Spiro compound, pharmaceutical composition and application

Abstract

The invention discloses a spiro compound, a pharmaceutical composition and application. In particular to a compound as shown in a formula I, pharmaceutically acceptable salts thereof, solvates thereof or solvates of the pharmaceutically acceptable salts thereof. The compound provided by the invention has better pharmaceutical performance and wide medicinal prospect. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a spiro compound, a pharmaceutical composition and application. Background Art

[0002] HPK1 is the abbreviation of hematopoietic progenitor kinase 1, also known as MAP4K1, and is a member of the MAP4K (mitogen-activated protein kinase) family. In addition, there are 5 other members in the family, including MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6. HPK1 is a serine / threonine protein kinase, which is a key negative feedback regulator of T cell receptor (TCR) signaling, negatively regulating dendritic cell activation and T cell and B cell feedback; inhibiting HPK1 can enhance T cell activity, thereby improving anti-tumor immunity.

[0003] Due to its important role in immunity, HPK1 inhibitors play an important role in malignant solid tumors or blood cancers (such as acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma), autoimmune diseases (such as systemic lupus erythematosus, psoriatic arthritis) and inflammatory responses.

[0004] HPK1 has always been a target of great interest in cancer immunology. Existing technologies WO 2016205942A1, WO2018049152A1, WO2018049191A1, WO 2018049200 A1, WO 2018049214 A1, and WO2021213317A1 all disclose HPK1 inhibitors. So far, the challenge facing HPK1 is that small molecule inhibitors usually do not have sufficient activity and safety, so developing highly active and highly safe HPK1 inhibitors has always been the direction of efforts of researchers in this field. Summary of the invention

[0005] The present invention provides a spirocyclic compound, a pharmaceutical composition and an application. The compound of the present invention has better pharmaceutical properties, such as better HPK1 kinase inhibitory activity and / or better safety.

[0006] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] X is CHR 1 NR1 , O or S;

[0010] n1 and n2 are each independently 1, 2 or 3;

[0011] n3 and n4 are each independently 1, 2 or 3;

[0012] R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl, "a 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 1-6 substituted 3-6 membered cycloalkyl or one or more R 1-7 Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0013] R 1-1 are each independently halogen, hydroxyl or cyano;

[0014] R 1-2 Each independently is a C1-C6 alkyl group, 1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c ;

[0015] R 1-3 Each independently is a C1-C6 alkyl group, 1-3-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl or one or more R 1-3-2 Substituted 3-6 membered cycloalkyl;

[0016] R 1-2-1 and R 1-3-1 are each independently hydroxy, cyano or halogen;

[0017] R 1-2-2 and R 1-3-2 are each independently hydroxy, cyano or halogen;

[0018] R 1a , R 1b and R 1c Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R1-2-3 Substituted C1-C6 alkyl;

[0019] R 1-2-3 are independently halogen, cyano, hydroxyl or -NR 1d R 1e ;

[0020] R 1d and R 1e Each is independently hydrogen or a C1-C6 alkyl group;

[0021] R 1-4 and R 1-5 Each is independently hydrogen or a C1-C6 alkyl group;

[0022] R 1-6 and R 1-7 Each is independently halogen or C1-C6 alkyl;

[0023] R 2 "a 10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-1 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 10-15 membered tricyclic fused heteroaryl groups", "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 6-10 membered bicyclic fused heteroaryl groups", substituted with one or more R 2-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 6-10 membered bicyclic fused heteroaryl having 1, 2 or 3 heteroatoms", C6-C 10 Aryl or one or more R 2-3 Substituted C6-C 10 Aryl;

[0024] R 2-1 and R 2-2 Each independently represents an oxo group, a C1-C6 alkyl group, a 2-1-1 Substituted C1-C6 alkyl or -C(=O)-R 2-1-2 ;

[0025] R 2-1-1 are each independently halogen, cyano or hydroxy;

[0026] R 2-1-2 Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy;

[0027] R 2a and R 2a-1 are each independently halogen, cyano or hydroxy;

[0028] R 2-3 Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-3-2 Substituted "3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", "5-12 membered heterocycloalkenyl having 1, 2 or 3 heteroatoms selected from N, O and S", "substituted by one or more R 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3- 6 R 2-3-7 ;

[0029] R 2-3-1 Each independently represents a "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", 2b Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ;

[0030] R 2b Each is independently C1-C6 alkyl, halogen or hydroxyl;

[0031] R 2c is hydrogen, C1-C6 alkyl, 2c-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, "3-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S" or one or more R 2c-2 Substituted 3-6 membered cycloalkyl;

[0032] R 2d is hydrogen, C1-C6 alkyl, 2d-1Substituted C1-C6 alkyl, 3-6 membered cycloalkyl or one or more R 2d-2 Substituted 3-6 membered cycloalkyl;

[0033] R 2c-1 and R 2d-1 are each independently halogen, cyano or hydroxy;

[0034] R 2c-2 and R 2d-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0035] R 2-3-2 Each is independently C1-C6 alkyl, halogen or hydroxyl;

[0036] R 2-3-3 Each is independently C1-C6 alkyl, halogen or hydroxyl;

[0037] R 2-3-4 and R 2-3-5 Each independently is hydrogen, C1-C6 alkyl or one or more R 2e Substituted C1-C6 alkyl;

[0038] R 2e Each independently represents a halogen, a "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", a 2e-1 Substituted "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 ;

[0039] R 2e-1 Each is independently halogen or C1-C6 alkyl;

[0040] R 2e-2 and R 2e-3 Each is independently hydrogen or C1-C6 alkyl;

[0041] R 2-3-6 and R 2-3-7 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 2f Substituted C1-C6 alkyl;

[0042] R 2f Each is independently halogen or "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S";

[0043] R 3It is hydrogen or C1-C6 alkyl.

[0044] In a certain embodiment, certain groups in the compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (referred to as "a certain embodiment").

[0045] In one scheme, R 1 , R 1-2 , R 1-3 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 2-1 , R 2-2 , R 2-1-2 , R 2-3 , R 2b , R 2c , R 2d , R 2c-2 , R 2d-2 , R 2-3-2 , R 2-3-3 , R 2-3-4 , R 2-3-5 , R 2e-1 , R 2e-2 , R 2e-3 , R 2-3-6 , R 2-3-7 and R 3 wherein the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example, methyl, ethyl or isopropyl.

[0046] In one scheme, R 1 , R 1-2 , R 1-3 , R 2c and R 2d wherein the 3-6 membered cycloalkyl groups are each independently cyclopropane, cyclobutane, cyclopentane or cyclohexane, for example cyclopropane, cyclobutane or cyclopentane.

[0047] In one scheme, R 1 In the above, the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl” and one or more R 1-7The substituted "3-6 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3" is each independently a 4-6 membered heterocycloalkyl group; the heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2.

[0048] In one scheme, R 1-1 , R 1-2-1 , R 1-3-1 , R 1-2-2 , R 1-3-2 , R 1-2-3 , R 2-1-1 , R 2a , R 2a-1 , R 2b , R 2c-1 , R 2d-1 , R 2c-2 , R 2d-2 , R 2-3-2 , R 2-3-3 , R 2e , R 2e-1 and R 2f In the above, the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0049] In one scheme, R 2 In the above, the “heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl group” and one or more R 2-1 In the substituted "heteroatom selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl" the 10-15 membered tricyclic fused heteroaryl is each independently a 12-13 membered tricyclic fused heteroaryl (e.g. 13 membered tricyclic fused heteroaryl), the heteroatom is preferably 1 or 2 of N and O, the number of heteroatoms is preferably 1 or 2, for example the 10-15 membered tricyclic fused heteroaryl is

[0050] In one scheme, R 2 In the above, the “heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, and the 6-10 membered bicyclic fused heteroaryl group” and one or more R 2-2 The substituted "6-10 membered bicyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 9-10 membered bicyclic fused heteroaryl group, wherein the heteroatoms are preferably 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 6-10 membered bicyclic fused heteroaryl group is Preferably

[0051] In one scheme, R 2 In the C6-C 10 Aryl and one or more R 2-3 Substituted C6-C 10 C6-C 10 Aryl is phenyl or naphthyl, for example phenyl.

[0052] In one scheme, R 2-1-2 In the above, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example, ethoxy.

[0053] In one scheme, R 2-3 In the above, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example, methoxy.

[0054] In one scheme, R 2-3 In the above, the C1-C6 alkylthio group is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio.

[0055] In one scheme, R 2-3 In the above, the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl” and one or more R 2-3-2 The substituted "3-12-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 4-6-membered heterocycloalkyl group, wherein the heteroatoms are preferably 1 or 2 of N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-12-membered heterocycloalkyl group is

[0056] In one scheme, R 2-3 In the above, the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heterocycloalkenyl” and one or more R 2-3-3 The substituted "5-12-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 5-6-membered heterocycloalkenyl group, the number of unsaturated double bonds is preferably 1, the heteroatoms are preferably 1 or 2 selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 5-12-membered heterocycloalkenyl group is

[0057] In one scheme, R 2-3-1In the above, the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl” and “substituted by one or more R 2b The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3. In the "3-6 membered heterocycloalkyl", each of the 3-6 membered heterocycloalkyl is independently a 5-6 membered heterocycloalkyl, and the heteroatom is preferably 1 or 2 of N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl is

[0058] In one scheme, R 2c In the “3-6 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3”, the 3-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, whose heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2.

[0059] In one scheme, R 2e In the above, the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl” and one or more R 2e-1 The substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 5-6 membered heterocycloalkyl group, wherein the heteroatoms are preferably 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl group is

[0060] In one scheme, R 2f In the “3-6 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3”, the 3-6 membered heterocycloalkyl group is independently a 5-6 membered heterocycloalkyl group, whose heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl group is

[0061] In one solution, X is CHR 1 NR 1 or O; for example, X is CH-NR 1-4 R 1-5 NR 1 or O; for example, X is NR 1 .

[0062] In one embodiment, n1 and n2 are each independently 1.

[0063] In one embodiment, n3 and n4 are each independently 1 or 2; for example, n3 and n4 are 1.

[0064] In one scheme, R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl or "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; for example, R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl; for example, R 1 are each independently hydrogen.

[0065] In one scheme, R 1-1 are each independently halogen or hydroxy; for example, R 1-1 are each independently a hydroxyl group.

[0066] In one scheme, R 1-2 Each independently is a C1-C6 alkyl group, 1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c .

[0067] In one scheme, R 1-3 Each is independently a 3-6 membered cycloalkyl group.

[0068] In one scheme, R 1-2-1 are each independently cyano or halogen.

[0069] In one scheme, R 1-2-2 are each independently halogen.

[0070] In one scheme, R 1a , R 1b and R 1c are independently hydrogen or replaced by one or more R 1-2-3 Substituted C1-C6 alkyl.

[0071] In one scheme, R 1-2-3 are each independently halogen.

[0072] In one scheme, R 1-4 and R1-5 Each is independently hydrogen or C1-C6 alkyl.

[0073] In one scheme, R 2 "a 10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" or one or more R 2-3 Substituted C6-C 10 Aryl; for example, one or more (eg, 2) R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl", preferably, the substituted one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" is Wherein, Y is a single bond, CH2, NH, S or O (for example, a single bond or CH2, preferably CH2); Z is NH, NR 2-2 , S or O (e.g. NR 2-2 or O, preferably NR 2-2 );R 2-2 Each independently represents an oxo group, a C1-C6 alkyl group, a 2-1-1 Substituted C1-C6 alkyl or -C(=O)-R 2-1-2 (For example, R 2-2 are each independently C1-C6 alkyl, preferably methyl); more preferably, R 2 for

[0074] In one scheme, R 2-1 and R 2-2 Each is independently oxo, C1-C6 alkyl or -C(=O)-R 2-1-2 ; For example, R 2 -1 and R 2-2 Each is independently a C1-C6 alkyl group.

