalkyl, C 3-7 azacycloalkyl, C 3-7 oxacycloalkyl, -NH2, -CN, -NO2, -OR 4a 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CO2R 4b 、-NR 4a COR 4b R 4c 、-COR 4a 、-CO2R 4a 、、-CONR 4a R 4b 、-COR 4a ; R 4a 、R 4b 、R 4c are each independently selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 cycloalkyl, -NH2, -CN, -NO2, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms, a 5- to 6-membered heteroaryl group containing 0 to 3 N, S, O ring heteroatoms, C 3-10 carbocyclic group-substituted C 1-8 alkyl, a 3- to 10-membered heterocyclic group containing 0 to 5 N, S, O ring heteroatoms-substituted C 1-8 alkyl.

5. The 2-amino-substituted nitrogen heterocyclic aromatic compound according to claim 1, characterized in that, In the said structure: R 5 selected from cyclohexyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, piperidyl, piperazinyl, homopiperazinyl, C 1-8 alkyl-substituted oxetane, C 1-8 alkyl-substituted morpholinyl, C 1-8 alkyl-substituted piperidyl, C 1-8 alkyl-substituted piperazinyl, C 1-8 alkyl-substituted homopiperazinyl, cyclohexyl-substituted C 1-8 alkyl, and each R 5 is substituted by 1-4 R 5a ; R 5a selected from hydrogen, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkoxy, C 3-7 azacycloalkyl, C with 0 to 5 N, S, O ring heteroatoms 3-10 C substituted with a carbocyclic group 1-8 alkyl, C substituted with a 3- to 10-membered heterocyclic group having 0 to 5 N, S, O ring heteroatoms 1-8 at least one substituent in the alkyl group.

6. The 2-amino-substituted azaromatic compound according to claim 5, wherein In the said structure: R 5 A structure selected from any of the following:

7. The 2-amino-substituted nitrogen heterocyclic aromatic compound according to claim 1, wherein A compound selected from any of the following:

8. The 2-amino-substituted nitrogen heterocyclic aromatic compound according to claim 1, wherein The pharmaceutically acceptable salt is a salt formed by the said compound and an acid selected from any of the following: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, acidic amino acids, ferulic acid.

9. A pharmaceutical composition, characterized in that, Comprising the 2-amino-substituted nitrogen heterocyclic compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

10. Use of the 2-amino-substituted nitrogen heterocyclic compound as claimed in claim 1 or the pharmaceutical composition as claimed in claim 9, or in combination with other relevant drugs, in the preparation of a drug for preventing and / or treating a disease mediated by hematopoietic progenitor cell kinase.

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