[0075] In one scheme, R 2-1-2 Each independently is one or more R 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy.

[0076] In one scheme, R 2a and R2a-1 are each independently halogen.

[0077] In one scheme, R 2-3 Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms", 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3-6 R 2-3-7 ; For example, R 2-3 Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms", 2-3-3 The substituted "5- to 12-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S"

[0078] In one scheme, R 2-3-1 Each independently represents a "3- to 6-membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ; For example, R 2-3-1 Each independently is -NH-SO2-R 2c or -NH-CO-NHR 2d .

[0079] In one scheme, R 2c It is a 3-6 membered cycloalkyl group.

[0080] In one scheme, R 2d For one or more R 2d-2 Substituted 3-6 membered cycloalkyl.

[0081] In one scheme, R 2d-2 Each is independently a C1-C6 alkyl group substituted by one or more halogens.

[0082] In one scheme, R 2-3-2 Each is independently a C1-C6 alkyl group or a hydroxyl group.

[0083] In one scheme, R 2-3-3 Each is independently a C1-C6 alkyl group.

[0084] In one scheme, R 2-3-4 and R 2-3-5 are each independently hydrogen or one or more R 2e Substituted C1-C6 alkyl.

[0085] In one scheme, R 2e Each independently is one or more R 2e-1 Substituted "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 For example, R 2e Each independently is NR 2e-2 R 2e-3 .

[0086] In one scheme, R 2e-1 are each independently halogen.

[0087] In one scheme, R 2e-2 and R 2e-3 Each is independently a C1-C6 alkyl group.

[0088] In one scheme, R 2-3-6 and R 2-3-7 Each is independently hydrogen or C1-C6 alkyl.

[0089] In one scheme, R 3 is hydrogen or C1-C6 alkyl, for example, R 3 For hydrogen.

[0090] In one scheme, when R 2 "a 10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-1 When the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl groups", R 1 Each is independently hydrogen or C1-C6 alkyl.

[0091] In one scheme, when R 2-3 -C(=O)-NR 2-3-4 R 2-3-5 , R 2-3-4 and R 2-3-5 are independently hydrogen or replaced by one or more R 2eWhen the C1-C6 alkyl group is substituted, R 1 are independently hydrogen, C1-C6 alkyl, trifluoromethyl, -C(=O)-R 1-2 or -SO2-R 1-3 .

[0092] In one scheme, when R 2-3-1 -NH-SO2-R 2c , R 2c When it is a 3-6 membered cycloalkyl group, R 1 are independently -C(=O)-R 1-2 , R 1-2 is independently trifluoromethyl.

[0093] In one embodiment, the compound represented by the above formula I is a compound represented by the following formula I-1, I-2 or I-3;

[0094]

[0095] R 2-4 is hydrogen or C1-C6 alkyl (e.g. methyl); m is 2 or 3;

[0096] n1, n2, n3, n4, X, R 2-2 and R 2-3 Each independently as described in any one of the present invention, preferably, R 2-2 It is methyl.

[0097] In one solution, X is CHR 1 NR 1 or O;

[0098] n1 and n2 are each independently 1;

[0099] n3 and n4 are each independently 1 or 2;

[0100] R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl or "3-6 membered heterocycloalkyl wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3";

[0101] R 1-1 are each independently halogen or hydroxy;

[0102] R 1-2 Each independently is a C1-C6 alkyl group,1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c ;

[0103] R 1-3 Each is independently a 3-6 membered cycloalkyl;

[0104] R 1-2-1 are each independently cyano or halogen;

[0105] R 1-2-2 are each independently a halogen;

[0106] R 1a , R 1b and R 1c are independently hydrogen or replaced by one or more R 1-2-3 Substituted C1-C6 alkyl;

[0107] R 1-2-3 are each independently a halogen;

[0108] R 1-4 and R 1-5 Each is independently hydrogen or a C1-C6 alkyl group;

[0109] R 2 "a 10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" or one or more R 2-3 Substituted C6-C 10 Aryl;

[0110] R 2-2 Each is independently oxo, C1-C6 alkyl or -C(=O)-R 2-1-2 ;

[0111] R 2-1-2 Each independently is one or more R 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy;

[0112] R 2a and R 2a-1 are each independently a halogen;

[0113] R 2-3Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms", 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3-6 R 2-3-7 ;

[0114] R 2-3-1 Each independently represents a "3- to 6-membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ;

[0115] R 2c is a 3-6 membered cycloalkyl group;

[0116] R 2d For one or more R 2d-2 Substituted 3-6 membered cycloalkyl;

[0117] R 2d-2 Each is independently a C1-C6 alkyl group substituted by one or more halogens;

[0118] R 2-3-2 Each is independently a C1-C6 alkyl or a hydroxyl group;

[0119] R 2-3-3 Each is independently a C1-C6 alkyl group;

[0120] R 2-3-4 and R 2-3-5 are each independently hydrogen or one or more R 2e Substituted C1-C6 alkyl;

[0121] R 2e Each independently is one or more R 2e-1 Substituted "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 ;

[0122] R 2e-1 are each independently a halogen;

[0123] R 2e-2 and R 2e-3 Each is independently a C1-C6 alkyl group;

[0124] R 2-3-6 and R 2-3-7 Each is independently hydrogen or C1-C6 alkyl;

[0125] R 3 It is hydrogen or C1-C6 alkyl.

[0126] In one embodiment, n1 and n2 are each independently 1.

[0127] In one embodiment, n3 and n4 are each independently 1 or 2.

[0128] In one scheme, R 1 is hydrogen, methyl, ethyl, -CH(CH3)2, -CH2CHF2, -CH2CF3, -C(=O)CH3, -C(=O)CF3, -NHCH3,

[0129] In one plan, for

[0130]

[0131] In one plan, for In one scheme, R 2 for

[0132] In one scheme, R 3 It is hydrogen or ethyl.

[0133] In one embodiment, the compound as shown in Formula I is any of the following compounds:

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] The present invention also provides a pharmaceutical composition, comprising:

[0142] (1) a compound of formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and

[0143] (2) Pharmaceutically acceptable excipients.

[0144] The present invention also provides the use of a compound as shown in formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a drug, wherein the drug is used to treat lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast duct cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, villous adenoma of the large intestine, melanoma, cell tumor and sarcoma, myelodysplastic syndrome, such as lung cancer.

[0145] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0146] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0147] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0148] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0149] The term "solvate" refers to a substance formed by the combination of a compound and a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0150] The term "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" are as described above; they refer to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0151] The expression "a group substituted with one or more substituents" means that one or more hydrogen atoms in a group are independently replaced by the substituents. When multiple substituents appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 1-1 group-substituted, that is, the group may be replaced by up to 3 R 1-1 Replace, the position R 1-1 Definition and other positions R 1-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0152] The term "plurality" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0153] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0154] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0155] The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0156] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 members, 3-6 members, 4-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (1, 2, or 3 of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, oxetanyl (e.g., ), oxolane (e.g. ) tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl and piperidinyl, piperazinyl (e.g. )wait.

[0157] The term "alkoxy" refers to the group -OR X , R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0158] The term "alkylthio" refers to the group -SR X , R X The definition of "alkyl" is the same as that of "alkyl". Alkoxy includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like.

[0159] The term "heterocycloalkenyl" refers to an unsaturated cyclic group having a specified number of ring atoms (e.g., 5-12 members, 3-6 members, 4-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (1, 2, or 3 of N, O, and S), 1, 2, or 3 unsaturated double bonds, and no aromaticity, which is a monocyclic, bridged, or spirocyclic (e.g., monocyclic). Heterocycloalkenyl includes, but is not limited to, azetidinyl, oxadienyl, azidine (e.g., )wait.

[0160] The term "aryl" refers to a radical having a specified number of carbon atoms (e.g., C6-C 10 ) and is composed only of carbon atoms, which is a monocyclic or polycyclic ring, and each ring has aromaticity (conforming to Huckel's rule). The aryl group is connected to other fragments in the molecule through the aromatic ring. Aromatic rings include, but are not limited to, benzene rings and naphthalene rings.

[0161] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-15 members, and also 6-10, 10-15 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (1, 2, or 3 of N, O, and S), which is a monocyclic, bicyclic, or tricyclic ring, wherein two adjacent rings in the bicyclic or tricyclic ring share two atoms and a bond, and at least one ring is aromatic (in accordance with Huckel's rule). A heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms. "Heteroaryl" includes, but is not limited to: wait.

[0162] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0163] The reagents and raw materials used in the present invention are commercially available.

[0164] The positive improvement effect of the present invention is that the compound of the present invention has better activity, for example, has better inhibitory activity on HPK1 kinase or has better safety. DETAILED DESCRIPTION

[0165] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0166] The structures of all the compounds of the present invention can be identified by nuclear magnetic resonance (1HNMR) and / or mass spectrometry (MS).

[0167] 1H NMR chemical shifts (δ) are reported in PPM (10-6). NMR was performed on a Bruker AVANCE-400 spectrometer.

[0168] LC-MS was determined by Agilent 1200 HPLC / 6120 mass spectrometer.

[0169] The thin layer silica gel plate is Liangchen Silicon Source HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as a carrier.

[0170] Example 1

[0171]

[0172] first step:

[0173] Dissolve 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (10.0 g, 46.89 mmol) in dichloromethane (100 mL), add DIPEA (16 ml, 90 mmol), cool to 0°C, slowly drop methylsulfonyl chloride (6.45 g, 56.27 mmol) into the reaction flask, stir the reaction solution at room temperature for 2 hours, concentrate to remove most of the dichloromethane, dilute with 400 ml of ethyl acetate, wash the organic phase with water (100 ml*3), wash with saturated brine (100 ml*3), dry over anhydrous sodium sulfate, and concentrate to obtain crude 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (13.5 g). LC-MS: 236.3[M+1-56] + .

[0174] Step 2:

[0175] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.7 g, 55.2 mmol) was dissolved in anhydrous DMF (50 mL), the system was cooled to 0°C, NaH (2.54 g, 64 mmol) was added to the reaction solution under nitrogen protection and stirred for 0.5 h, 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (13.5 g, 46 mmol) was dissolved in anhydrous DMF (3 0ml) and added to the reaction solution, heated to 110℃ for 5h, cooled and removed most of DMF, added ethyl acetate (400ml) for dilution, washed the organic phase with water (100ml*3), washed with saturated brine (100ml*3), dried over anhydrous sodium sulfate, and concentrated to obtain crude 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (17.7g). LC-MS: 390.3[M+1] + .

[0176] Step 3:

[0177] Dissolve the crude product tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (17.7 g, 45.5 mmol) in THF (100 mL), add sodium hydroxide (3.65 g, 91.2 mmol) and 20 ml of water. The reaction solution is cooled to 0°C, and hydrogen peroxide (15 ml, 91.1 mmol) is slowly added dropwise. After the addition is complete, the reaction solution is stirred at room temperature overnight. After the reaction was completed, dilute hydrochloric acid was added dropwise to adjust to neutrality, diluted with 400 ml of ethyl acetate, the organic phase was washed with water (100 ml*3), washed with saturated brine (100 ml*3), dried over anhydrous sodium sulfate, and concentrated to obtain crude 6-(4-hydroxy-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (15 g). LC-MS: 236.1 [M+1-56] + .

[0178] Step 4:

[0179] 5-Bromo-3-chloropyrazin-2-amine (3.75 g, 18 mmol) and tert-butyl 6-(4-hydroxy-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 21.5 mmol) were dissolved in DMF (50 ml), and cesium carbonate (7.9 g, 24.3 mmol) was added. The reaction solution was heated to 100° C. for 3 h. After the reaction was completed, some DMF was removed and 250 ml of ethyl acetate was added for dilution, filtered (with diatomaceous earth as the filter aid), the organic phase was washed with water (100 ml*3), washed with saturated brine (100 ml*3), dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried (petroleum ether: ethyl acetate 5:1) to obtain 6-(4-((3-amino-6-bromopyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4 g, 42%). LC-MS: 396.2 [M+1-56] + .

[0180] Step 5:

[0181] 6-(4-((3-amino-6-bromopyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 22.17 mmol) and 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (0.73 g, 25.5 mmol) were dissolved in 1,4-dioxane (50 mL). Potassium carbonate (0.4 g, 28.6 mmol) and [1,1'-bis( The reaction mixture was heated to 100°C under nitrogen protection, stirred for 2 hours, cooled and concentrated, and then chromatographed on a silica gel column (dichloromethane / methanol 100:0-100:6) to obtain the target compound 6-(4-((3-amino-6-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 55%). LC-MS: 532.3[M+1] + .

[0182] Step 6:

[0183] Dissolve 6-(4-((3-amino-6-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 1.22 mmol) in 5 ml of dichloromethane, and add 5 ml of trifluoroacetic acid. Stir the reaction solution at room temperature for 2 h. Concentrate, and adjust the pH to alkaline with saturated sodium bicarbonate solution. Directly concentrate and mix the sample and purify it on a column (dichloromethane: ammonia-methanol = 100:5) to obtain the target product 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (237 mg, 45%). LC-MS:432.3[M+1] + ; 1 H NMR (400 MHz, DMSO)δ 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.41(s,1H),7.70(d,J=4.9Hz,2H),7.57(s,1H),7.43(s,2H),4.57( s,1H),3.54(s,6H),3.39–3.18(m,2H),2.67(d,J=17.7Hz,6H),2.36(s,3H),2.27(s,3H),2.16(s,2H).

[0184] Example 2

[0185]

[0186] first step:

[0187] The crude product 6-(4-hydroxy-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.8g, 7mmol, purity 70%) was dissolved in 50ml of anhydrous THF and protected by nitrogen. LAH (10ml, 14mmol, 1.4M) was slowly added under ice bath. After addition, the temperature was raised to 85℃ and reacted for 2h. After the reaction was completed, the temperature was lowered to 0℃, and 0.6ml of water was slowly added dropwise by syringe to quench, 0.6ml of sodium hydroxide (15%), and finally 1.8ml of water was added to quench. The product was highly polar and soluble in water, so it was directly concentrated and loaded on the column (ammonia-methanol (7M): dichloromethane 0-15%) to obtain the target compound 1-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1H-pyrazole-4-ol (0.85g, 63%), LC-MS: 194.0[M+1]+.

[0188] Step 2:

[0189] The preparation method is similar to the fourth step in Example 1.

[0190] Step 3:

[0191] The preparation method is similar to the fifth step in Example 1.

[0192] LC-MS:446.0[M+1] + . 1 H NMR (400MHz, DMSO) δ8.19(s,1H),8.13(s,1H),7.61(s,1H),7.48(s,1H),7.35(s,1H),6.65(s,2H),4.82–4. 69(m,1H),3.49(s,2H),3.37(s,2H),3.23(s,2H),2.72–2.54(m,8H),2.35(s,3H),2.25(s,3H),2.22(s,3H)

[0193] Example 3

[0194]

[0195] The raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and acetaldehyde (10 mg, 0.23 mmol) were dissolved in 2 ml of methanol, stirred at room temperature for 1 h, then sodium cyanoborohydride (22 mg, 0.36 mmol) was added and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by preparative plate separation (dichloromethane:methanol=100:10) to obtain the target product 5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-ethyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (10 mg, 18.7%); LC-MS: 461.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.19(s,1H),8.14(s,1H),7.61(s,1H),7.48(s,1H),7.35(s,1H),6.65(s,2H),4.83–4.70(m,1H),3.49( s,2H),3.30(s,3H),3.20(s,2H),2.71–2.55(m,8H),2.43(d,J=7.1Hz,2H),2.35(s,3H),2.22(s,3H),0.87(t,J=7.1Hz,4H).

[0196] Example 4

[0197]

[0198] The raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and acetaldehyde (10 mg, 0.23 mmol) were dissolved in 2 ml of methanol, stirred at room temperature for 1 h, then sodium cyanoborohydride (22 mg, 0.36 mmol) was added and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by preparative plate separation (dichloromethane:methanol=100:10) to give the target product 5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-ethyl-3-((1-(2-ethyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (10 mg, 17.8%); LC-MS: 488.2 [M+1] + . 1H NMR (400MHz, DMSO) δ8.24(s,1H),8.15(s,1H),7.63(s,1H),7.46(s,1H),7.34(s,1H),7.09(t,J=5.6Hz,1H),4.84–4.72(m,1H),3.50(s ,3H),3.31(s,4H),2.90(s,2H),2.74(s,2H),2.70–2.58(m,9H),2.36(s,3H),2.21(s,3H),1.20(t,J=7.1Hz,3H),0.90(t,J=7.2Hz,4H).

[0199] Example 5

[0200]

[0201] The raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and triethylamine (50 mg, 0.5 mmol) were dissolved in 3 ml of dichloromethane, and 2,2-difluoroethanol methanesulfonate (28 mg, 0.174 mmol) and 1 The reaction was completed after 3 h. After concentration, the mixture was separated and purified on a preparative plate (dichloromethane:methanol=100:10) to give the target product 3-((1-(2-(2,2-difluoroethyl)-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (11 mg, 19.3%); LC-MS: 496.3 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.21(s,1H),8.12(s,1H),7.63(s,1H),7.53(s,1H),7.39(s,1H),6.67(s,2H),5.94(t,J=55.8Hz,1H),4.75 (dd,J=16.2,8.1Hz,1H),3.75(s,2H),3.39(s,5H),3.29(s,2H),2.88(s,2H),2.84–2.70(m,4H),2.70–2.55(m,4H),2.23(s,3H).

[0202] Example 6

[0203]

[0204] The raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and triethylamine (50 mg, 0.5 mmol) were dissolved in 3 ml of dichloromethane, and trifluoroethyl trifluoromethanesulfonate (40 mg, 0.174 mmol) was added. After 1 hour, After the reaction was completed, the mixture was concentrated and purified by preparative plate separation (dichloromethane:methanol=100:10) to obtain the target product 5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((1-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-yl)oxy)pyrazin-2-amine (10 mg, 16%); LC-MS: 514.3 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.20(s,1H),8.14(s,1H),7.63(d,J=10.2Hz,1H),7.49(s,1H),7.37(s,1H),6.65(s,2H),4.86–4.69(m,1H),4.52(d,J= 44.9Hz,1H),4.19(d,J=43.1Hz,1H),3.56(s,2H),3.47(s,2H),3.16(dd,J=20.4,10.2Hz,2H),2.87–2.57(m,8H),2.39(s,3H),2.22(s,3H).

[0205] Example 7

[0206]

[0207] The preparation method is based on the first to sixth steps of Example 1.

[0208] LC-MS: 500.2[M+1] + . 1 H NMR(400MHz,MeOD)δ8.12(s,2H),7.44(s,1H),7.32(s,1H),4.00(d,J=28.0Hz,2H),3 .78–3.40(m,3H),3.11–2.58(m,8H),2.48(s,3H),2.26(s,3H),1.32(d,J=8.4Hz,2H).

[0209] Example 8

[0210]

[0211] The preparation method is similar to that of Example 6.

[0212] LC-MS: 582.2[M+1] + . 1 H NMR (400MHz, MeOD) δ8.12 (d, J = 1.9Hz, 2H), 7.46 (s,

[0213] 1H),7.33(s,1H),3.66(s,2H),3.59(s,2H),3.50(s,2H),3.13(q,J=9.7Hz,2H),2. 84(s,4H),2.78(t,J=8.1Hz,4H),2.51(s,3H),2.27(s,3H),2.21(t,J=7.6Hz,1H).

[0214] Example 9

[0215]

[0216] The preparation method is similar to that of Example 6.

[0217] LC-MS:474.3[M+1]+. 1 H NMR (400MHz, DMSO) δ8.20 (s, 1H), 8.15 (d, J = 6.4Hz,

[0218] 1H),7.64(d,J=3.6Hz,1H),7.48(s,1H),7.36(s,1H),4.88–4.73(m,1H),4.24(s,1H),4.13(s,1H),3.96(s,1H),3. 85(s,1H),3.74(d,J=6.9Hz,1H),3.51(s,2H),2.77–2.61(m,9H),2.36(s,3H),2.21(s,3H),1.75(d,J=10.4Hz,4H).

[0219] Example 10

[0220]

[0221] Cyclopropanecarboxylic acid (11 mg, 0.128 mmol), HATU (1.2 eq), and triethylamine (1.5 eq) were dissolved in 3 ml of dichloromethane, and 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.1 16mmol), the reaction was completed after 3h, and the product was concentrated and purified by preparative plate separation (dichloromethane: methanol = 100: 10) to obtain the target product [2-[4-[3-amino-6-(2,5-dimethyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrazin-2-yl]oxypyrazol-1-yl]-6-azaspiro[3.3]heptane-6-yl]-cyclopropylmethanone (10mg, 17%). LC-MS: 500.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),8.14(d,J=3.3Hz,1H),7.63(d,J=2.3Hz,1H),7.49(s,1H),7.36(s,1H),6.64(s,2H),4.87-4.75(m,1H),4.3 7(s,1H),4.26(s,1H),3.98(s,1H),3.87(s,1H),3.60(s,2H),2.83-2.64 (m,8H),2.41(s,3H),2.22(s,3H),1.52-1.44(m,1H),0.74–0.57(m,4H).

[0222] Embodiment 11

[0223]

[0224] The preparation method is similar to that of Example 10.

[0225] LC-MS: 536.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.15(s,1H),7.65(s,1H),7.52(s,1H),7.38(s,1H),6.65(s,2H),4.86-4.78(m,1H),4.50– 4.16(m,2H),4.09-4.01(m,1H),3.96-3.89(m,1H),3.68(s,2H),2.91-2.67(m,8H),2.47(s,3H),2.23(s,3H),2.08–1.75(m,3H).

[0226] Example 12

[0227]

[0228] The preparation method is similar to that of Example 6.

[0229] LC-MS: 474.3[M+1]+. 1H NMR (400MHz, DMSO) δ8.20(s,1H),8.15(d,J=6.4Hz,1H),7.64(d,J=3.6Hz,1H),7.48(s,1H),7.36(s,1H),4.88–4.73(m,1H),4.24(s,1H),4.1 3(s,1H),3.96(s,1H),3.85(s,1H),3.74(d,J=6.9Hz,1H),3.51(s,2H) ,2.77–2.61(m,9H),2.36(s,3H),2.21(s,3H),1.75(d,J=10.4Hz,4H).

[0230] Example 13

[0231]

[0232] The preparation method is similar to that of Example 10.

[0233] LC-MS: 499.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.20 (s, 1H), 8.14 (d, J = 2.2

[0234] Hz,1H),7.64(d,J=3.3Hz,1H),7.49(s,1H),7.36(s,1H),6.64(s,2H),4.87-4.75(m,1H),4.28(s,1H),4.18(s,1H ),4.04(s,1H),3.94(s,1H),3.73(s,1H),3.71(s,1H),3.56(s,2H),2.76-2.66(m,8H),2.40(s,3H),2.22(s,3H).

[0235] Embodiment 14

[0236]

[0237] The preparation method is similar to that of Example 6.

[0238] LC-MS: 536.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.14(s,1H),7.63(s,1H),7.48(s,1H),7.35(s,1H),6.62(s,2H),4.86-4.75(m,1H), 4.03(s,2H),3.93(s,2H),3.53(s,2H),2.90–2.60(m,9H),2.37(s,3H),2.21(s,3H),1.05-0.98(m,2H),0.95-0.88(m,2H).

[0239] Embodiment 15

[0240]

[0241] The raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and 2,2,2-trifluoroethylamine (1 eq) and triethylamine (1 eq) were dissolved in dichloromethane (5 ml), and triphosgene (1 eq) was slowly added under ice bath. After the addition, the reaction was allowed to proceed overnight, and the product precipitated in the reaction solution, which was filtered to obtain 2-[4-[3-amino-6-(2,5-dimethyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrazin-2-yl]oxypyrazol-1-yl]-N-(2,2,2-trifluoroethyl)-6-azaspiro[3.3]heptane-6-carboxamide (25 mg, 38.8%). LC-MS: 557.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.13(s,1H),7.62(s,1H),7.47(s,1H),7.34(s,1H),7.02-6.96(m,1H),6.62(s,2H),4.84 -4.72(m,1H),3.97(s,2H),3.87(s,2H),3.75(qd,J=9.8,6.2Hz,2H),3.49(s,2H),2.84–2.61(m,8H),2.34(s,3H),2.20(s,3H).

[0242] Example 16

[0243]

[0244] The preparation method is similar to that of Example 15.

[0245] LC-MS: 558.2[M+H] + .1 H NMR(400MHz,MeOD)δ8.08(s,1H),8.03(s,1H),7.74(s,1H),7.50(s,1H),7.38(s,1H),4.82–4.75(m,1H), 4.57(q,J=8.7Hz,2H),4.15(d,J=41.6Hz,4H),3.65(s,2H),2.94–2.74(m,8H),2.49(s,3H),2.28(s,3H).

[0246] Embodiment 17

[0247]

[0248] The preparation method is similar to that of Example 3.

[0249] LC-MS: 474.2[M+1]+. 1H NMR(400MHz,DMSO)δ8.20(s,1H),8.15(s,1H),7.62(s,1H),7.48(s,1H),7.36(s,1H),6.65(s,2H),4.82–4.75 (m,1H),3.50(s,2H),3.32–3.23(m,5H),2.73–2.57(m,10H),2.36(s,3H),2.22(s,3H),0.89(d,J=5.8Hz,6H).

[0250] Embodiment 18

[0251]

[0252] Add the raw material 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol), triethylamine (50 mg, 0.5 mmol), 3 ml of ethanol, and then add dimethyl propylene oxide (10 mg, 0.128 mmol) into a microwave tube. , reacted at 100°C in a microwave for 1h, concentrated and purified by preparative plate separation (dichloromethane: methanol = 100: 10) to obtain the target product 1-(6-(4-((3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-methylpropan-2-ol (6 mg, 10.3%). LC-MS: 504.3[M+1] + . 1H NMR (400MHz, DMSO) δ8.19(s,1H),8.13(s,1H),7.84(s,1H),7.61(s,1H),7.48(s,1H),7.36(s,1H),6.63(s,2H),4.82–4.69(m,1H),4. 13(s,1H),3.50(s,2H),3.45(s,2H),3.34(s,3H),2.62(dt,J=20.6,10.6Hz,8H),2.39(s,2H),2.36(s,3H),2.22(s,3H),1.04(s,6H).

[0253] Embodiment 19

[0254]

[0255] The raw materials 3-((1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (50 mg, 0.116 mmol) and 1-ethoxy-1-trimethylsilyloxycyclopropane (40 mg, 0.23 mmol) were dissolved in 10 ml of methanol, two drops of glacial acetic acid were added, and the mixture was stirred at 60°C for 1 h, then sodium cyanoborohydride (22 mg, 0.36 mmol) was added and reacted for 3 h. After completion of the reaction, the mixture was concentrated and separated and purified by preparative plate (dichloromethane:methanol=100:10) to give the target product 3-((1-(2-cyclopropyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)oxy)-5-(2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (10 mg, 18.2%) LC-MS: 472.3 [M+1]+. 1H NMR (400MHz, DMSO) δ8.19(s,1H),8.13(s,1H),7.61(s,1H),7.48(s,1H),7.36(s,1H),6.64(s,2H),4.81–4.68(m,1H),3.52( s,2H),3.33(s,4H),2.71–2.55(m,9H),2.37(s,3H),2.33(s,1H),2.21(s,3H),0.31(d,J=4.3Hz,2H),0.20(d,J=3.0Hz,2H).

[0256] Embodiment 20

[0257]

[0258] The preparation method is similar to that of Example 3.

[0259] LC-MS: 486.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.13(s,1H),7.61(s,1H),7.48(s,1H),7.35(s,1H),6.64(s,2H),4.81-4.73(m,1H),4.55-4.4 9(m,2H),4.34-4.28(m,2H),3.75–3.56(m,1H),3.54(s,2H),3.31(s,2H),3.21(s,2H),2.79–2.55(m,8H),2.38(s,3H),2.21(s,3H).

[0260] Embodiment 21

[0261]

[0262] The preparation method is similar to that of Example 3.

[0263] LC-MS: 488.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.13(s,1H),7.61(s,1H),7.48(s,1H),7.35(s,1H),6.64(s,2H),4.81-4.73(m,1H),4.55-4.4 9(m,2H),4.34-4.28(m,2H),3.75–3.56(m,1H),3.54(s,2H),3.31(s,2H),3.21(s,2H),2.79–2.55(m,8H),2.38(s,3H),2.21(s,3H).

[0264] Embodiment 22

[0265]

[0266] The preparation method is similar to that of Example 3.

[0267] LC-MS: 500.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.13(s,1H),7.59(s,1H),7.47(J=1.8Hz,1H),7.34(d,J=1.8Hz,1H),6.61(s,2H),4.7 4(p,J=8.2Hz,1H),3.48(s,2H),3.17(s,2H),3.07(s,2H),2.70–2.54(m,9H),2.34(s,3H),2.21(s,3H),1.63–1.23(m,8H).

[0268] Embodiment 23

[0269]

[0270] first step:

[0271] The preparation method is the same as the first step in Example 1.

[0272] Step 2:

[0273] The preparation method is similar to the second step in Example 1.

[0274] Step 3:

[0275] The preparation method is similar to the third step in Example 1.

[0276] Step 4:

[0277] The preparation method is the same as the first step in Example 2.

[0278] Step 5:

[0279] The preparation method is similar to the fourth step in Example 1.

[0280] Step 6:

[0281] The preparation method is similar to the fifth step in Example 1.

[0282] LC-MS: 460.3 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.04 (s, 1H), 8.00 (d, J = 3.0

[0283] Hz,1H),7.71(d,J=3.0Hz,1H),7.45(s,1H),7.33(s,1H),4.83–4.70(m, 1H),3.58(s,2H),2.76(m,2.78-2.74,5H),2.70–2.67(m,1H),2.66–2.63 (m,1H),2.63–2.56(m,4H),2.55–2.49(m,1H),2.44(s,3H),2.38(s,1H) ,2.34(s,2H),2.23(s,3H),2.10(t,J=6.8Hz,1H),2.01(t,J=7.1Hz,1H).

[0284] Embodiment 24

[0285]

[0286] The preparation method is as in Example 1.

[0287] LC-MS: 460.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.15(s,1H),7.60(s,1H),7.47(s,1H),7.34(s,1H),6.64(s,2H),4.87(p,J=8.6Hz,1H),3 .47(s,2H),2.79–2.58(m,7H),2.41-2.35(m,2H),2.33(s,3H),2.20(s,6H),1.63-1.58(m,2H),1.58-1.52(m,2H),1.23(s,1H).

[0288] Embodiment 25

[0289]

[0290] The preparation method is similar to that of Example 3.

[0291] LC-MS: 516.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.15(s,1H),7.60(s,1H),7.47(s,1H),7.34(s,1H),6.62(s,2H),4.87(p,J=8.4Hz,1H),4.54-4.48(m,2 H),4.43-4.38(m,2H),3.48(s,2H),2.83–2.56(m,4H),2.40-2.30(m,6 H),2.27–2.04(m,8H),1.91(s,1H),1.71-1.61(dt,J=19.1,5.5Hz,4H).

[0292] Embodiment 26

[0293]

[0294] The preparation method is similar to that of Example 3.

[0295] LC-MS: 528.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.15(s,1H),7.60(s,1H),7.47(s,1H ),7.34(s,1H),6.64(s,2H),4.86(p,J=8.5Hz,1H),3.47(s,2H),2.68–2.57

[0297] (m,4H),2.40-2.12(m,6H),2.34(s,3H),2.20(s,3H),1.83-1.72(br,2H),1.71–1.53(m,6H),1.54–1.11(m,7H).

[0298] Embodiment 27

[0299]

[0300] first step:

[0301] The preparation method was similar to the first step of Example 1 except that DIPEA was replaced by Et3N.

[0302] Step 2:

[0303] The preparation method is similar to the second step in Example 1.

[0304] Step 3:

[0305] The preparation method is similar to the third step in Example 1.

[0306] Step 4:

[0307] The preparation method is the same as the first step in Example 2.

[0308] Step 5:

[0309] The preparation method is similar to the fourth step in Example 1.

[0310] Step 6:

[0311] The preparation method is similar to the fifth step in Example 1.

[0312] LC-MS: 460.3 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.04 (s, 1H), 8.00 (d, J = 3.0

[0313] Hz,1H),7.71(d,J=3.0Hz,1H),7.45(s,1H),7.33(s,1H),4.83–4.70(m, 1H),3.58(s,2H),2.76(m,2.78-2.74,5H),2.70–2.67(m,1H),2.66–2.63 (m,1H),2.63–2.56(m,4H),2.55–2.49(m,1H),2.44(s,3H),2.38(s,1H) ,2.34(s,2H),2.23(s,3H),2.10(t,J=6.8Hz,1H),2.01(t,J=7.1Hz,1H).

[0314] Embodiment 28

[0315]

[0316] The preparation method is based on the first to fifth steps of Example 1.

[0317] LC-MS: 433.2[M+H] + . 1 H NMR(400MHz,MeOD)δ8.08(s,1H),8.02(s,1H),7.74(s,1H),7.51(s,1H),7.39(s,1H),4.85( s,3H),4.74(s,3H),4.61(s,1H),3.66(s,2H),3.00–2.69(m,8H),2.50(s,3H),2.29(s,3H).

[0318] Embodiment 29

[0319]

[0320] first step:

[0321] At room temperature, tert-butyl 6-(4-(3-amino-6-bromopyrazin-2-yl)oxy]-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carbonate (50 mg, 0.1108 mmol), 1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methyl-piperazine (50 mg, 0.1505 mmol), Pd(dppf)Cl2 (12 mg, 0.016400 mmol), potassium phosphate (60 mg, 0.282 67mmol), dioxane (8mL), water (2mL, 100mass%). Nitrogen replacement protection. The reaction solution was heated to 100°C and reacted overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated and purified by thin layer preparation silica gel plate to obtain tert-butyl 6-(4-((3-amino-6-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)oxy)-1hydro-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonate tert-butyl ester 18.0mg, as a yellow solid (yield: 28.17%). LC-MS: 577.3[M+1]+.

[0322] Step 2:

[0323] At room temperature, dichloromethane (5 ml), tert-butyl 6-(4-((3-amino-6-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)oxy)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonate (18.0 mg, 0.0312 mmol), and trifluoroacetic acid (1.5 ml) were added to a 50 ml glass reaction bottle. The reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated and chromatographed on a silica gel plate (dichloromethane / methanol 0-10%) to obtain the target compound 3-((1-(2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-yl)oxy)-5-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (8.0 mg, 53.78%). LC-MS: 477.3[M+1]+. 1H NMR (400MHz, MeOD) δ8.10(s,1H),8.00(s,1H),7.76(s,1H),7.45(d,J=1.7Hz,1H),7.42–7.37(m,1H),7.01(d,J=8.2H z,1H),4.75(m,1H),3.92(s,3H),3.89(s,2H),3.79(s,2H),3.13(s,4H),2.85–2.70(m,4H),2.66(s,4H),2.38(s,3H).

[0324] Embodiment 30

[0325]

[0326] The preparation method is as in Example 3.

[0327] LC-MS: 505.3 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.10(s,1H),8.00(s,1H),7.76(s,1H),7.45(d,J=1.8Hz,1H),7.41(dd,J=8.2,1.8Hz,1H),7.01(d,J=8.3H z,1H),4.83–4.71(m,1H),3.91(s,3H),3.13(m,4H),2.73(m,4H),2.67(m,4H),2.58(m,4H),2.38(s,3H),1.02(t,J=7.2Hz,3H).

[0328] Embodiment 31

[0329]

[0330] The preparation method is similar to that of Example 29.

[0331] LC-MS: 507.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.15(s,1H),7.96(s,1H),7.82(s,1H),7.13(s,2H),4.80(m,1H),4. 23(s,2H),4.16(s,2H),3.88(s,6H),2.80–2.89(m,8H),2.64(s,3H),1.25–1.40(m,4H).

[0332] Embodiment 32

[0333]

[0334] first step:

[0335] 2-[4-(3-amino-6-bromo-pyrazin-2-yl)oxypyrazol-1-yl]-6-azaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester (430 mg, 0.95 mmol), 4-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-1-methyl-3,6-dihydro-2H-pyridine (310 mg, 0.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (78 mg, 0.095 mmol) and potassium carbonate (198 mg, 1.43 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), heated to 100° C. under argon protection, and reacted for 5 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The product was purified by silica gel column chromatography (Combiflash, dichloromethane / methanol: 100 / 5-100 / 8) to obtain 150 mg of brown oil with a yield of 24.5%.

[0336] Step 2:

[0337] Dissolve tert-butyl 2-[4-[3-amino-6-[3,5-dimethyl-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenyl]pyrazin-2-yl]oxypyrazol-1-yl]-6-azaspiro[3.3]heptane-6-carboxylate (50 mg, 0.087 mmol) in 5 mL of dichloromethane, and add 2 mL of trifluoroacetic acid under ice bath. After stirring at room temperature for 1 hour, the solvent was removed by rotary evaporation, and the concentrate was purified by TLC (dichloromethane / 7M ammonia methanol: 100 / 8) to obtain 20 mg of yellow solid with a yield of 48.5%. LC-MS: 472.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.12(s,1H),7.60(s,1H),7.47(s,2H),6.66(s,2H),5.39(s,1H),4.78- 4.65(m,1H),3.65–3.39(m,6H),2.98(s,2H),2.72–2.54(m,5H),2.29(s,3H),2.20(s,6H),2.18-2.12(m,2H).

[0338] Embodiment 33

[0339]

[0340] The preparation method refers to Example 32.

[0341] LC-MS: 418.3 [M+H] + . 1 H NMR (400MHz, MeOH-d4) δ8.06(s,1H),7.98(s,1H),7.71(s,1H),7.60(dd,J=8.0,1.9Hz,1H),7.51(d,J=1.8Hz,1H),7.15(d,J= 8.0Hz,1H),4.72(p,J=8.2Hz,1H),3.81(s,2H),3.71(s,2H),3.63(s,2H),2.97-2.91(m,2H),2.85–2.60(m,6H),2.46(s,3H).

[0342] Embodiment 34

[0343]

[0344] The preparation method is similar to that of Example 3.

[0345] LC-MS: 446.3[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.19(s,1H),8.10(s,1H),7.62(s,1H),7.57(d,J=8.0Hz,1H),7.50(s,1H),7.12(d,J=8.0Hz,1H),6.65(s,2H),4.76(p,J =8.1Hz,1H),3.51(s,2H),3.25(s,2H),3.15(s,2H),2.84-2.77(m,2H),2 .64-2.53(m,6H),2.42-2.37(m,2H),2.35(s,3H),0.86(t,J=7.2Hz,3H).

[0346] Embodiment 35

[0347]

[0348] The preparation method refers to Example 32.

[0349] LC-MS: 444.2[M+H] + . 1H NMR (400MHz, MeOD) δ8.11(s,1H),8.00(s,1H),7.76(s,1H),7.64(d,J=8.0Hz,1H),7.60(s,1H),7.19(d,J=8.4Hz,1H),4.78(m,1H) ,3.60(m,1H),3.21(m,2H),3.12(m,3H),2.95(m,1H),2.82(m,4H),2.77–2.66(m,4H),2.50–2.44(m,1H),2.00(m,2H),1.80(m,1H).

[0350] Embodiment 36

[0351]

[0352] The preparation method is similar to that of Example 3.

[0353] LC-MS: 472.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.06(s,1H),7.72(s,1H),7.64(d,J=8.1Hz,1H),7 .62(s,1H),7.20(d,J=7.9Hz,1H),4.30–4.18(m,1H),3.69–3.61(m,1H),3.24–3.19( m,1H),3.18–3.11(m,3H),3.08(m,2H),2.94(m,1H),2.79–2.74(m,1H),2.71(m,2H), 2.54(m,2H),2.23(m,4H),2.18–2.09(m,2H),1.98(m,2H),1.80(m,1H),1.17(m,3H).

[0354] Embodiment 37

[0355]

[0356] The preparation method is similar to that of Example 3.

[0357] LC-MS: 486.3[M+H] + . 1H NMR (400MHz, MeOD) δ8.10 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7. 61(s,1H),7.19(d,J=8.0Hz,1H),4.77(m,1H),3.67–3.57(m,1H),3.45(m,2H),3.37( m,1H),3.36(m,2H),3.25–3.18(m,1H),3.16–3.09(m,2H),2.95(m,1H),2.76–2.68(m ,6H),2.53–2.43(m,2H),2.03–1.95(m,2H),1.85–1.77(m,1H),0.99(d,J=6.3Hz,6H).

[0358] Embodiment 38

[0359]

[0360] The preparation method is similar to that of Example 6.

[0361] LC-MS: 526.3 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.15(s,1H),7.97(s,1H),7.78(d,J=8.1Hz,1H),7.76(s,1H),7.73(s,1H),7.33(d,J=8.1Hz,1H) ,4.79–4.74(m,1H),3.72(m,1H),3.59(m,2H),3.54–3.44(m,5H),3.15(m,4H),2.73(m,5H),2.24(m,2H),2.14(m,1H).

[0362] Embodiment 39

[0363]

[0364] The preparation method refers to Example 32.

[0365] LC-MS: 433.2[M+H] + . 1 H NMR(400MHz,MeOD)δ8.32(s,1H),8.03(dd,J=13.6,5.6Hz,3H),7.80(dd,J=9.9,9.1H z,2H),4.86–4.76(m,1H),4.26(s,2H),4.19(s,2H),3.02–2.77(m,4H),1.70(s,6H).

[0366] Embodiment 40

[0367]

[0368] The preparation method refers to Example 32.

[0369] LC-MS: 446.3[M+H] + . 1 H NMR(400MHz,MeOD)δ8.16(s,1H),7.98(s,1H),7.77(d,J=13.1Hz,3H),7.29(s,1H),4.75–4.55(m ,1H),4.38(s,2H),4.26(s,2H),4.19(s,2H),3.02–2.74(m,4H),2.43(s,3H),2.40–1.83(m,8H).

[0370] Embodiment 41

[0371]

[0372] The preparation method is similar to that of Example 6.

[0373] LC-MS: 528.3 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.14(s,1H),8.02(s,1H),7.75(s,1H),7.67(d,J=7.3Hz,2H),7.19(s,1H),4.82–4.67(m,1H),3. 92(s,2H),3.58(s,2H),3.48(s,2H),3.14(q,J=9.7Hz,2H),2.88(s,4H),2.82–2.61(m,4H),2.42(s,3H),1.94(s,4H).

[0374] Embodiment 42

[0375]

[0376] The preparation method refers to Example 32.

[0377] LC-MS: 535.3 [M+H] + . 1H NMR (400MHz, MeOD) δ8.13(s,1H),8.02(s,1H),7.74(s,1H),7.54(s,2H),5.20(d,J=56.5Hz,1H),4.78(m,1H),3.98(s,2H),3.88(s,2 H),3.55(q,J=6.8Hz,2H),3.05(dd,J=7.8,4.1Hz,1H),2.99(m,1H),2.79(m,7H),2.50(m,1H),2.37(s,6H),2.21(m,1H),2.02(m,1H).

[0378] Embodiment 43

[0379]

[0380] The preparation method is similar to that of Example 6.

[0381] LC-MS: 617.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.12(s,1H),8.03(s,1H),7.72(s,1H),7.54(s,2H),3.57(dd,J=12.6,5.7Hz,4H),3.48(s,2H),3.2 2–2.93(m,4H),2.85–2.65(m,7H),2.50(dd,J=15.4,8.4Hz,1H),2.37(s,6H),2.27–2.17(m,2H),2.04(d,J=9.2Hz,2H).

[0382] Embodiment 44

[0383]

[0384] The preparation method is similar to that of Example 10.

[0385] LC-MS: 602.3 [M+H] + . 1H NMR (400MHz, MeOD) δ8.13(s,1H),8.04(d,J=11.6Hz,1H),7.75(d,J=5.0Hz,1H),7.54(s,2H),5.20(d,J=53.8Hz,1H),4.80(m,1H),4.41(s,1H) ,4.31(s,1H),4.19(s,1H),4.08(s,1H),3.56(t,J=6.8Hz,2H),3.02(m ,2H),2.79(m,8H),2.50(m,1H),2.37(s,6H),2.25(m,2H),2.03(m,1H).

[0386] Embodiment 45

[0387]

[0388] The preparation method is similar to that of Example 10.

[0389] LC-MS: 603.4 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.23(s,1H),8.19(t,J=5.8Hz,1H),8.14(d,J=5.0Hz,1H), 7.64(d,J=2.6Hz,1H),7.50(s,2H),6.71(s,2H),5.29–5.06(m,1H),4.85-4.75(m, 1H),4.36(s,1H),4.25(s,1H),3.97(s,1H),3.85(s,1H),3.40–3.34(m,2H),2.95– 2.54(m,9H),2.43-2.33(m,1H),2.25(s,6H),2.21–1.77(m,3H),0.66–0.59(m,4H).

[0390] Embodiment 46

[0391]

[0392] The preparation method is similar to that of Example 6.

[0393] LC-MS: 320.2 [M+2H] 2+ . 1H NMR(400MHz,MeOH-d4)δ8.09(s,1H),8.01(s,1H),7.71(s,1H),7.50(s,2H),5.30-5.08(m,1H),4.81-4.71(m,1H),4.09(s,2H),3.98( s,2H),3.60-3.49(m,2H),3.13-2.91(m,2H),2.85-2.72(m,6H),2.58-2.48(m,2H),2.34(s,6H),2.26-1.91(m,3H),1.12-0.96(m,4H).

[0394] Embodiment 47

[0395]

[0396] The preparation method is similar to that of Example 5.

[0397] LC-MS: 599.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.13(s,1H),8.03(s,1H),7.72(s,1H),7.54(s,2H),4.75(dd,J=16.5,8.3Hz,1H),3.60–3.50(m,4H),3.44(s,2H),3.10–2 .93(m,2H),2.87(td,J=15.6,4.2Hz,2H),2.82–2.64(m,7H),2.51(dd, J=15.1,8.4Hz,1H),2.37(s,6H),2.27–2.15(m,2H),2.09–1.99(m,2H).

[0398] Embodiment 48

[0399]

[0400] The preparation method is similar to that of Example 3.

[0401] LC-MS: 591.3 [M+H] + . 1H NMR (400MHz, MeOD) δ8.13(s,1H),8.04(s,1H),7.73(s,1H),7.54(s,2H),4.74(t,J=6.7Hz,2H),4.54(d,J=5.3Hz,2H),4.51–4.42(m,2H),3.56(t ,J=6.7Hz,1H),3.49(s,1H),3.38(d,J=7.5Hz,2H),2.77(dd,J=19.2,11.8Hz,3H),2.59–2.43(m,1H),2.37(s,6H),2.22(dd,J=14.1,6.6Hz,2H).

[0402] Embodiment 49

[0403]

[0404] first step:

[0405] The preparation method refers to the first step of Example 32.

[0406] Step 2:

[0407] The preparation method refers to the second step of Example 32.

[0408] Step 3:

[0409] The preparation method is similar to that of Example 6.

[0410] LC-MS: 538.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.11(s,1H),8.03-8.01(m,1H),7.93(s,1H),7.61(s,1H),7.49(s,1H),7.39-7.33(m,1H ),6.88(s,2H),4.78-4.66(m,1H),3.46(s,2H),3.36(s,2H),3.20-3.11(m,2H),2.69-2.56(m,4H),2.43(s,3H),2.42(s,3H).

[0411] Embodiment 50

[0412]

[0413] The preparation method is similar to that of Example 6.

[0414] LC-MS: 560.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.14(s,1H),8.02(s,1H),7.94(s,1H),7.63(s,1H),7.49(s,1H),7.40-7.34(m,1H),6.89(s,2 H),4.83-4.73(m,1H),4.03(s,2H),3.94(s,2H),2.79–2.66(m,5H),2.44(s,3H),2.42(s,3H),1.05-0.99(m,2H),0.95–0.87(m,2H).

[0415] Embodiment 51

[0416]

[0417] The preparation method refers to Example 15.

[0418] LC-MS: 582.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.13(s,1H),8.02(s,1H),7.94(s,1H),7.62(s,1H),7.49(s,1H),7.39-7.32(m,1 H),6.88(s,2H),4.81-4.71(m,1H),4.69-4.60(m,2H),4.18–3.93(m,4H),2.79–2.62(m,4H),2.43(s,3H),2.42(s,3H).

[0419] Embodiment 52

[0420]

[0421] The preparation method is similar to that of Example 6.

[0422] LC-MS: 552.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 8.14 (d, J = 4.8

[0423] Hz,1H),8.03(s,1H),7.94(s,1H),7.63(d,J=2.9Hz,1H),7.49(s,1H),7.40-7.32(m,1H),6.89(s,2H),4.84-4 .72(m,1H),4.56(s,1H),4.45(s,1H),4.22(s,1H),4.12(s,1H),2.86–2.67(m,4H),2.44(s,3H),2.42(s,3H).

[0424] Embodiment 53

[0425]

[0426] The preparation method refers to Example 32.

[0427] LC-MS: 435.2[M+H] + . 1 H NMR (400MHz, MeOD) δ8.17 (d, J = 3.6Hz, 1H), 8.11

[0428] (d,J=3.5Hz,1H),7.98(s,1H),7.73(s,1H),7.63(s,1H),7.43(s,1H),4.91(dd,J=16 .3,6.8Hz,4H),4.78(m,1H),2.84(qd,J=12.6,10.5Hz,4H),2.45(s,3H),1.32(m,4H).

[0429] Embodiment 54

[0430]

[0431] The preparation method is similar to that of Example 6.

[0432] LC-MS: 517.2[M+H] + . 1 H NMR (400MHz, MeOD) δ8.17 (d, J = 2.2Hz, 1H), 8.11 (d,

[0433] J=4.6Hz,1H),7.97(s,1H),7.71(s,1H),7.63(s,1H),7.43(s,1H),4.93(m,2H),4.88(d,J=6.9Hz,2H), 4.75(m,1H),3.59(s,2H),3.50(m,2H),3.14(q,J=9.8Hz,2H),2.74(dd,J=6.5,4.1Hz,4H),2.45(s,3H).

[0434] Embodiment 55

[0435]

[0436] The preparation method refers to Example 15.

[0437] LC-MS: 561.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.16(s,1H),8.12(s,1H),7.98(s,1H),7.72(s,1H),7.63(s,1H),7.43(s,1H),4.93(d,J=6.9Hz,2H),4.88( d,J=6.9Hz,2H),4.79(dd,J=16.3,8.2Hz,1H),4.57(q,J=8.8Hz,2H),4.16(d,J=40.9Hz,4H),2.81(d,J=8.1Hz,4H),2.45(s,3H).

[0438] Embodiment 56

[0439]

[0440] The preparation method refers to Example 15.

[0441] LC-MS: 560.2[M+H] + . 1 H NMR(400MHz,MeOD)δ8.17(s,1H),8.13(s,1H),7.99(s,1H),7.72(s,1H),7.63(s,1H),7.43(s,1H),4.93(d,J=6.8Hz,2H),4.8 8(d,J=6.8Hz,2H),4.80(d,J=8.1Hz,1H),4.12(s,2H),4.02(s,2H),3.82(q,J=9.3Hz,2H),2.80(d,J=8.2Hz,4H),2.48(s,3H).

[0442] Embodiment 57

[0443]

[0444] The preparation method is similar to that of Example 6.

[0445] LC-MS: 531.2 [M+H] + . 1H NMR(400MHz,MeOD)δ8.17(s,1H),8.12(t,J=5.0Hz,1H),7.99(s,1H),7.73(s,1H),7.63(s,1H),7.43(s,1H),4.93(d,J=6.6Hz,2H),4.88 (d,J=6.4Hz,2H),4.83(m,1H),4.62(s,1H),4.52(s,1H),4.30(s,1H),4.21(s,1H),2.86(dd,J=8.1,2.1Hz,4H),2.46(d,J=11.0Hz,3H).

[0446] Embodiment 58

[0447]

[0448] The preparation method is similar to that of Example 6.

[0449] LC-MS: 539.2[M+H] + . 1 H NMR (400MHz, MeOD) δ8.17(s,1H),8.12(s,1H),7.98(s,1H),7.72(s,1H),7.63(s,1H),7.43(s,1H),4.93(d,J=6.9Hz,2H),4.88(d,J=6. 9Hz,2H),4.79(m,1H),4.11(s,2H),4.02(s,2H),2.82(d,J=8.1Hz,4H),2.58(dt,J=12.8,6.5Hz,1H),2.45(s,3H),1.1(d,J=6.0Hz,4H).

[0450] Embodiment 59

[0451]

[0452] first step:

[0453] The preparation method refers to the first step of Example 32.

[0454] Step 2:

[0455] The preparation method refers to the second step of Example 32.

[0456] Step 3:

[0457] The preparation method is similar to that of Example 6.

[0458] LC-MS: 587.3 [M+H] + . 1H NMR (400MHz, MeOD) δ8.14 (s, 1H), 8.02 (d, J = 10.9Hz,

[0459] 1H),7.77(d,J=4.0Hz,1H),7.57(s,2H),4.51(s,1H),4.30(s,1H),4.20(s,1H),3.77(t,J=6.8Hz ,2H),3.43(t,J=6.8Hz,2H),3.23(q,J=7.4Hz,2H),3.03(s,6H),2.94–2.78(m,4H),2.37(s,6H).

[0460] Embodiment 60

[0461]

[0462] The preparation method is similar to that of Example 15.

[0463] LC-MS: 617.3 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.12(s,1H),8.03(s,1H),7.74(s,1H),7.54(s,2H),4.57(q,J=8.7Hz,2H),4.20(s,1H),4.10 (s,2H),3.59–3.53(m,2H),2.88–2.76(m,4H),2.69(t,J=7.1Hz,2H),2.42(s,6H),2.36(s,6H),2.25–2.18(m,2H).

[0464] Embodiment 61

[0465]

[0466] first step:

[0467] The preparation method refers to the first step of Example 32.

[0468] Step 2:

[0469] The preparation method refers to the second step of Example 32.

[0470] Step 3:

[0471] The preparation method is similar to that of Example 15.

[0472] LC-MS: 636.2[M+H] + . 1H NMR(400MHz,MeOD)δ8.03(d,J=12.3Hz,2H),7.73(s,1H),7.48(s,2H),4.77(dd,J=16.2,8.1Hz,1H),4.61–4.53(m,2H), 4.33(s,2H),4.20(s,2H),4.09(s,2H),2.80(pd,J=11.5,6.7Hz,4H),2.46(s,6H),1.25–1.19(m,1H),1.13–1.01(m,4H).

[0473] Embodiment 62

[0474]

[0475] The preparation method is similar to that of Example 6.

[0476] LC-MS: 606.2[M+H] + . 1 H NMR(400MHz, CDCl3)δ7.75(dd,J=20.6,8.5Hz,2H),7.61–7.52(m,1H),7.38( s,2H),5.45–5.28(m,3H),4.67(dd,J=14.2,7.8Hz,1H),4.50(d,J=20.2Hz,2 H),4.40(d,J=4.5Hz,2H),4.27(s,2H),2.95–2.80(m,4H),2.46(d,J=9.7Hz, 6H), 2.23 (d, J=7.7Hz, 1H), 2.07–2.01 (m, 2H), 1.65 (dd, J=14.5, 7.1Hz, 2H).

[0477] Embodiment 63

[0478]

[0479] The preparation method is similar to that of Example 10.

[0480] LC-MS: 523.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.32 (d, J=2.4Hz, 1H), 8.14

[0481] (d,J=5.9Hz,1H),8.02(d,J=5.3Hz,1H),7.94(d,J=4.0Hz,1H),7.62(d,J=5.5Hz,1H),7.49(s,1H),7.39-7.33(m,1H),6.88(s,2H),4.83- 4.72(m,1H),4.27(s,1H),4.18(s,1H),4.03(s,1H),3.93(s,1H),3.72(s,1H),3.70(s,1H),2.78-2.64(m,4H),2.43(s,3H),2.42(s,3H).

[0482] Embodiment 64

[0483]

[0484] first step:

[0485] The preparation method refers to the first step of Example 32.

[0486] Step 2:

[0487] The preparation method refers to the second step of Example 32.

[0488] Step 3:

[0489] The preparation method refers to Example 15.

[0490] LC-MS: 683.2[M+1] + . 1 H NMR (400MHz, DMSO) δ8.22(s,1H),8.13(s,1H),7.64(s,1H),7.49(s,2H),6.67(d,J=6.9Hz,3H),6.03(s,1H),4.84–4.75(m ,1H),4.23(d,J=4.8Hz,2H),4.13(s,2H),4.00(s,2H),2.80–2.66(m,4H),2.35(s,6H),1.17(t,J=6.5Hz,2H),1.02(s,2H).

[0491] Embodiment 65

[0492]

[0493] The preparation method is similar to that of Example 6.

[0494] LC-MS: 653.2[M+1] + . 1H NMR (400MHz, DMSO) δ8.22(s,1H),8.14(d,J=4.7Hz,1H),7.64(s,1H),7.49(s,2H),6.68(s,2H),6.59(s,1H),5.97(s,1H),4.82(d,J= 7.0Hz,1H),4.57(s,1H),4.46(s,1H),4.24(s,3H),4.13(s,1H),2.87–2.68(m,4H),2.33(d,J=15.6Hz,6H),1.17(s,2H),1.03(s,2H).

[0495] Embodiment 66

[0496]

[0497] first step:

[0498] The preparation method is similar to the fifth step in Example 1.

[0499] Step 2:

[0500] The preparation method is similar to step 6 of Example 1.

[0501] Step 3:

[0502] The preparation method is similar to that of Example 6.

[0503] LC-MS: 610.3[M+1] + . 1 H NMR (400MHz, CDCl3) δ8.15 (s, 1H), 7.81 (dd, J = 12.7, 7.3Hz, 1H), 7.74 (dd, J = 7.5 ,3.7Hz,1H),7.58–7.52(m,1H),7.47(d,J=9.5Hz,1H),5.37(td,J=5.8,3.4Hz,2H ),5.05(s,2H),4.92–4.76(m,2H),4.78–4.62(m,1H),4.61–4.46(m,2H),4.27(d, J=19.2Hz,2H),3.95(dt,J=16.8,5.9Hz,2H),2.91(t,J=5.9Hz,4H),2.34(s,3H).

[0504] Embodiment 67

[0505]

[0506] first step:

[0507] The preparation method is similar to the fifth step in Example 1.

[0508] Step 2:

[0509] The preparation method is similar to step 6 of Example 1.

[0510] Step 3:

[0511] The preparation method is similar to that of Example 6.

[0512] LC-MS: 670.2[M+1] + . 1 H NMR(400MHz,MeOD)δ8.10(s,1H),8.06(s,1H),7.72(s,1H),7.54(s,1H),7.46(s,1H),4.83–4.76(m,1H),4.67( q,J=8.7Hz,4H),4.56(q,J=8.7Hz,2H),4.21(s,2H),4.11(s,2H),3.80(s,2H),2.93–2.74(m,6H),2.31(s,3H).

[0513] Effect Example 1

[0514] Test substances: compounds of the present invention, prepared by the methods of Examples.

[0515] Test method:

[0516] 1. Prepare 1x MAP4K1 (HPK1) kinase (Carna, 07-410) buffer

[0517] 50 mM HEPES, pH 7.5 (Sigma)

[0518] 10 mM MgCl2 (Sigma, M2670)

[0519] 4 mM DTT (Sigma, D0632)

[0520] 0.01% Tween-20

[0521] 0.01% BSA

[0522] 2. Compound Preparation

[0523] 1) Prepare the compound at 100 times the initial concentration and add it to the second well of the 384-well Echo plate. Add 30 μl of 100% DMSO to the other wells. Take 15 μl of the compound from the second well and add it to the third well. Dilutions are made 3 times in sequence, for a total of 10 concentrations.

[0524] 2) Transfer 30 μl of 100% DMSO to two empty wells as controls without compound or enzyme;

[0525] 3) Use Echo 550 to transfer 100 nl of compound into a 384-well assay plate

[0526] 3. Prepare 2x Kinase Solution

[0527] 1) Prepare 2x kinase solution using 1x kinase buffer.

[0528] 2) Transfer 5 μl of 2x enzyme solution to the reaction wells of a 384-well plate and add 1x kinase buffer to the negative control wells.

[0529] 3) Mix by shaking at 450 rpm and incubate at room temperature for 10 minutes

[0530] 4. Prepare 2x substrate solution

[0531] 1) Use 1x kinase buffer to prepare 2x substrate solution.

[0532] 2) Add 5 μl of 2x substrate solution to the 384-well reaction plate and shake at 450 rpm to mix.

[0533] 5. Kinase reaction

[0534] The reaction was carried out at room temperature for 90 min

[0535] 6. Detection of reaction results

[0536] 1) Prepare 2 times the amount of the stop reaction solution containing the antibody.

[0537] 2) Add 10 μl of the above reagent to a 384-well reaction plate and centrifuge at 1000 rpm for 1 minute.

[0538] 3) Place at room temperature for 60 minutes and test the results

[0539] 7. Data reading

[0540] The values ​​were read on Envision2104 Multilable Reader with excitation at 340 nm and emission at 520 nm and 495 nm.

[0541] 8. Data calculation

[0542] 1) Ratio of replicate fluorescence readings (Lantha signal (520nm / 495nm))

[0543] 2) Convert the above data into inhibition percentage using the formula

[0544] Percent inhibition=(max-Lantha signal) / (max-min)*100

[0545] "min" is the reading of the control well without enzyme reaction; "max" is the reading of the control well with DMSO added

[0546] 3) The data were imported into MS Excel and the IC50 results were curve fitted using XLFit excel add-in version 5.4.0.8

[0547] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X) ^ HillSlope)

[0548] Table 1 Enzyme activity test results

[0549]

[0550]

[0551]

[0552] Conclusion: It can be seen from Table 1 that the compounds of the present invention have a good inhibitory effect on HPK1 kinase.

[0553] Effect Example 2

[0554] Test substances: compounds of the present invention, prepared by the methods of Examples.

[0555] Test method:

[0556] 1 Cell culture and treatment

[0557] CHO cells (Invitrogen, R75807) stably expressing hERG were cultured in a 35 mm diameter cell culture dish, placed in an incubator at 37°C, 5% CO2, and subcultured every 48 hours at a ratio of 1:5. The culture medium formula was: 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen) and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, and the cells were rinsed with extracellular fluid and then added with 0.25% Trypsin-EDTA (Invitrogen) solution and digested at room temperature for 3-5 minutes. The digestion solution was aspirated, and the cells were resuspended with extracellular fluid and transferred to the experimental dish for electrophysiological recording for use.

[0558] 2. Compound Preparation

[0559] On the day of the test, the compound was prepared with DMSO to a 10mM stock solution, and then diluted 1000 times with extracellular fluid to obtain the final concentration to be tested. Preparation of the positive control compound cisapride: 10μL of 150μM cisapride DMSO stock solution was added to 4990μL extracellular fluid, and diluted 500 times to obtain the final concentration of 300nM to be tested. The DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel.

[0560] 3 Electrophysiological recording process

[0561] CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -100 mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -100 mV to +20 mV, then repolarized to -50 mV, and returned to -100 mV after 1s. This voltage stimulation was given every 5s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute). Compounds were administered for at least 1 min to steady state of action or for a maximum of 5 min at each tested concentration, and at least 2 cells (n≥2) were tested at each concentration.

[0562] 4 Data processing

[0563] Data analysis was performed using pClamp 10, GraphPad Prism and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0564] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.

[0565] The structural formula of the positive compound is as follows:

[0566] Table 2 hERG test results

[0567]

[0568] Conclusion: It can be seen from Table 2 that the compounds of the present invention have low inhibitory effect on hERG and have better safety.

Claims

1. A compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; in, X is CHR 1 NR 1 , O or S; n1 and n2 are each independently 1, 2 or 3; n3 and n4 are each independently 1, 2 or 3; R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl, "a 3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 1-6 substituted 3-6 membered cycloalkyl or one or more R 1-7 Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; R 1-1 are each independently halogen, hydroxyl or cyano; R 1-2 Each independently is a C1-C6 alkyl group, 1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c ; R 1-3 Each independently is a C1-C6 alkyl group, 1-3-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl or one or more R 1-3-2 Substituted 3-6 membered cycloalkyl; R 1-2-1 and R 1-3-1 are each independently hydroxy, cyano or halogen; R 1-2-2 and R 1-3-2 are each independently hydroxy, cyano or halogen; R 1a , R 1b and R 1c Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 1-2-3 Substituted C1-C6 alkyl; R 1-2-3 are independently halogen, cyano, hydroxyl or -NR 1d R 1e ; R 1d and R 1e Each is independently hydrogen or a C1-C6 alkyl group; R 1-4 and R 1-5 Each is independently hydrogen or a C1-C6 alkyl group; R 1-6 and R 1-7 Each is independently halogen or C1-C6 alkyl; R 2 is a "10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", and is surrounded by one or more R 2-1 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 10-15 membered tricyclic fused heteroaryl groups", "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 6-10 membered bicyclic fused heteroaryl groups", one or more R 2-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 6-10 membered bicyclic fused heteroaryl having 1, 2 or 3 heteroatoms", C6-C 10 Aryl or one or more R 2-3 Substituted C6-C 10 Aryl; R 2-1 and R 2-2 Each independently represents an oxo group, a C1-C6 alkyl group, a 2-1-1 Substituted C1-C6 alkyl or -C(=O)-R 2-1-2 ; R 2-1-1 are each independently halogen, cyano or hydroxy; R 2-1-2 Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy; R 2a and R 2a-1 are each independently halogen, cyano or hydroxy; R 2-3 Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", one or more R 2-3-2 Substituted "3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", "5-12 membered heterocycloalkenyl having 1, 2 or 3 heteroatoms selected from N, O and S", "substituted by one or more R 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3-6 R 2-3-7 ; R 2-3-1 Each independently represents "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", 2b Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ; R 2b Each is independently C1-C6 alkyl, halogen or hydroxyl; R 2c is hydrogen, C1-C6 alkyl, 2c-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, "3-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S" or one or more R 2c-2 Substituted 3-6 membered cycloalkyl; R 2d is hydrogen, C1-C6 alkyl, 2d-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl or one or more R 2d-2 Substituted 3-6 membered cycloalkyl; R 2c-1 and R 2d-1 are each independently halogen, cyano or hydroxy; R 2c-2 and R 2d-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; R 2-3-2 Each is independently C1-C6 alkyl, halogen or hydroxyl; R 2-3-3 Each is independently C1-C6 alkyl, halogen or hydroxyl; R 2-3-4 and R 2-3-5 Each independently is hydrogen, C1-C6 alkyl or one or more R 2e Substituted C1-C6 alkyl; R 2e Each independently represents a halogen, a "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S", a cycloalkyl having 1, 2 or 3 heteroatoms, ... 2e-1 Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 ; R 2e-1 Each is independently halogen or C1-C6 alkyl; R 2e-2 and R 2e-3 Each is independently hydrogen or C1-C6 alkyl; R 2-3-6 and R 2-3-7 Each independently is hydrogen, C1-C6 alkyl or substituted by one or more R 2f Substituted C1-C6 alkyl; R 2f Each is independently halogen or "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; R 3 It is hydrogen or C1-C6 alkyl.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies one or more of the following conditions: (1)R 1 , R 1-2 , R 1-3 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 2-1 , R 2-2 , R 2-1-2 , R 2-3 , R 2b , R 2c , R 2d , R 2c-2 , R 2d-2 , R 2-3-2 , R 2-3-3 , R 2-3-4 , R 2-3-5 , R 2e-1 , R 2e-2 , R 2e - 3 , R 2-3-6 , R 2-3-7 and R 3 wherein the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, ethyl or isopropyl; (2)R 1 , R 1-2 , R 1-3 , R 2c and R 2d wherein the 3-6 membered cycloalkyl groups are each independently cyclopropane, cyclobutane, cyclopentane or cyclohexane, such as cyclopropane, cyclobutane or cyclopentane; (3)R 1 In the above, the "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" and one or more R 1-7 In the substituted "3-6-membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3", the 3-6-membered heterocycloalkyl group is independently a 4-6-membered heterocycloalkyl group; the heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2; (4)R 1-1 , R 1-2-1 , R 1-3-1 , R 1-2-2 , R 1-3-2 , R 1-2-3 , R 2-1-1 , R 2a , R 2a-1 , R 2b , R 2c-1 , R 2d-1 , R 2c-2 , R 2d-2 , R 2 -3-2 , R 2-3-3 , R 2e , R 2e-1 and R 2f wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine; (5)R 2 In the above, the "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl" and one or more R 2-1 The substituted "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl" wherein the 10-15 membered tricyclic fused heteroaryl is independently a 12-13 membered tricyclic fused heteroaryl, preferably a 13 membered tricyclic fused heteroaryl, the heteroatoms are preferably 1 or 2 of N and O, and the number of heteroatoms is preferably 1 or 2, for example, the 10-15 membered tricyclic fused heteroaryl is (6)R 2 In the above, the "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, and the 6-10 membered bicyclic fused heteroaryl group" and one or more R 2-2 The substituted "6-10 membered bicyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 9-10 membered bicyclic fused heteroaryl group, wherein the heteroatoms are preferably 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 6-10 membered bicyclic fused heteroaryl group is Preferably (7)R 2 In the C6-C 10 Aryl and one or more R 2-3 Substituted C6-C 10 C6-C 10 Aryl is phenyl or naphthyl, for example phenyl; (8)R 2-1-2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, such as ethoxy; (9)R 2-3 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, such as methoxy; (10)R 2-3 wherein the C1-C6 alkylthio group is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio; (11)R 2-3 In the above, the "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" and one or more R 2-3-2 The substituted "3-12-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 4-6-membered heterocycloalkyl group, wherein the heteroatoms are preferably 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-12-membered heterocycloalkyl group is (12)R 2-3 In the above, the "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heterocycloalkenyl" and one or more R 2-3-3 The substituted "5-12-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 5-6-membered heterocycloalkenyl group, the number of unsaturated double bonds is preferably 1, the heteroatoms are preferably 1 or 2 selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 5-12-membered heterocycloalkenyl group is (13)R 2-3-1 In the above, the "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" and "substituted by one or more R 2b The substituted heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3. In the "3-6 membered heterocycloalkyl", each of the 3-6 membered heterocycloalkyl is independently a 5-6 membered heterocycloalkyl, and the heteroatom is preferably 1 or 2 of N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl is (14)R 2c In the "3-6 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3", the 3-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, whose heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2; (15)R 2e In the above, the "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" and one or more R 2e-1 The substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" is each independently a 5-6 membered heterocycloalkyl group, wherein the heteroatoms are preferably 1 or 2 heteroatoms selected from N and O, and the number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl group is and (16)R 2f In the "3-6 membered heterocycloalkyl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3", the 3-6 membered heterocycloalkyl group is independently a 5-6 membered heterocycloalkyl group, whose heteroatoms are preferably 1 or 2 of N and O, and whose number of heteroatoms is preferably 1 or 2. For example, the 3-6 membered heterocycloalkyl group is 3. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies one or more of the following conditions: (1) X is CHR 1 NR 1 or O; for example, X is CH-NR 1-4 R 1-5 NR 1 or O; for example, X is NR 1 ; (2) n1 and n2 are each independently 1; (3) n3 and n4 are each independently 1 or 2; for example, n3 and n4 are 1; (4)R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl or "a 3-6 membered heterocycloalkyl group wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3"; for example, R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl; for example, R 1 each independently is hydrogen; (5)R 1-1 are each independently halogen or hydroxy; for example, R 1-1 are each independently hydroxyl; (6)R 1-2 Each independently is a C1-C6 alkyl group, 1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c ; (7)R 1-3 Each is independently a 3-6 membered cycloalkyl; (8)R 1-2-1 are each independently cyano or halogen; (9)R 1-2-2 are each independently a halogen; (10)R 1a , R 1b and R 1c are independently hydrogen or replaced by one or more R 1-2-3 Substituted C1-C6 alkyl; (11)R 1-2-3 are each independently a halogen; (12)R 1-4 and R 1-5 Each is independently hydrogen or a C1-C6 alkyl group; (13)R 2 is a "10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", and is surrounded by one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" or one or more R 2-3 Substituted C6-C 10 Aryl; for example, one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl", preferably, the substituted one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" is wherein Y is a single bond, CH2, NH, S or O, for example a single bond or CH2, preferably CH2; Z is NH, NR 2-2 , S or O, such as NR 2-2 or O, preferably NR 2-2 ; R 2-2 Each independently represents an oxo group, a C1-C6 alkyl group, a 2-1-1 Substituted C1-C6 alkyl or -C(=O)-R 2-1-2 , for example, R 2-2 are each independently C1-C6 alkyl, preferably methyl; more preferably, R 2 for (14)R 2-1 and R 2-2 Each is independently oxo, C1-C6 alkyl or -C(=O)-R 2-1-2 ; For example, R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group; (15)R 2-1-2 Each independently is one or more R 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy; (16)R 2a and R 2a-1 are each independently a halogen; (17)R 2-3 Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3-6 R 2-3-7 ; For example, R 2-3 Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; (18)R 2-3-1 Each independently represents "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ; For example, R 2-3-1 Each independently is -NH-SO2-R 2c or -NH-CO-NHR 2d ; (19)R 2c is a 3-6 membered cycloalkyl group; (20)R 2d For one or more R 2d-2 Substituted 3-6 membered cycloalkyl; (21)R 2d-2 Each is independently a C1-C6 alkyl group substituted by one or more halogens; (22)R 2-3-2 Each is independently a C1-C6 alkyl or a hydroxyl group; (23)R 2-3-3 Each is independently a C1-C6 alkyl group; (24)R 2-3-4 and R 2-3-5 are each independently hydrogen or one or more R 2e Substituted C1-C6 alkyl; (25)R 2e Each independently is one or more R 2e-1 Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 , for example, R 2e Each independently is NR 2e- 2 R 2e-3 ; (26)R 2e-1 are each independently a halogen; (27)R 2e-2 and R 2e-3 Each is independently a C1-C6 alkyl group; (28)R 2-3-6 and R 2-3-7 Each is independently hydrogen or C1-C6 alkyl; (29)R 3 is hydrogen or C1-C6 alkyl, for example, R 3 is hydrogen; (30) When R 2 is a "10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", and is surrounded by one or more R 2-1 When the substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 10-15 membered tricyclic fused heteroaryl groups", R 1 Each is independently hydrogen or C1-C6 alkyl; (31) When R 2-3 -C(=O)-NR 2-3-4 R 2-3-5 , R 2-3-4 and R 2-3-5 are independently hydrogen or replaced by one or more R 2e When the C1-C6 alkyl group is substituted, R 1 are independently hydrogen, C1-C6 alkyl, trifluoromethyl, -C(=O)-R 1-2 or -SO2-R 1-3 ;and (32) When R 2-3-1 -NH-SO2-R 2c , R 2c When it is a 3-6 membered cycloalkyl group, R 1 are independently -C(=O)-R 1-2 , R 1-2 is independently trifluoromethyl.

4. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: In the compound shown in formula I, X is CHR 1 NR 1 or O; n1 and n2 are each independently 1; n3 and n4 are each independently 1 or 2; R 1 Each independently represents hydrogen, C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl, -C(=O)-R 1-2 、-SO2-R 1-3 、-NR 1-4 R 1-5 , 3-6 membered cycloalkyl or "a 3-6 membered heterocycloalkyl group wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3"; R 1-1 are each independently halogen or hydroxy; R 1-2 Each independently is a C1-C6 alkyl group, 1-2-1 Substituted C1-C6 alkyl, 3-6 membered cycloalkyl, substituted by one or more R 1-2-2 Substituted 3-6 membered cycloalkyl, -NR 1a R 1b OR 1c ; R 1-3 Each is independently a 3-6 membered cycloalkyl; R 1-2-1 are each independently cyano or halogen; R 1-2-2 are each independently a halogen; R 1a , R 1b and R 1c are independently hydrogen or replaced by one or more R 1-2-3 Substituted C1-C6 alkyl; R 1-2-3 are each independently a halogen; R 1-4 and R 1-5 Each is independently hydrogen or a C1-C6 alkyl group; R 2 is a "10-15 membered tricyclic fused heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S", and is surrounded by one or more R 2-2 The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 6-10 membered bicyclic fused heteroaryl" or one or more R 2-3 Substituted C6-C 10 Aryl; R 2-2 Each is independently oxo, C1-C6 alkyl or -C(=O)-R 2-1-2 ; R 2-1-2 Each independently is one or more R 2a Substituted C1-C6 alkyl or one or more R 2a-1 Substituted C1-C6 alkoxy; R 2a and R 2a-1 are each independently a halogen; R 2-3 Each independently is a C1-C6 alkyl group, 2-3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, substituted by one or more R 2-3-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", 2-3-3 Substituted "5-12 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -C(=O)-NR 2-3-4 R 2-3-5 or -SO2-NR 2-3-6 R 2-3-7 ; R 2-3-1 Each independently represents "a 3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S", -NH-SO2-R 2c or -NH-CO-NHR 2d ; R 2c is a 3-6 membered cycloalkyl group; R 2d For one or more R 2d-2 Substituted 3-6 membered cycloalkyl; R 2d-2 Each is independently a C1-C6 alkyl group substituted by one or more halogens; R 2-3-2 Each is independently a C1-C6 alkyl or a hydroxyl group; R 2-3-3 Each is independently a C1-C6 alkyl group; R 2-3-4 and R 2-3-5 are each independently hydrogen or one or more R 2e Substituted C1-C6 alkyl; R 2e Each independently is one or more R 2e-1 Substituted "3-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or NR 2e-2 R 2e-3 ; R 2e-1 are each independently a halogen; R 2e-2 and R 2e-3 Each is independently a C1-C6 alkyl group; R 2-3-6 and R 2-3-7 Each is independently hydrogen or C1-C6 alkyl; R 3 It is hydrogen or C1-C6 alkyl.

5. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) n1 and n2 are each independently 1; (2) n3 and n4 are each independently 1 or 2; (3)R 1 is hydrogen, methyl, ethyl, -CH(CH3)2, -CH2CHF2, -CH2CF3, -C(=O)CH3, -C(=O)CF3, -NHCH3, (4)R 2 for and (5)R 3 It is hydrogen or ethyl.

6. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I is a compound represented by formula I-1, I-2 or I-3; R 2-4 is hydrogen or C1-C6 alkyl, such as hydrogen or methyl; m is 2 or 3; n1, n2, n3, n4, X, R 2-2 and R 2-3 Each independently as claimed in any one of claims 1 to 5, preferably, R 2-2 It is methyl.

7. The compound of formula I according to claim 1 or 6, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: for Preferably, for 8. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound as shown in formula I is any of the following compounds:

9. A pharmaceutical composition, comprising: A compound as shown in formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of the compound of formula I according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a drug; The drug is used to treat lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast duct carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma, myelodysplastic syndrome, such as lung cancer.

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